Archive for the ‘Cure’ Category

Analysis of 2009 NIH Human Stem Cell Research Policy

July 15, 2009

ANALYSIS OF 2009 NIH HUMAN STEM CELL RESEARCH  POLICY
Wise Young PhD MD, W. M. Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey, Piscataway, NJ 08543-8082
Created July 9, 2009; Revised July 10, 2009

On July 9, 2009, the National Institutes of Health (NIH) issued the 2009 NIH Human Stem Cell Research Policy.  NIH issued this policy in response to an Executive Order 13505 on March 9 by President Barack Obama, rescinding the stem cell policy of President George W. Bush and asking NIH to propose a new policy for legally and ethically responsible human stem cell research.  On April 23, NIH published Draft Guidelines (74 Fed. Reg. 18578).   NIH received over 49,000 comments on the Draft Guidelines from advocacy groups, scientific societies, academic institutions, religious organizations, and private citizens.

I had earlier posted a critique of the Draft Guidelines on the CareCure web site, pointing out that the Guidelines misdefined human embryonic stem cells (hESC) by saying that the cells come from human embryos, had to be cell lines (i.e. grow for prolonged periods in culture without differentiation), and had to make cells of all three primary germ layers.  Embryo refers to all stages of human development from implantation through fetus.  Strictly speaking, hESC come from the inner cell mass of blastocysts.  The cells do not have to grow for prolonged periods in culture to be hESC.  Many hESC cell lines have not been shown to produce cells of all three primary germ layers.  These requirements would allow many hESC-derived cells to escape regulation.

The Draft Guidelines further restricted hESC research in several ways.  First, it proposed strict new consent rules that would make many existing hESC lines ineligible and would ironically even exclude many hESC lines approved under the previous presidential policy.  Second, it explicitly forbids NIH funding of hESC lines derived from blastocysts created by somatic cell nuclear transfer (SCNT) and parthenogenesis, as well as blastocysts created by fertilization for research. Third, the draft guidelines restrict transplantation of hESC cells into subhuman primates and other animals where the hESC may interact with germ cells and the animals can reproduce.

The NIH response and the final 2009 Guidelines for Human Stem Cell Research are of great interest because they determine the federal policy towards human stem cells.  In the following sections, I will first summarize the NIH response to the commentary and the changes that they made in the final Guidelines in response.  Then, I will discuss the consequences of each of the major decisions and the likely impact on human stem cell research in the United States.

NIH Response to Commentary

Public comments on the Draft Guidelines fell into several categories, summarized below.

  • Terminology.  Patient advocacy and scientific groups criticized the Draft Guidelines for inaccurately defining human embryonic stem cells (hESC).  NIH modified the definition of hESC to “cells that are derived from the inner cell mass of blastocyst stage human embryos, are capable of dividing without differentiating for a prolonged period in culture, and are known to develop into cells and tissues of the three primary germ layers.”
  • Financial Gain.  Some respondents were concerned that derivers of hESC will profit but not the donors. Others noted that the Guidelines favored certain existing patents and this will restrict competition, which may inhibit research and increase cost of eventual clinical therapies. NIH responded that the research would be subject to existing NIH policies and guidance regarding intellectual property and distribution.
  • Institutional Review.  Many respondents pointed out that existing institutional review board (IRB) procedures under the Common Rule can assess whether the research matches core ethical principles and provide oversight of hESC research.  Others urged that NIH establish a NIH registry of eligible hESC lines to avoid burdensome and repetitive assurances of the same cell lines by many NIH applicants. NIH agreed that IRBs provide a comprehensive framework for review but pointed that a uniform standard is needed.  They will establish an NIH Registry of hESC subject to this standard.
  • Ineligible Sources.  The Draft Guidelines disallowed sources of hESC derived from embryos created expressly for research purposes, including parthenogenesis or somatic cell nuclear transfer (SCNT).  Only stem cells from embryos created for reproductive purposes will be eligible. Some respondents asked about embryos being discarded after pre-implantation genetic diagnosis (PGD).  In the Guidelines, NIH continued to forbid funding of research on hESC derived from parthenogenesis and SCNT but allowed PGD.
  • Informed Consent.  Many respondents argued that the draft Guidelines were “too procedurally proscriptive” and retrospective application would disallow many existing hESC lines. They urged NIH to “grandfather” existing hESC lines without review.  In response, NIH will now grandfather lines already in the NIH Stem Cell Registry and established a review process for other lines and overseas lines.
  • Conflict of Interest.  Some respondents wanted explicit separation of the IVF physician and hESC researcher to avoid the situation where the IVF doctor may create extra embryos for research. NIH agreed that the IVF physician and researcher should be separate but declined to make this a requirement because there may be certain situations where the IVF doctor and researcher can and should be the same person. •
  • HESC versus embryos.  Several respondents requested clarification of a statement in the Guidelines:  “although human embryonic stem cells are derived from embryos, such stem cells are not themselves human embryos”.  The Dickey amendment prohibits research that may harm embryos.  NIH has consistently distinguished between hESC and embryos.  Congress has accepted this distinction since 2001.
  • Revocation of consent.  The draft Guidelines stipulated that embryo donors could revoke consent at any time.  Respondents pointed out that this might not be possible after hESC are derived and have been “de-identified” from the original donor.  NIH modified the guidelines to stipulate that donors can revoke consent until the cells have been derived or information linking the embryo to the donor is no longer retained.

Definition of Human Embryonic Stem Cells

The Draft Guidelines misdefined hESC, describing them as cells derived from human embryos and required that they can grow for prolonged periods in culture without differentiation and that they can produce cells from all three primary germ layers.  Since the term embryo encompasses all stages of development from fertilized egg until birth, this definition would have included all pluripotent stem cell lines from all stages of prenatal development whereas the term hESC is usually reserved only for cells derived from the inner cell mass of blastocysts, a well-defined early pre-implantation stage of development.

The NIH modified the definition so that hESC now refers explicitly to cells derived from the inner cell mass of blastocysts.  However, the definition continues to specify that the cells must grow for prolonged periods in culture without differentiation, essentially requiring the cells to behave like a cell line.  Furthermore, the definition requires that cells to produce cells of all three primary germ layers:  epidermal, mesodermal, and endodermal.  While hESC lines ideally should be able to grow in culture for long periods without differentiation and should be able to produce cells of all three primary germ layers, not all hESC can do these two tasks.

The fallacy of this definition becomes clear when one considers which hESC today would fulfill this definition.  As specified in the current definition, a majority of hESC would not fulfill the definitions as set out by the Guidelines.  Many researchers study hESC without making them into cell lines.  After all, a transient existence is the natural history of hESC.  Many hESC lines have been shown to produce cells of only two and not all three primary germ layers.  If a cell does not been made into a cell line, does this mean that it is not and should not be regulated as a hESC?

The Guidelines also do not consider the progeny of hESC.  Consider neural stem cells that are derived from hESC.  These cells would not fulfill the definition of hESC because they produce cells of only one primary germ layer and many are not and cannot be grown for prolonged periods without differentiation, unless one immortalized the cells with v-myc or other genetic manipulations.  Neural stem cells can be derived from stem cells collected from the inner mass of blastocysts.  Since they do not come from cells that would fulfill the definition of hESC, such neural stem cells would not be subject to the policy.

NIH should simply refer to hESC cells as pluripotent stem cells derived from the inner cell mass of blastocysts and expand Guidelines to refer to hESC and their progeny.  It is the source of the cells and not its characteristics that is crucial for regulation.  As it stands now, the NIH has established a review process for cell lines that can be put into the NIH Stem Cell Registry.  Hopefully, the reviewers will understand more about what hESC than the writers of the Guidelines and make appropriate decisions concerning what can be included and what should be excluded.

Definition of Embryo

In its response to comments on the Draft Guideline, NIH acknowledges the Dickey Amendment, which prohibits NIH funding of research that may harm human embryos.  The Guidelines stated, “Although human embryonic stem cells are derived from embryos, such stem cells are not themselves human embryos”.  The Dickey Amendment defines the human embryo as “any organism not protected as a human subject under 45 C.F.R. Part 46 that is derived by fertilization, parthenogenesis, cloning or any other means from one or more human gametes or human diploid cells.”

NIH distinguishes between research on hESC derived from embryos versus research that derive hESC from embryos.  If a hESC were an embryo, then hESC research that harms the cells would be against the law. NIH points out that the Department of Health and Human Services (HHS) has consistently recognized the distinction between embryonic stem cell and embryo. Congress has known and accepted this distinction since 2001 when it allowed the research plan proposed by President George W. Bush.

NIH is indirectly acknowledging that a blastocyst is an embryo.  If so, NIH cannot fund procedures that harvest, create, or grow blastocysts that be damaged if stem cells are removed from the blastocysts.  According to the Dickey Amendment, the term embryo includes those created by “fertilization, parthenogenesis, cloning, or any other means from one or more human gametes or human diploid cells”.  But, this prohibition does not prevent NIH funded studies of stem cells from such blastocysts.

Most Americans are not aware that a blastocyst is pre-implantation, i.e. before the egg implants into the uterus.   The egg is usually fertilized in the Fallopian tubes and develops into a blastocyst as it progresses towards the uterus.  At the time when the inner mass of blastocysts is removed for hESC, the blastocyst has not yet developed the primitive streak, a mark indicating the eventual midline of the embryo.  At this point, the blastocyst does not have any recognizable body parts, limbs, organs, or brain.  It is just a ball of cells with potential to grow into a fetus.

Most scientists do not consider a blastocyst to be an embryo, in the same way that they would not consider a fertilized egg, a morula or a gastrula to be an embryo.  These are pre-embryo stages of development.  The definition of embryo usually commences upon implantation and development of a midline.  A fetus usually refers to stages when limbs and organs are present.  The NIH Guidelines should have taken the opportunity to present the stage of development to the public, to explain the difference instead of obscuring the definition further.

Consent Requirements

The Draft Guidelines imposed strict consent requirements that would have ruled out most existing HESC lines from NIH research.  Many respondents commented that the new consent approach was too “procedurally proscriptive, overly relies on specific details and formats of informed consent documents, and fails to consider the complexity of informed consent processes”. These restrictions would have ruled out many cell lines, even those that were eligible under the previous President’s policy.

In response to the criticism, NIH modified the Guidelines to grandfather all cells currently listed on the NIH Stem Cell Registry but will require all other cell lines to be submitted with supporting information for administrative review by the NIH.   These will be reviewed by a Working Group of the Advisory Committee to the Director (ACD), to ascertain whether “core ethical principles and procedures were observed in the process for obtaining informed consent.”

The Guidelines also made an exception for hESC lines derived overseas, recognizing that other countries may not change their donation requirements to comply precisely with the NIH Guidelines and that hESC lines from outside of the United States represent an important scientific asset for the U.S. The NIH ACD will review conditions and procedures. The committee will advise the NIH Director whether the policies in other countries are at least equivalent to those in the Guidelines.

The Guidelines, however, continued to require that consent be obtained at the time of embryo donation and that a blanket authorization at the beginning of IVF procedures would not be sufficient.  Although this was criticized, NIH maintained this requirement in the final Guidelines, stating “a general authorization for research donation when consenting for reproductive treatment would comply with the Guidelines only when specific consent for the donation is obtained at the time of donation.”

The Guidelines relented on its requirement that donors may withdraw consent at any time.  If this requirement had been maintained, it would have allowed donors to revoke consent just before clinical trial or commercial application in exchange for payment.  NIH modified the Guidelines to allow donors to withdraw consent only until the embryos are actually used to derive embryonic stem cells or when information that could link the donor identity with the embryo was no longer retained.

In summary, NIH relaxed some consent-related requirements and set up administrative procedures for reviewing eligibility of stem cells for inclusion into the NIH Stem Cell Registry.  For cells that have already been derived, a committee will review them to ensure that they meet core ethical principles.  While NIH continued to require consent at the time of donation, they imposed a time limit on consent revocation.  While the procedure are still clumsy, the procedures are now workable.

Parthenogenesis, Cloning, or Expressly Created Blastocysts

The 2009 Guidelines explicitly forbids NIH funding of hESC derived from embryos expressly created for research by fertilization, parthenogenesis, or somatic cell nuclear transfer (SCNT).  NIH explained that the “Guidelines allow for funding of research using hESC derived from embryos created using in vitro fertilization (IVF) for reproductive purposes and no longer needed for these purposes, assuming the research has scientific merit and the embryos were donated after proper informed consent was obtained from the donor(s).  The Guidelines reflect the broad public support for federal funding of research using hESC created from such embryos based on wide and diverse debate on the topic in Congress and elsewhere.  The use of additional sources of human pluripotent stem cells proposed by the respondents involve complex ethical and scientific issues on which a similar consensus has not emerged.”

This explanation is disconcerting because it implies that the decision to prohibit the research is political and is not based on ethical, scientific, or legal reason.  The Dickey Amendment forbids NIH to fund any research that may harm blastocysts created by fertilization, parthenogenesis, or somatic cell nuclear transfer.  NIH asserted that hESC are not embryos and therefore they can fund research on hESC regardless of source.  At the same time, they are asserting that using cells from in vitro fertilization clinics is acceptable because of “broad public support” for such use.  However, they prohibit other sources because “a similar consensus” has not emerged.  In other words, they are saying that the decision to exclude other sources of stem cells is politically based.

This decision to forbid hESC cells from other sources has serious consequences.  One of the most important benefits of hESC research is that it would provide pluripotent human cell lines that contain genetic diseases.  If a scientist or organization used fertilization, parthenogenesis, or SCNT to create hESC cell lines from individuals who have genetic diseases, these cell lines would not be eligible for NIH funded research.  Fortunately, NIH did allow one source of hESC with genetic disease.  In vitro fertilization clinics do pre-implantation genetic diagnosis (PGD) by taking several cells and genetically analyzing them for genetic disease.  Blastocysts that contain undesirable genetics are discarded.  NIH can fund studies of hESC derived from such blastocysts donated by the parents.

In summary, the Guidelines prohibit NIH funding of studies of hESC from blastocysts other than those that were created for reproductive purposes.  The rationale for this prohibition was clearly political and not based on clear scientific or ethical principles.  One of the most important and accepted benefits of hESC research is that it would allow the creation of human pluripotent cell lines that contain genetic disease.  The prohibition of NIH funding of hESC expressly derived from blastocysts created for the purpose to producing such cells would have stopped this potential benefit of hESC research.  However, NIH did allow the study of hESC derived from blastocysts that are discarded after PGD.

Restrictions of Human/Animal Chimera Research

The 2009 Guidelines restricts research involving hESC transplantation into non-human primates and into animals where the transplanted cells may contact with germ cells and the animals may have an opportunity to procreate.  Creation of such human/animal chimera are controversial, presumably reflecting the unsubstantiated fear that such animals may develop human qualities.  However, instead of leaving this matter for Institutional Review Boards (IRB), Animal Use and Care Committee (IACUC), and Embryonic Stem Cell Research Oversight (ESCRO) Committee to assess, NIH decided to use the Guidelines to ban this important arena of research.

The restriction of human/animal chimera experiments has important and potentially devastating consequences on hESC research.

  1. Tests of pluripotency.  The accepted test of pluripotency of human hESC is to transplant the hESC into developing animals and seeing whether the cells incorporate into multiple tissues.  The hESC cells may interact with germ cells in the developing animal.  Another test is to transplant hESC into adult animals to determine whether the cells develop into a teratoma, a tumor that contains many types of cells.  The restrictions imposed by the Guidelines would make such experiments difficult.
  2. Human-animal chimera models.  These models have been used for many years to do in vivo research on human cells without having to use human subjects.  For example, chimeric mouse models containing human bone marrow stem cells have been used for many years to assess human immune response to vaccines.  Many other disease models involve implanting human cells into animals. There is no convincing evidence that hESC cells pose significantly greater risk than other types of human cells.
  3. Studies of hESC in transgenic animals.  Transplantation of human ESC cells into transgenic mice and other animals is one of the most important methods to study hESC function in different tissue environments.  The Guidelines do not provide details concerning how one would protect against unknown risks of chimera studies.  For example, would mice receiving hESC transplants have to be spayed before the transplants to avoid any possibility of reproduction by the animals?

One of the most worrisome aspects of these proscriptions is that they not only include hESC but also induced pluripotent stem (IPS) cells.  IPS cells are derived by genetically modifying differentiated cells.  It is not clear why NIH is prohibiting such research.  Human/animal chimera research has been carried out for many years.  There is no evidence that either transplantation of hESC or IPS cells into animals pose a significant risk or a greater risk than transplantation of other human cells, such as cancer cells.  In the absence of data that indicate that the hESC transplantation in subhuman primates or other animals carries a significant risk of causing harm, there is no justification for prohibiting the research, particularly when such prohibitions will substantially slow progress in the field.

IRB, IACUC, and ESCRO

All NIH grants are subject to extensive ethical and scientific review before funding.  For example, the IRB (Institutional Review Board) is involved whenever human subjects are involved.  Since hESC are human, IRB should be notified even when the research involve hESC.  Likewise, if animals are involved, IACUC (Institutional Animal Care and Use Committee) are involved.  The NIH provides both scientific and ethical review.

NIH has traditionally allowed IRB, IACUC, and other review committees to evaluate research risks.  Respondents to the Draft Guidelines asked why NIH did not make greater use of these existing review structures for execution of their policy. In their response, NIH agreed that Institutional Review Boards (IRB) procedures under the Common Rule do provide a comprehensive framework for evaluating research risk for human subjects.  However, they pointed out that many different organizations have published standards for stem cell research and that a uniform standard was required.

While the lack of uniform standards for evaluating stem cell research is true to some extent and the Guidelines address such lack, it is not clear why the NIH did not utilize IRB and IACUC structures more.  This was particularly true in two areas:  evaluation of the consent procedures and assessment of risk of hESC and IPS transplantation in subhuman primates and other animals where the cells may interact with germ cells.  While the final Guidelines provided new administrative pathways for review and appeal within NIH, it barely mentioned IRB and IACUC review.

Perhaps the most puzzling is why NIH chose to ignore the ESCRO (Embryonic Stem Cell Research Oversight) committees. In 2005, the National Academy of Science recommended the formation of ESCRO committees to evaluate research that involve human embryonic stem cells.  Many institutions formed ESCRO committees and they have provided both ethical and scientific review of human embryonic stem cell research for the past four years.  Strangely, the Guidelines make no mention of ESCRO committees. It would be useful if the Guidelines defined the roles of IRB, IACUC, and ESCRO committees in institutional reviews of hESC research.

The Guidelines left many questions unanswered.  For example, why are existing mechanisms inadequate for evaluating the risk of transplanting hESC into non-human primates and into reproductively active animals?  What is the rationale for prohibiting these activities?  Do these activities pose such critical dangers that that NIH must prohibit important areas of research without review?  As pointed out by the International Society for Stem Cell Research, until such risk can be demonstrated, existing ethical standards should be used (Cell Stem Cell August 2007, 1: 159-163).  The NIH has long used well-established regulatory mechanisms to assess ethical and scientific risk of NIH funded research.  The NIH should take advantage of these mechanisms for stem cells.

Summary and Conclusions

The Final 2009 NIH Guidelines for Human Stem Cell Research was released on 9 July 2009.  The NIH received 49,000 comments on Draft Guidelines published in April 2009.  NIH modified the final Guideline in response to the comments:

  1. Definition of Human Embryonic Stem Cells (hESC).  The Guidelines modified the definition of hESC so that it now specifies that the cells come from the inner cell mass of human blastocysts.  However, the Guidelines continue to require that the cells grow for prolonged periods in culture without differentiation and that they produce cells of three primary germ layers.  These requirements will allow many hESC to be unregulated.
  2. Less Restrictive Consent Requirements.  The Draft Guidelines imposed informed consent criteria that would have made most existing hESC ineligible for the NIH registry.  The NIH allowed cell lines that are currently in the NIH Stem Cell Registry but required that all other cells be submitted to a committee that will advise the NIH Director whether the cells meet core ethical principles. HESC derived overseas will be reviewed separately.
  3. Timing and Revocation of Consent.  The Draft Guidelines required that consent be given just before embryo donation and allowed consent to be revoked at any time.  These requirements would have disallowed some hESC cells.  Revoking consent after derivation of the cells would be difficult to enforce and may allow donors to blackmail companies by revoking consent on the even of commercialization.  NIH decided to require consent at donation but limited consent revocation to before the cell were derived or de-identified.
  4. Parthenogenesis, Cloning, or Expressly Created Blastocysts.  The Guidelines explicitly forbids funding studies of stem cells derived from blastocysts created for their stem cells. This would forbid NIH to fund studies of pluripotent human stem cells derived from blastocysts created because they contain genetic disease.  Fortunately, NIH allowed use of blastocysts discarded from pre-implantation genetic testing.
  5. Restrictions of hESC Transplants into Animals.  The Guidelines restrict hESC and induced pluripotent stem (IPS) cell transplants into non-human primates and animals where the cells might interact with germ cells. There is little evidence that hESC transplants post greater risk than other human cells, e.g. human cancer cells.  These restrictions will restrict studies of hESC pluripotency and interactions with other cells.
  6. Failure to utilize IRB, IACUC, and ESCRO committees.  The Guidelines ignored well-established institutional mechanisms that have traditionally assessed ethical and scientific risks, including ESCRO committees that the National Academy of Sciences recommended as an institutional mechanism for reviewing hESC research.

In conclusion, the 2009 NIH Guidelines for Human Stem Research are better than the Draft Guidelines but unnecessarily banned studies of hESC derived from blastocysts not created for reproductive purposes, i.e. for research by parthenogenesis, cloning, or other methods.  The Guidelines restrict transplantation of hESC and even IPS cells into non-human primates or animals where the cells may interact with germ cells.  The NIH should use well-established institutional mechanisms to review ethical and scientific risk instead of prohibiting broad areas of research based on theoretical risk and politics.

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Cerebrolysin Review

February 10, 2009

Cerebrolysin Review
Wise Young, Ph.D., M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, Piscataway, New Jersey 08540-8087
Originally posted 1 April 2006, minor revisions (10 Feb 2009)

Cerebrolysin is a peptide mixture isolated from pig brain. A neurotrophic peptidergic mixture produced by standardized enzymatic breakdown of lipid-free porcine brain proteins, cerebrolysin is composed of 25% low molecular weight peptides (<10K DA) and 75% free amino acids, based on free nitrogen content [1]. The mixture has relatively high concentrations of magnesium, potassium, phosphorus, and selenium [2], as well as other elements [3, 4]. While the drug has antioxidant properties, it is much less than trolox or vitamin E [5]. The active ingredient(s) in the mixture are not known. Two concentrates of the peptide fraction of cerebrolysin are being tested, one called EO21 and the other N-PEP-12 [6].

Multiple clinical trials have reported that cerebrolysin is beneficial in Alzheimer’s disease, stroke, and other neurological conditions. The drug has been studied since the early 1970’s. Double-blind placebo controlled trials have reported sustained improvements and slowing down of progressive memory loss, cognition impairment, mood changes, and motor and sensory symptoms of stroke and neurodegenerative diseases (http://www.alzforum.org/drg/drc/detail.asp?id=39). The drug has been approved for treatment of Alzheimer’s disease in the United States. Ebewe Pharmaceutical (http://www.ebewe.com/) makes the drug. Over 176 articles have been published since 1973 on the subject of cerebrolysin treatment of various neurological disorders. I will review this literature below.

Chronic Stroke. In 1990, Ischenko & Ostrovskaia [26] compared the effects of cerebrolysin and various other agents on blood viscosity in 128 patients with circulatory encephalopathy. They found that cerebrolysin marked increased blood viscosity and suggesting that the drug be cautiously used in patients with ischemic blood circulation disorders. In Austria, Kofler, et al. [27] studied contingent negative variation (CNV) in 41 geriatric patients with moderate “organic brain syndrome” and showed that 10 infusions of cerebrolysin plus multi-vitamin infusions increased CNV amplitudes, compared to the placebo group that received multivitamin alone. Kofler, et al. also did psychometric measures in 27 patients with organic brain syndrome and treated with a course of ten cerebrolysin treatments, compared to 14 clinically comparable patients, showing significant improvements in the cerebrolysin treated group. In 1991, Vereschchagin, et al. [28] treated 30 patients with multi-infarct dementia and compared them with 30 patients that received placebo. Cerebrolysin improved memory, abstract thinking, and reaction time of the patients, confirmed with EEG-mapping. Pruszewicz, et al. [29] gave cerebrolysin to severe central hearing loss and observed improvement in 36%. In 1996, Iakno, et al. [30] treated 20 patients with vascular dementia and showed EEG effects and the most improvement in patients with the least cognitive deficit. In 2004, Gafurov and Alikulova [31] treated 2 groups of patients with ischemic brain hemispheric stroke and reported that cerebrolysin improved both groups.

Pediatric Treatments. Several Russian groups have been using cerebrolysin to treat neurological disorders in children. In 1998, Gromova, et al. [2] gave cerebrolysin to 36 3-8 year old children with minimal cerebral dysfunction. Gruzman, et al. [32] used intravenous cerebrolysin injections to treat resistant forms of night enuresis in children. In 2000, Sotnikova, et al. [33] found that cerebrolysin (1 ml per 10 kg) increased CD19+ cells and CD4+ lymphocytes with normalization of serum IgG and IgA levels and CD16+ cells (NK) at one month after treatment, in children (age 3-8 years) with minimal cerebral dysfunction; in addition, cerebrolysin activated T helper cells in vitro. Sukhareva, et al. [34] treated 120 children (age 4-15 years) with “neurosensory hypoacusis” with “pharmacopuncture” injecting cerebrolysin and several other drugs. They reported that the treatment improved speech intelligibility, headache, and other problems in 85% of cases. Sotnikova [35] gave cerebrolysin (1 ml/10kg) intramuscularly for one month to children with attention deficit syndrome, reporting that this resulted in “a simultaneous normalization of neurological and immune disorders and a reduction in the illness rate.” In 2003, Krasnoperova, et al. [36] gave cerebrolysin (0.1 ml daily for 5 days) to 19 children with childhood autism and 8 with Asperger’s syndrome (aged 2-8 ) and found positive effects in all the patients with Asperger’s syndrome and 89% of the patients with autism. Guseva and Dubovsakia [37] treated 646 children (age 8 weeks to 18 years) with optic nerve disease by giving retrobulbar cerebrolysin once daily, in combination with microcirculatory drugs, in the irrigation system, or just microcirculatory drugs alone through the irrigation system, reporting that cerebrolysin treatment improved vision.

Extrapyramidal hyperkinesis. This is a motor syndrome that results from neuroleptic (dopaminergic) drugs used to treat various neurological disorders including Parkinson’s disease, schizophrenia, and depression. In 1997, Kontsevoi, et al. [38] did an open-label study of cerebrolysin treatment of 30 Parkinson patients who had prolonged extrapyramidal complications from neuroleptic therapy, finding that cerebrolysin markedly reduced severity of extrapyramidal symptoms in 46.6% of the patients and partial response in 26.6%. In 1999, Panteleeva, et al. [39] gave cerebrolysin and magme B6 (a drug) to 51 patients with diagnoses of schizophrenia or depression, suffering from extrapyramidal and somato-vegetative effects of neuroleptic and anti-depressive drugs. Both drugs reduced the hyperkinetic and cardiovascular side effects of neuroleptic drugs. In 2004, Lukhanina, et al. [40] examined the effects of cerebrolysin on EEG activity of 19 patients with Parkinson’s disease and 18 healthy controls, They found twofold improvements in CNV mean amplitudes, strengthening of postexcitatory inhibition in the auditory system after paired stimulation, and other measures. An open-label prospective study in Russia assessed 25 patients with childhood autism (ages 3-8 ) who received 2 therapeutic courses of cerebrolysin. The patients all demonstrated a significant improvement in mental function, cognitive activity, attention during task performance, perception, and fine motor function [41].

Alzheimer’s Disease. In 1994, Ruther, et al. [42] did a double-blind placebo control study of cerebrolysin treatment of 120 patients with moderate Alzheimer’s dementia and found modest beneficial effects. In 1997, Rainer, et al. [43] treated 645 demented patients with 30 ml of cerebrolysin daily for an average of 17.8 days, reporting that the treatment improved clinical global impression in 80% of the patients and significantly more in younger and less afflicted patients. In 1998, several reviewers [44, 45] pointed out cerebrolysin as a potential therapy for Alzheimer’s disease. Windisch, et al. [46] called for clinical trials to ascertain whether cerebrolysin induces repair in chronic brain injury and whether the effects are long lasting. In 1999, Roshchina, et al. [47] found that cerebrolysin (30 ml) enhanced the beneficial effects of amridin (80 mg daily for 10 weeks) in 20 patients with Alzheimer’s, compared to 23 patients treated only with amiridin. In 2000, Bae, et al. [48] did a double-blind placebo-controlled multicenter study of cerebrolysin in 53 men and women with Alzheimer’s disease. They found that the cerebrolysin significantly improved cognitive deficits and global function in patients with mild to moderate dementia. Based on these results, Molloy and Standish [49] suggested that cerebrolysin be given to patients with Alzheimer’s disease. Ruther, et al. [50] evaluated 101 patients 6 months after completion of a 4-week course of 30 ml cerebrolysin or placebo, showing a clear sustained beneficial effect of cerebrolysin over placebo. Windisch [51] reviewed the literature and concluded that three placebo-controlled double-blind randomized studies had shown significant improvements of cognitive performance, global function, and activities of daily patients with Alzheimer’s disease, indicating a “powerful disease modifying activity” of cerebrolysin. In 2001, Ruether, et al. [52] did a 28-week, double-blind, placebo-controlled study of 4- week cerebrolysin treatment in 149 patients with Alzheimer’s disease, showing a 64.5% responder rate on the clinical global impression compared to 41.4% in the placebo group, as well as a 3.2 point difference in the ADAS-cog scale. The effects were maintained for 3 months after end of treatment. The treatment was repeated after a 2-month therapy-free period and improvements were maintained [53]. In 2002, Muresanu, et al. [54] showed that cerebrolysin improved activities of daily living in patients with Alzheimer’s disease. Panisset, et al. [55] randomized 192 patients with Alzheimer’s disease to cerebrolysin (30 ml, 5 days per week, 4 weeks) or placebo, finding that cerebrolysin is well tolerated and significantly improved global score for 2 months after end of active treatment. Gavrilova, et al. [56] correlated ApoE4 genotype in patients with mild-to-moderate Alzheimer’s disease and efficacy of cerebrolysin therapy and cholinergic (exelon) therapy. A 4-month treatment showed that 1.7 fold higher response rate to cerebrolysin than the exelon group but further analysis revealed that those with genotype ApoE4(-) had 3- fold higher effect from cerebrolysin than people with ApoE4(+) genotype. Roshchina, et al. [57] did a neuropsychological evaluation of Alzheimer patients treated with two doses cerebrolysin (10 or 30 ml) over 19 months. Patients receiving the higher dose showed better cognitive function and less disease progression. In 2006, Alvarez, et al. [58] did a 24-week double-blind placebo-controlled study of 10, 30, and 60 ml of cerebrolysin (5 days a week for the first four weeks and then 2 infusions per week for 8 weeks). The results indicate a reversed U-shaped dose response relationship. The 10 ml dose improved cognitive performance but, while the 30 and 60 ml dose did not further improve cognitive function, the higher doses showed significantly better global outcome impression scores. Thus, many clinical trials have confirmed long-term beneficial effects of cerebrolysin in people with Alzheimer’s disease.

Acute Stroke. In 1994, Gusev, et al. [59] treated 30 patients with acute ischemic strokes with daily intravenous doses of 10, 20, 30 ml for 10 days, reporting that the treatment accelerated recovery in those with moderate strokes, compared to control subjects. In 1995, Domzai & Zaleska [60] treated 10 patients with acute middle cerebral artery strokes with 15 mg/day of cerebrolysin for 21 days and found similar recovery compared to a larger group of 108 patients given other drugs. Sidorenko, et al. [61] treated patients with partial optic atrophy with retrobulbar injections of cerebrolysin and apparently saw “favorable” effects in 50% of cases, compared to only 25% of control untreated patients. In the same year, Koppi & Barolin [62, 63] compared 318 stroke patients that received standard hemodilution with 100 patients that received hemodilution with cerebrolysin; reporting the cerebrolysin accelerated recovery. In 1998, Funke, et al. [64] did a remarkable double-blind placebo-controlled study showing that cerebrolysin increased parietal EEG signal in 48 healthy subjects subjected to transient brain ischemia, comparing 10, 30, and 50 ml doses. In 2004, Skvortsova, et al. [65] randomized 36 patients (age 45-85 years) with ischemic stroke of the carotid territory to cerebrolysin (10 ml/day or 50 ml/day) or placebo on day 3 of the stroke. They found EEG improvement in 72.7% of the treated patients. Ladurner, et al. [66] randomized 146 patients to placebo or cerebrolysin within 24 hours after stroke and examined at various times up to 90 days later. While the cerebrolysin group showed no significant improvement in clinical neurological scores, the Barthel Index, or Clinical Global Impression when compared to the placebo Cerebrolysin Review – Wise Young – Page 6 group, patients on cerebrolysin showed significant better cognitive function on the Syndrome Short Test.

Other Conditions. Cerebrolysin has been reported to be beneficial in several other neurological conditions, including diabetic neuropathy, glaucoma, neurosurgical procedures, Rett syndrome, vascular dementia, and traumatic brain injury In 1997, Bisenbach, et al. [67] treated 20 patients with type II diabetes, giving them 20 ml of cerebrolysin-infusion daily over 10 days, comparing with an age matched placebo control group. Cerebrolysin treatment resulted in significant subjective improvement of painful diabetic neuropathy for at least 6 weeks. In 2000, Lunusova [68] used cerebrolysin to treat patients with persistent glaucoma, reporting that the treatment (along with others) arrested the glaucomatous process, improved visual acuity, and extended visual field. In 2000, Matula and Schoeggl [69] suggested that cerebrolysin may be useful for preventing neurological deficits such as confusion, disorientation, or cognitive deficits after neurosurgery. Deigner, et al. [70] suggested that cerebrolysin may act in neurodegenerative diseases by preventing neuronal apoptosis. In 2001, Gorbachevskaya, et al. [71] gave cerebrolysin to 9 girls with Rett syndrome (age 2-7 years). Treatment resulted in increased behavioral activity, attention level, motor function, and non-verbal social communication, as well as EEG. In 2001, Vereshchagin, et al. [72] gave cerebrolysin for 28 days (15 mg/day) annually for 2 years to 42 patients with vascular dementia in a double-blind placebo-controlled study. The trial suggested stabilization of cognitive loss and prevention of progression of vascular dementia. Alvarez, et al. [73] used cerebrolysin to treat patients with brain trauma and found significant improvement in patient’s clinical outcomes during the first year with no adverse events. In 2005, Wong, et al. [74] reported a beneficial effect of cerebrolysin on moderate and severe head injury patients. At 6 months after treatment, 67% of the patients in the cerebrolysin group attained good outcome (GOS 3-5) compared to a historical cohort. Cerebrolysin has been reported to be beneficial for a wide variety of neurodegenerative disorders [75, 76], organic mental disorders [77], multiple sclerosis [78], anti-aging [79], and ischemic encephalopathy [80].

Animal Studies

Early animal studies did not shed much light on the mechanism(s) of cerebrolysin. In 1975, Lindner, et al. [81] applied the hydrolysate to cultures of chick peripheral and central neurons and found that high concentrations reduced nerve fiber growth but increased migration of non-neuronal cells. Zommer & Kvandt [82] gave doses of 0.005-0.025 ml of cerebrolysin to neonatal rats and found earlier differentiation of cytoarchitectonic fields in cerebral cortex, as well as early accumulation and increase in granular secretions in the pituitary gland of the animals. In 1976, Trojanova, et al. [83] reported that single injections of cerebrolysin given intraperitoneally to rats did not change their resistance to anoxia but repeated (5x) dosing increased resistance of young female rats (35 day old) to anoxia and that higher doses also increased resistance of adult rats to anoxia, compared to control mixtures of amino acids, oligopeptides, and nucleotides.

Neural Development and Cerebral Metabolism. By the 1980’s, several groups reported the cerebrolysin affected neuronal development and cerebral metabolism in animals. In 1981, Wenzel, et al. [84] reported that cerebrolysin treatment significantly increased the number of dendritic spines in the dentate gyrus (hippocampus) of neonatal rats. In 1985, Windisch & Poiswanger [85] treated rats for 3, 5, 7 or 14 days and examined cerebral protein, lactic acid, and oxygen consumption of brain homogenates, finding that higher doses (2.5 ml/kg) significantly increased respiratory activity of the homogenates. These effects apparently were most prominent in young rats up to 4 weeks and then in older 12-18 month old rats [86].

Experimental Demyelination and Immune Modulation. In 1991, Bespalova, et al. [87] assessed brain cerebrosides, sulfocerebrosides and gangliosides in rats subjected to experimental demyelination and treated with cerebrolysin. Zuber [88] examined the effects of cerebrolysin on brain phospholipids in rats with experimental demyelination. In 1992, Belokrylov and Malchanova [89] reported that treatment with cerebrolysin increased the number of Thy-1 positive cells and in vivo immune responses. In 1998, Grechko [90] compared cerebrolysin with a number of other peptide immunomodulators drugs and found that cerebrolysin had greater effect on free open-field group behavior of animals than most.

Hippocampal lesions. In the early 1990’s, several groups studied the effects of cerebrolysin on recovery from fimbria-fornix lesions. In 1992, Akai, et al. [91] of Kinki University in Osaka, Japan examined the effects of cerebrolysin (FPF1070) on septal cholinergic neurons after transection of the fimbria-fornix in rat brain. They found that intraperitoneal injections of the aqueous mixture of protein-free solution (containing 85% free amino acid and 15% small peptides) stimulated growth of embryonic dorsal root ganglion cultures. Apparently, the FPF1070 mixture prevented degeneration and atrophy of injured cholinergic neurons. In 1996, Francis-Turner & Valouskova [92, 93] compared intraperitoneal cerebrolysin with different concentrations of intraventricular infusions with NGF and bFGF on amnesia induced by fimbria-fornix transections. Cerebrolysin treatment or cerebrolysin combined with bFGF eliminated retrograde amnesia in the rats. In 1998, Cruz, et al. [94] showed the cerebrolysin (2.5 mg/kg x 7 days) had only a modest effect on glutathione related enzymes after fimbria-fornix transection. However, Gonzalez, et al. [95] found that cerebrolysin preserved SOD and CAT activity in the brain after a septohippocampal lesion.

Blood-Brain Barrier. In 1995, Boado [96] at UCLA reported that cerebrolysin transiently increased the glucose transporter GLUT-1 expression in blood-brain-barrier (BBB) within 2 hours and then a reduction at 20-48 hours, suggesting that cerebrolysin modulates expression of BBB-GLUT-1 expression. Boado [97] then used a luciferin-luciferase reporter gene to show that cerebrolysin markedly increased the BBB-GLUT1 expression and that the mechanism did not involve phosphokinase C. In 1998, Boado [98, 99] showed that cerebrolysin increased GLUT-1 expression via mRNA stabilization. In 1999, Boado, et al. [100] showed that acute or chronic administration of cerebrolysin increases the transport of glucose from blood to brain. In 2000, Boado [101] further showed that cerebrolysin stabilized GLUT1 transporter mRNA by increasing p88 TAF. In 2000, Gschanes, et al. [102] showed that both cerebrolysin and its peptide fraction EO21 increased the abundance of GLUT1 transporter in the brains of both old and young rats. In 2001, Boado [103] showed that cerebrolysin markedly increases the expression of BBB-GLUT1 reporter genes containing regulatory cis-elements involved in stabilization and translation, increases glucose uptake by the BBB, and increases GLUT1 protein expression.

Hippocampal slices. In Toronto, Baskys, et al. [104] assessed cerebrolysin effects on hippocampal slices, finding that it suppressed synaptic responses in CA1 neurons but not dentate gyrus neurons. Xiong, et al. [105, 106] found that cerebrolysin caused presynaptic inhibition that can be blocked with adenosine A1 receptor blockers and, since cerebrolysin does not contain detectable amounts of adenosine, proposed that cerebrolysin acted indirectly perhaps be release of endogenous adenosine. Cerebrolysin also appears to inhibit hippocampal responses by activating the GABA-B receptor [107]. Meanwhile, in 1995, Zemkova, et al. [108] of the Czech Republic, found that cerebrolysin potentiates GABA-A receptors in culture mouse hippocampal slices and that this could be blocked by bicucullin (a GABA-A receptor blocker). Ischemia. In 1993, Sugita, et al. [109] assessed the effects of FPF1070 (cerebrolysin) on delayed neuronal death in the gerbil global ischemia model. They measured the formation of hydroxyl free radicals in the brain and found that both DMSO (a hydroxyl free radical scavenger) and FPF1070 significantly reduced delayed neuronal death and evidence of hydroxyl radicals in the brains, proposing that hydroxyl radical scavenging may be the mechanism of cerebrolysin effect. In 1996, Schwab, et al. [110] assessed the effects of cerebrolysin on cytoskeletal proteins after focal ischemia in rats. In 1997, Schwab, et al. [111] compared the effects of hypothermia and cerebrolysin, finding that the latter enhanced the neuroprotective effects of the former. Cerebrolysin also improved EEG signal and motor activity of rats after mild forebrain ischemia [112]. Gschanes, et al. [113] found that cerebrolysin improved spatial memory and motor activity in rats after ischemic-hypoxic injury. In 1998, Schwab, et al. [114] showed that cerebrolysin reduced the size of cerebral infarct and microtubule protein loss after middle cerebral artery occlusion. In 2005, Makarenko, et al. [115] compared different fractions of cerebrolysin on a bilateral hemorrhagic rat stroke model. They found the most pronounced effects for the cerebral-1 fraction and particularly the 1.2 subfractions.

Spreading depression, hypoxia, and hypoglycemia. In 1998, Bures, et al. [116] showed that cerebrolysin (2.5 mg/kg daily x 10 days) remarkably protected the hippocampus against damage during repeated spreading depressions. Koreleva, et al. [117] compared the effects of MK801 and cerebrolysin on focal ischemia, finding that cerebrolysin increased amplitude of evoked spreading depression. In the same year, Gannushkina, et al. [118] studied the effects of cerebrolysin on 389 rats after bilateral common carotid occlusion, showing that the treatment did not increase blood flow but increased EEG recovery that may enhance ischemia damage. In 1999, Buresh, et al. [119] reported that cerebrolysin completely prevented hypoxia induced loss of CA1 neurons in the hippocampus. Koroleva, et al. [120] found that cerebrolysin treatment protected the hippocampus against carbon monoxide poisoning and spreading depression. In 2000, Veinbergs, et al. [121] pre-treatment with cerebrolysin was necessary to provide significant neuroprotection for kainic acid injections. In 2003, Patockova, et al. [122] showed that cerebrolysin significantly reduced lipid peroxidation induced by insulin hypoglycemia in the hearts and brains of mice.

Alzheimer’s disease. In 1999, Masliah, et al. [123] showed that cerebrolysin ameliorates performance deficits and neuronal damage in apolipoprotein E-deficient mice (a model of Alzheimer’s disease). In 2002, Rockenstein, et al. [124] treated transgenic mice expressing human amyloid precursor protein (APP751) under the Thy-1 promoter. Cerebrolysin significantly reduced the amyloid burden in the frontal cortex of 5-month-old mice, as well as the levels of A-beta (1-42). In 2003, Rockenstein, et al. [125] showed that cerebrolysin is neuroprotective in a transgenic mouse expressing human mutant amyloid precursor protein (APP) under the Thy1 promoter, start 3 or 6 months after birth. The treatment significantly ameliorated performance deficits and protected neurons. Rockenstein, et al. [126] investigated various gene expression and found no change in BACE1, Notch1, Nep, and IDE but did find higher levels of active cyclin-dependent kinase-1 (CDK5) and glycogen synthetase kinase-3 beta (GSK3beta).

Memory. In 1996, Hutter-Paier, et al. [127-130] reported that a single injection of cerebrolysin improved passive avoidance reactions in rats after transient cerebral ischemia. Gschanes & Windisch [131] likewise found that cerebrolysin improved spatial navigation in rats after transient brain ischemia. In 1998, Gschanes and Windisch [132] assessed the effects of cerebrolysin on spatial navigation in old (24-month) rats and found that cerebrolysin and EO21 (the concentrated peptide fraction of cerebrolysin) both improved spatial learning and memory of the rats. In 1999, Gschanes and Windisch [133] found that cerebrolysin or EO21 also improved spatial learning and memory in young rats, lasting up to 3 months after treatment stopped. In 1998, Valouskova and Francis- Turner [134] reported that cerebrolysin restored learning capability in rats when given 4 months after brain lesions. In 1999, Reinprecht, et al. [135] gave cerebrolysin or EO21 to 24-month old rats and found that the peptide mixtures improved cognitive performance of the rats and increased number of synaptophysin-immunostaining in the hippocampus. In 1999, Valouskova and Gschanes [136] compared NGF, bFGF, and cerebrolysin on rat performance in the Morris water maze test after bilateral frontoparietal cortical lesions, showing that cerebrolysin had a significant beneficial effect that declined to control levels by 8 months. Windolz, et al. [137] found that cerebrolysin or EO21 increased synaptophysin immunoreactivity in the brains of 6-week old rats. Eder, et al. [138] reported that cerebrolysin increased expression of the glutamate receptor subunit 1 (GluR1).

Spinal Motoneurons and Injury. Haninec, et al. [139] reported that insulin-like growth factor I (IGF-I) and cerebrolysin improves survival of motoneurons after ventral root avulsion. Either IGF-1 or cerebrolysin were effective when given intrathecally to the spinal cord. In 2004, Haninec, et al. [140] showed that BDNF and cerebrolysin both increased reinnervation of the rat musculocutaneous nerve stump after avulsion and its direct reconnection with the C5 spinal cord segment. BDNF was better than cerebrolysin. In 2005, Bul’on, et al. [141] studied the effects of cytoflavin or cerebrolysin in rats after spinal cord compression injury. The neuroprotective effects of cytoflavin were greater than for cerebrolysin.

Cell Cultures. In 1998, Hutter-Paier, et al. [142] showed that cerebrolysin counteracted the excitotoxic effects of glutamate and hypoxia [143] in cultured chick cortical neurons. In 1999, Lombardi, et al. [144] applied cerebrolysin to cultures of rat astrocytes and microglia, showing that the peptide mixture prevented microglial activation after LPS activation and reduced interleukin-1b expression. Mallory, et al. [145] reported that cerebrolysin applied to the human teratocarcinoma cell line (NT2) markedly increased expression of synaptic-associated proteins, suggesting that it has synaptotrophic effects mediated through regulation of APP expression. Alvarez, et al. [146] likewise showed that cerebrolysin reduced microglial activation both in vitro and in vivo. Satou, et al. [147] reported that cerebrolysin had a inverted U-dose response on neurite growth and suggested that cerebrolysin has different effects depending on the subpopulation of neuron. Wronski, et al. [148] showed that cerebrolysin prevented MAP2 loss in primary neuronal cultures after brief hypoxia. Cerebrolysin also inhibits the calcium-dependent protease calpain [149]. In 2001, Hartbauer, et al. [1] showed that cerebrolysin is anti-apoptotic in embryonic chick cortical neuronal cultures and stimulates outgrowth and protection of neurites [150]. In 2002, Gutmann, et al. [151] showed cerebrolysin protects cultured chick cortical neurons from cell death from a wide variety of causes, including glutamate, iodoacetate, and ionomycin; they propose that cerebrolysin stabilizes calcium ionic homeostasis. Safarova, et al. [152] showed that cerebrolysin improved survival of PC12 cells in serum-free medium, reducing apoptosis from 32% to 10%. In 2005, Schauer, et al. [153] found that a single addition of cerebrolysin to culture medium resulted in significant protection of tissue cultures against ischemia and hypoxia for up to 2 weeks. The treatment can even be delayed as long as 96 hours and still have beneficial effects. In 2006, Riley, et al. [154] applied cerebrolysin to organotypic brain slices and showed that the most pronounced neuroprotective effects of other drugs was seen when the drug was added both before and after glutamate.

Discussion and Summary

On the surface, cerebrolysin seems to be the worst sort of “drug” to investigate. First, it is not clear what cerebrolysin actually contains. Second, it is difficult to imagine why an intravenous injection of an extract of enzyme-digested pig brain proteins, composed of 25% low molecular weight peptides and 75% free amino acids, would be helpful. While we know that many peptides and amino acids act as growth factors and neurotransmitters, the blood brain barrier prevents the movement of peptides and amino acids from the blood to the brain. Third, if peptides and amino acids readily crossed the blood brain barrier, our brains would be subject to the whims of every steak and meal that we eat.  Finally, cerebrolysin is digested proteins from pig brain. It should be quite immunogenic to inject all these foreign peptides intravenously. Immunogenic reactions are complex and not well understood. Thus, in theory and from the viewpoint of safety, cerebrolysin should not only be ineffective but may pose significant risks.

Early 1970’s anecdotal clinical reports in Russia did not contribute to the credibility of cerebrolysin. It was being used in patients with cerebral arteriosclerosis, infantile cerebral palsy, and dementia. None of the studies were adequately controlled and the outcomes were vague and it all just seemed too good to be true. Likewise, early animal and cell culture studies likewise did not provide much information. However, in Russia, cerebrolysin was widely used and tried on many different kinds of diseases, mostly hopeless and poorly documented. This is of course a natural tendency. If a safe and effective therapy exists for a condition, that therapy would of course be the first choice of doctors. Conditions that have no known effective therapies are the ones that are most likely to be treated by cerebrolysin.

Animal studies turned the tide of skepticism. In the early 1980’s, the work of Wenzel, et al. [84] showing changes in neuronal synapses and Windisch & Poiswanger [85] reporting dose-related effects of cerebrolysin on cerebral metabolism suggested that the hydroxylate was doing something to the brain. Cerebrolysin also appeared to affect brain phospholipids [88] and may even have some effects of the immune system [89]. By the 1990’s, several groups reported remarkable effects of cerebrolysin on hippocampal lesions, preventing degeneration and atrophy of cholinergic neurons [91] and amnesia [92, 93], In 1995, Boado [96] showed that cerebrolysin remarkably upregulates the glucose transporter in the blood brain barrier, through a specific mechanism involving stabilization of the GLUT1 mRNA and associated not only with increase in GLUT1 protein but also increased glucose transport across the blood-brain-barrier [100].

Many clinical trials have now reported that cerebrolysin is an effective and safe therapy for many neurological disorders, ranging from stroke to Alzheimer’s disease. The drug’s primary effect seems to be on hippocampal function. Some studies suggest that cerebrolysin may be modestly neuroprotective in stroke and facilitates recovery from stroke. The side effects of the drug seem to be negligible. There are efforts underway to develop an oral version of the drug but the vast majority of the studies involve daily intravenous injections. The apparently broad spectrum of neuroprotective and neuroreparative effects of the drug both in the acute and chronic phases of brain injury suggest that this drug should be useful for both acute and chronic stroke and traumatic brain injury. Several studies suggest that the drug stabilizes excitability of the brain and can reduce hyperkinetic syndromes associated with neuroleptic drugs used for Parkinson’s disease. It may also be useful for preventing progressive deterioration in Parkinson’s disease although no clinical trial has addressed this issue yet.

An impressive array of clinical trials support beneficial effects of cerebrolysin on Alzheimer’s disease, beginning with Ruther, et al. [42] with 120 patients in 1994 and Rainer, et al. [43] with 645 patients in 1997. In 1999, Roshchina, et al. [47], Bae, et al. [48], and Ruther, et al. [50] confirmed these results. The effects of the cerebrolysin are not only statistically but also clinically significant [54]. The cerebrolysin responder rate on global clinical impression scale was 64.5% compared to 41.4% in placebo treated patients [52]. Several clinical trials also showed a clear dose-response [58] and several animal studies [6] are suggesting that the active ingredient is in the peptide fraction and not the amino acid fraction of cerebrolysin. People with genetic causes of the disease appear to be more responsive to cerebrolysin [56]. More interesting, the drug effects appear to last many months or even years after treatment has stopped [52, 53, 55]. This long-lasting effects suggest that cerebrolysin is not merely improving the balance of neurotransmitters or increasing the excitability of neurons, although EEG studies suggest that changes of excitability do occur with cerebrolysin treatment. Thus, it seems that cerebrolysin may be stimulating repair or perhaps even neuronal replacement in the brain. One interesting possibility is the cerebrolysin may be stimulating stem cells in the brain and repair processes that we do not understand.

Some clinical evidence suggest that cerebrolysin may be beneficial for other neurological conditions, including extrapyramidal hyperkinesis associated with neuroleptic therapy [38-40], with acute [65, 66] and chronic [28, 30, 31] stroke, diabetic neuropathy [67], Rett syndrome [71], vascular dementia [72], brain trauma [73, 74], organic mental disorders [77], multiple sclerosis [78], anti-aging [79], ischemic encephalopathy [80], and other neurodegenerative disorders [75, 76], Little data is available concerning the effect of the drug on spinal cord injury. Only one recent study is available regarding cerebrolysin therapy of a rat spinal cord compression model and it suggests a modest effect of the drug compared to another antioxidant. More studies are needed to ascertain the benefits of cerebrolysin for both acute and chronic spinal cord injury.

References

Geron’s Oligodendroglial Precursor Cell Therapy Trial

January 27, 2009

Geron’s Oligodendroglial Precursor Cell Therapy Trial
by Wise Young, PhD MD.
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, 604 Allison Road, Piscataway, NJ 08854-8082
Posted 26 January 2009, updated 29 January 2009

On January 21, 2009, Geron announced that they received the approval of the U.S. Food and Drug Administration (FDA) to do the first clinical trial that will evaluate the safety of cells derived from human embryonic stem cells (HESC). The trial will transplant oligodendroglial precursor cells (OPC’s) derived from an early HESC line isolated in 1997 by Jamie Thomson and colleagues in Wisconsin.

This is a landmark trial not only because it is the first trial of an HESC-derived cell but because it is the first such trial for spinal cord injury. HESC’s are derived from blastocysts, the first stage of development after fertilization. Geron had funded the work of Jamie Thomson in the late 1990’s.  President George W. Bush banned federal funding of research on HESC derived after August 2001.

In 1999, John McDonald and his colleagues [1] transplanted predifferentiated mouse embryonic stem cell into contused spinal cords of rats, comparing them against fibroblasts expressing neurotrophins. At 2-5 weeks, the transplanted cells had differentiated into astrocytes, oligodendroglia, and neurons, migrating as far as 8 mm from the injury site. Gait analysis showed that the transplanted rats showed better hindlimb weight support and partial hindlimb coordination.

In 2005, Faulkner & Keirstead derived [2] oligodendroglial progenitor cells (OPC) from human embryonic stem cells.  OPC’s transplanted into rat spinal cord at 7 days after contusion enhanced remyelination and improved locomotor recovery [3].   In other studies, Keirstead, et al. showed that contused rat spinal cords undergo progressive demyelination [5], OPC implants were not harmful in rats [6], transplanted OPC cells replaced oligodendroglia [7], and myelin loss is greater in contusion injury [8] and older animals [9].

Armed with this data, Geron proposed to carry out a phase 1 clinical trial to evaluate the safety of transplanting OPC derived from human embryonic stem cells (HESC) on people with subacute spinal cord injury. This would be the first time any cell from a known and well-characterized human embryonic stem cell line would be used to treat any condition. It was also the first proposal to use HESC-derived cells to treat human spinal cord.

Geron did extensive studies of the safety and mechanisms of OPC effects on spinal cord injury. In 2006, Zhang, et al. [10] reported that the HESC-derived OPC secrete neurotrophic factors, suggesting an alternative mechanism for the beneficial effects of the cells on recovery after contusion injury. In 2007, Okamura, et al. [11] reported that the HESC-derived OPC cells do not stimulate strong immune responses in vitro, providing the rationale for using non-HLA matched heterologous cells.

From 2005 on, Geron repeatedly announced their intentions to transplant the HESC-derived OPC cells into people with spinal cord injury but the FDA did not approve the clinical trial [12]. It became clear that FDA approval of the first HESC-derived cell transplant faced significant scientific [13] and bioethical hurdles [14]. In May 2008, the FDA placed a hold on the Geron’s application [15] but Geron said that they were addressing the concerns and were confident of approval [16].

On January 21, 2009, Geron announced that the FDA approved the application for the [17]. The media response was massive [18]. The story was carried by almost every news source [18-20]. The community response was initially strongly positive. Coming on the 3rd day after President Barack Obama’s inauguration, some thought that the approval of the first HESC trial was due to Obama’s coming to power.

The exuberance faded as people read the fine print. First, the trial is not for people with chronic spinal cord injury. It is intended to be used within 2 weeks after injury for people with complete thoracic spinal cord injury. Second, the goal of the trial is to show safety and feasibility, not necessarily efficacy. Third, the cells have been differentiated to the point that they are no longer acting as stem cells but only as oligodendroglia.

The trial focuses on subacute spinal cord injury in part because animal data suggest that the cells alone would be effective only when transplanted into rats within two weeks after injury. This does not necessarily mean that the cells would not be effective in chronic human spinal cord injury, especially when combined with some other therapy (such as chondroitinase, Cethrin, or Nogo-A antibody).

The trial is designed to establish safety of the cells. One worry of the FDA and the scientific community is that HESC will produce teratomas (a stem cell tumor).  Geron played it very safe. They differentiated these cells so that they produce only oligodendroglial cells and are very unlikely to produce teratomas. They chose to transplant the cells into patients with thoracic complete spinal cord injuries so that if the cells turned into tumors, the neurological consequences will be minimized.

According to the New York Times by Andrew Pollack [21], Thomas B. Okarma, Geron’s chief executive, did not think that the Bush Administration’s objections to embryonic stem cells delayed approval. “We really have no evidence, ” Dr. Okarma said, “that there was any political overhang.” But Robert Klein, chairman of California Institute of Regenerative Medicine thought that Bush had pressured the FDA.

Some scientists were critical of the trial. For example, according to the Pollack article, John A. Kessler, who is chair of Neurology and director of the Stem Cell Institute at Northwestern University and father of a spinal-injured daughter, said that a treatment might not apply to more seriously injured people. “We really want the best trial to be done for this first trial, and this might not be it,” he said.

Kessler was referring to the use of myelinating cells to treat people with so-called “complete” spinal cord injury. People with such severe injuries should have fewer axons crossing the injury site to myelinate.  Okarma responded that this trial was designed to establish the safety of the treatment and lack of efficacy in this trial was not a problem.

The same article cited Steven Goldman, chair of neurology at the University of Rochester, “It’s not ready for prime time, at least in my mind, until we can be assured that the transplanted cells have completely lost the capacity for tumorogenicity.” Okarma pointed out that Geron has done numerous studies to show that the cells do not contain any residual embryonic stem cells and did not form tumors when transplanted into animals, even after a year.

Geron’s application for the clinical trial was over 22,000 pages long and the preparatory work cost $45 million. While Okarma said that he did not think that the Bush Administration impeded the application for this particular trial, he did think that the Federal government slowed the progress in the field by making it difficult for researchers to do embryonic stem cell research. Clearly, given the $45 million and 4 years required for the approval of the clinical trial, it was not an easy process.

Geron’s web site and news reports indicate that the trial will treat 8-10 patients who are within 2 weeks after “complete” thoracic spinal cord injury. It will probably start in July 2009. However, many details are unclear. Before the FDA placed a hold on the trial application in May 2008, Geron had said that the cells would be transplanted into the spinal cord of patients undergoing spinal cord decompressive surgery and all the patients will receive a 2-month period of pharmacological immunosuppression . It is not clear that the same regimen will be used.

In the meantime, the reaction of the spinal cord injury community has ranged from exuberance over the approval of the first HESC trial [22] to deep pessimism over comments by Okarma, who said that people with “complete” spinal cord injury have no chance of recovering any function, or something to this effect. Many people in the spinal cord injury community [23] were disappointed at being excluded from the study which is only for the newly injured.

As John Smith commented in CareCure [25]:

Tom Okarma is cool, groovy, dope or whatever other adjective you might use to convey a leader with media savvy. Our 21st century world is so ravenous to scoop one another there is little respect for the truth and process.

I’ve met the man. I’ve spoken to him privately twice and questioned him about Geron’s commitment to SCI and the meaning of this trial for chronics. This trial is of staggering importance for Geron and those of us living the life. However, it is not momentous for us in the sense of being a cure-all.

There is no way Okarma is going to speculate beyond the scope of this trial’s goals. That would be a terrible error in judgment and one to which he is immune. He is a doctor and a scientist, not a snake oil salesman. He is also the CEO of Geron. Their reputation is on the line with this trial. I admire him for the self-control necessary to put a brake on the message.

I asked him point blank, one on one, away from the glare of cameras and the notepads of journalists what this trial meant for chronics. He repeated what was quoted in the various articles reporting on the FDA approval. Evidence exists that this therapy will not work for chronics due to scarring.

My son is six years post injury. Naturally, his answer was disappointing. But, of course, that is not the end of the story, though it is likely that is all Okarma will dare to say on the subject.

He knows all about efforts to deal with the scar tissue that range from bridging the injury site to dissolving the scar to the work headed by Keirstead at UCI (post #13). Nonetheless, he’s not going to comment on that or leapfrog the purpose of the current trial. He is going to stay on point. Bless him for that; now is not the time to get sidetracked from the journey ahead.

As this trial proceeds through its various stages, the world of SCI research is going to be turned upside down. In part, it will be due to the incredible science funded by Geron. It will also be because of the confluence of research supported by the soon to be minted CDRPA, Stem Cell Research Enhancement Act, The CIRM and ongoing studies conducted by the likes of Dr. Davies, Dr. Keirstead, Dr. Kerr, the China-SCI Network and others.

I’m 62, and I plan on seeing my son walk again. I accept that curing SCI is a process. So, hold on, it’s going to be quite a ride.

Others thought that the Geron trial is opening doors for other companies and other trials. ChipS [26] pointed out:

I think all the pessimists are missing the big picture here. First off, this is a huge hurdle that has been overcome. The political tide is changing, and to have this trial announced on the heals of this transition will establish a new era of support for this type of work.

Next, this study involves only the limited lines of hESC that was developed prior to the 2001 ban. Given the promised policy change that will likely overturn that ban on fed funding for new lines, this could increase the possibilities of the effectiveness for more treatments in the very near future.

Now that this news has been plastered all over the internet and TV news, the public has been reminded that there are many people suffering from paralysis who are hoping for this trial to be a success. Publicity is an ally. We need to do our part to exploit this opportunity. Write letters to congress, local papers, ect…

Lastly, now that Geron has been given the green light and popped the FDA’s cherry on these types of trials, many more start-ups will be able to come to join the party. Suddenly, all is possible again. Geron took a huge gamble here. The fate of the company is riding on this. I am praying this is a success. This had to happen here. I suspect that other nations will soon follow suit as many labs will be collaborating internationally and sharing information in an attempt of cracking the next walnut, and gaining a foothold in this new and promising market.

Good things are coming folks. It may not be as soon as we want, but the flood gates are cracked and are opening more and more.

In summary, the first clinical trial of cells derived from human embryonic stem cells has been approved by the U.S. FDA and will soon start. It is not the trial that many hoped to see, i.e. a trial that will show that human embryonic stem cells cure spinal cord injury. Rather, it is a small trial to assess the safety and efficacy of transplanting oligodendroglial precursor cells derived from one of the first human embryonic stem cell lines isolated in 1997. The trial will test the cells in patients that are within 2 weeks after severe spinal cord injury. Its most likely outcome is to show that these cells can be safely transplanted to the spinal cord. If this trial is successful, it will lead to other trials. This is the first and an important step.

References

1. McDonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, Gottlieb DI and Choi DW (1999). Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 5: 1410-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10581084

2. Faulkner J and Keirstead HS (2005). Human embryonic stem cell-derived oligodendrocyte progenitors for the treatment of spinal cord injury. Transpl Immunol 15: 131-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16412957

3. Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K and Steward O (2005). Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 25: 4694-705. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15888645

4. Nistor GI, Totoiu MO, Haque N, Carpenter MK and Keirstead HS (2005). Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia 49: 385-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15538751

5. Totoiu MO and Keirstead HS (2005). Spinal cord injury is accompanied by chronic progressive demyelination. J Comp Neurol 486: 373-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15846782

6. Cloutier F, Siegenthaler MM, Nistor G and Keirstead HS (2006). Transplantation of human embryonic stem cell-derived oligodendrocyte progenitors into rat spinal cord injuries does not cause harm. Regen Med 1: 469-79. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17465839

7. Yang H, Lu P, McKay HM, Bernot T, Keirstead H, Steward O, Gage FH, Edgerton VR and Tuszynski MH (2006). Endogenous neurogenesis replaces oligodendrocytes and astrocytes after primate spinal cord injury. J Neurosci 26: 2157-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16495442

8. Siegenthaler MM, Tu MK and Keirstead HS (2007). The extent of myelin pathology differs following contusion and transection spinal cord injury. J Neurotrauma 24: 1631-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17970626

9. Siegenthaler MM, Ammon DL and Keirstead HS (2008). Myelin pathogenesis and functional deficits following SCI are age-associated. Exp Neurol 213: 363-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18644369

10. Zhang YW, Denham J and Thies RS (2006). Oligodendrocyte progenitor cells derived from human embryonic stem cells express neurotrophic factors. Stem Cells Dev 15: 943-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17253955

11. Okamura RM, Lebkowski J, Au M, Priest CA, Denham J and Majumdar AS (2007). Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells. J Neuroimmunol 192: 134-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17996308

12. Keim B (2007). The Company Who Cried Clinical Trial: Geron’s Unfulfilled Stem Cell Promises. blog.wired.com. http://blog.wired.com/wiredscience/2007/07/the-company-who.html

13. Puceat M and Ballis A (2007). Embryonic stem cells: from bench to bedside. Clin Pharmacol Ther 82: 337-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17637781

14. Hviid Nielsen T (2008). What happened to the stem cells? J Med Ethics 34: 852-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19043108

15. Anonymous (2008). FDA’s delay of Geron ESC trial raises concerns. {May 15, 2008. http://www.fiercebiotech.com/story/fda-s-delay-of-geron-esc-trial-raises-concerns/2008-05-15?utm_medium=rss&utm_source=rss&cmp-id=OTC-RSS-FB0

16. Smith A (2008). Human stem cell tests could be near. CNNMoney.com. http://money.cnn.com/2008/02/11/news/companies/geron/index.htm?postversion=2008021212

17. Anonymous (2009). Geron Receives FDA Clearance to Begin World’s First Human Clinical Trial of Embryonic Stem Cell-Based Therapy. Geron. http://www.geron.com/media/pressview.aspx?id=863

18. Anonymous (2009). Geron Corp. (GERN) Gains FDA Clearance to Begin World’s First Human Clinical Trial of Embryonic Stem Cell-Based Therapy. http://blogs.finditt.com/QualityStocks/Post.aspx?postID=32925

19. Coghlan A (2009). Historic trial to treat spinal injury with stem cells New Scientist http://www.newscientist.com/article/dn16475-historic-trial-to-treat-spinal-injury-with-stem-cells.html

20. Madrigal A (2009). FDA OKs First Human Trials of Embryonic Stem Cells Wired. January 23, 2009. http://blog.wired.com/wiredscience/2009/01/fda-approves-em.html

21. Pollack A (2009). F.D.A. Approves a Stem Cell Trial. New York Times. January 23, 2009. http://www.nytimes.com/2009/01/23/business/23stem.html?_r=1

22. Childs D and Bhatt J (2009). New Prez, New Studies: New Era for Stem Cells. {Jan. 26, 2009. http://abcnews.go.com/Health/President44/story?id=6727016&page=1

23. Carecure (2009). Geron. http://sci.rutgers.edu/. 27 January 2009. http://sci.rutgers.edu/forum/showthread.php?t=113884

24. Smith J (2009). Geron. Care Cure Community. 27 January 2009. http://sci.rutgers.edu/forum/showpost.php?p=990125&postcount=20

25. ChipS (2009). Geron. Care Cure Community. 27 December 2009. http://sci.rutgers.edu/forum/showpost.php?p=990160&postcount=21

Is There a Conspiracy to Stop the Cure?

January 24, 2009

Is There a Conspiracy to Stop the Cure?
by Wise Young PhD MD, W. M. Keck Center for Collaborative Neuroscience
Rutgers University, 604 Allison Road, Piscataway, NJ 08854-8082
posted 24 January 2009, last updated 25 January 2009

I was recently asked the following question on carecure:

Originally Posted by JWJR1970
Hello again Dr. I was wanting to ask you another question…it’s something that I’ve heard through the grapevine over the years since I’ve been injured. Hopefully you can debunk it. I’ve always heard that it’s taken this long for a cure and that “they” meaning all the pharmacuetical companies, medical equipment companies etc really don’t want a cure because there’s more money to be made if there’s not a cure. Is there any truth at all to that? Gosh I surely hope not. Well thanks again for your time! Take care! Jack

I had answered this question as follows:

The conspiracy theory that pharmaceutical companies are making so much money from spinal cord injury that they are obstructing or hiding the cure is wrong for the following reasons:
1. A cure for spinal cord injury would make them far more money than selling bandages, generic drugs such as baclofen.
2. Spinal cord injury doesn’t make any company all that much money. All the treatments for spinal cord injury are used in many conditions.
3. Many companies would love to have a cure for spinal cord injury. The problem is that they are not convinced that a cure is possible or worth the billion dollar investment they would have to make.

After thinking about the answer some more, I thought that I would expand the answer to try to put the question away once and for all. In the mid-1990’s, the internet web sites were rife with rumors that pharmaceutical companies were conspiring together to prevent the cure. In fact, some people claim that the cure had already been discovered but the companies were hiding them so that it would not take away profits that they are making from people with spinal cord injury. Like all such conspiracy theories, this comes from several false assumptions based on half-truths.

It is true that people with spinal cord injury use a lot of supplies and drugs, which some companies are profiting from. The average person with spinal cord injury probably spends $22,000 per year on drugs, supplies (catheters and other items), and durable equipment (wheelchairs, FES, and other equipment). Multiplied by 250,000, the estimated number of people that are severely disabled by spinal cord injury, this gives $5.5 billion. While not insubstantial, this market is spread out over many companies, none of whom make so much from spinal cord injury that they might be motivated to stop a curative therapy from occurring.

It is true that few companies are investing in developing curative therapies for spinal cord injury. However, companies are refraining from such investments not because they are afraid that such therapies would steal profit from their other products but because they do not believe that they can make a profit from such products.  Many companies believe that the spinal cord injury market is too small, that curative therapies for spinal cord will take too long and will cost too much to develop. If the potential market is 250,000 people, a 10% penetration into that market with $10,000 profit per person would add to only $250 million. This is not enough to warrant the average $1 billion cost of moving a therapy from discovery to market.

It is true that some wheelchair corporations will lose some business if many people with spinal cord injury no longer required wheelchairs. However, spinal cord injured people represent only a fraction of the wheelchair users, which includes people with multiple sclerosis, spina bifida, cerebral palsy, muscular dystrophy, stroke, amyotrophic lateral sclerosis, back pain, and many other problems. There is an estimated 1.6 million full-time wheelchair users in the United States [1], of which probably less than 15% have spinal cord injury.  So, the sudden loss of even all spinal cord injuries from the wheelchair market would be significant but not devastating for the industry.

It is true that some companies are having trouble getting spinal cord injury therapies into clinical trial.   For example, Geron [2] recently announced that they have received FDA approval for a phase 1 trial of oligodendroglial cell transplant to treat subacute spinal cord injury.  According to news reports, the company has spent four years and $45 million to get this therapy into clinical trial.   However, this is because it is the first human embryonic stem cell trial and it has been subject to extra scrutiny and criticism with consequent bureacratic and other delays.

It is true that Congress did not pass the Christopher and Dana Reeve Paralysis Act (CDRPA) to fund research to reverse paralysis.  The bill was obstructed for over four years in Congress despite the support of several prominent Republican legislators (such as Arlen Spector and Orin Hatch) who strongly supported both the stem cell and spinal cord injury research.  However, the CDRPA was blocked and prevented from coming to a vote.  Was there a conspiracy in Congress to stop spinal cord injury cure research? I don’t think so.  I think that it was just plain old politics.

In short, I do not believe that there is a conspiracy to stop the cure for spinal cord injury. We were simply unlucky in the last 8 years. The attack on 9/11/01 diverted the America’s resources and attention. Then we were hit by the worst finanical crisis since World War II.   We were victims of stem cell politics, first by George W. Bush when he decided to restrict federal funding of stem cell rsearch, then by a Republican Congress who refused to allow the bill to come to a vote, and then two vetoes by George W. Bush. Even the Christopher and Dana Reeve Paralysis Act became a political football that could not be passed until after Bush stepped down from office.

As Christopher Reeve once pointed out, he wouldn’t mind so much if scientists had told him that the cure was a scientifically intractable problem and that it would take many years to come up with a cure. What upset him was that scientists told him that it was doable but the problems were lack money and politics. Those were the last two obstacles he expected to slow down the cure for spinal cord injury. Money and politics are things that we can do something about. Unfortunately, we have just lost 8 years and we must move quickly to make up for the lost time.

References

1. http://www.jan.wvu.edu/media/Wheelchair.html
2. http://www.geron.com/

FAQ #4: What Can I Do Now to Be Ready for the Cure?

January 13, 2009

FAQ #4.  What Can I Do Now to Be Ready for the Cure?
By Wise Young, Ph.D., M.D., Rutgers University
W. M. Keck Center for Collaborative Neuroscience
604 Allison Road, Piscataway, NJ 08854-8082
Posted 11 January 2009, last updated 13 January 2009

The fourth most frequently asked question, usually asked after the questions if a cure is possible, when it will be available, and whether it would be applicable to chronic spinal cord injury, is what people can do to prepare for the cure.  Obviously, the first priority should be to take care of the body, to prevent muscle and bone atrophy, and other changes that prevent recovery of function.

Muscles undergo atrophy when they are not used.  Such atrophy is reversible.  Spasticity naturally prevents atrophy and therefore should not be over suppressed with drugs.  Standing will prevent atrophy of extensor anti-gravity muscles and will exercise balancing reflexes.  Stimulating muscles for certain functions, such as walking and standing, can rebuild muscles.

Bones also undergo atrophy when not used.  Until recently, no therapy had been shown to be effective for reversing bone loss after spinal cord injury. Recent studies suggest that the bisphosphonate alendronate restores bone mineral density but it is not clear that it increases bone strength and reduces fracture risk.   So, it seems reasonable to do both, i.e. weight bearing and alendronate.

It is also common sense to avoid irreversible surgery.  For example, tendon transfers, the Mitrofanoff procedure and bladder augmentation, colostomy, and sphincterotomy can significantly improve quality of life but may not be readily reversible.  People should recognize that the surgery may not be reversible.

What about locomotor training? Many studies suggest that weight-supported treadmill training can restore unassisted ambulation, even after severe incomplete spinal cord injury.  However, recent studies suggest that toverground walking may achieve similar results in people with incomplete spinal cord injuries.

Finally, what should we do about the brain?  Over half of the brain is devoted to input from and output to the spinal cord.  Non-use of neurons may cause atrophy or new connections in brain and spinal cord.  These connections are responsible for recovery, spasticity, spasms, and neuropathic pain.  Exercise, training, electrical stimulation, and pharmacological therapies can affect neural reorganization and function.

In the following sections, I will discuss some practical approaches to reversing atrophy of muscle and bone, some surgical therapies to avoid, the effects of locomotor training and spinal cord stimulation, the role of CNS reorganization, and the importance of education.  The goal is to provide a framework for how people can best prepare their bodies and central nervous system for recovery after spinal cord injury.

Reversing Muscle Atrophy

Immobilization causes muscle atrophy.  An immobilized leg will show measurable loss of muscle and bone calcium.  Spinal cord injury causes  muscle and bone losses in body parts innervated by spinal cord below the injury.  Muscle atrophy was recognized in the earliest descriptions of spinal cord injury [1].  Atrophy is most marked in patients with flaccid paraplegia resulting from lower thoracic or lumbar spinal cord injury [2].  Studies in rats revealed significant changes in muscles at 3, 7 and 30 days after spinal cord injury, similar to changes seen after denervation [3].  Scelsi, et al. [4] biopsied muscle from 22 paraplegic patients and found similar muscle degeneration.

Spasticity [5, 6] naturally prevents muscle atrophy.  In fact, I wonder if spasticity had not evolved as a mechanism to prevent atrophy.  In 1988, Robinson, et al. [7] showed that patients with greater spasticity had greater stimulated muscle responses and strength in their legs. While extensor spasms may interfere with transfers and flexor spasms at night may interfere with sleep [8], these activities are a form of free exercise and spasticity should not be completely suppressed with drugs.  High doses of anti-spasticity drugs, such baclofen given orally [9] or intrathecally, will reduce spasticity [10] and convert it to flaccidity [11].

Standing prevents atrophy of leg muscles. Standing is a reflex and balancing involves multiple reflexes [12].  When a person stands, pressure on the soles of the feet activates extensor muscles.  Of many approaches to rebuilding muscles [13], standing is the least costly and has extensively documented health benefits, including relief of skin pressure [14], reduction of constipation [15], improved bladder function, and better ability to straighten legs [16, 17]. Consumer pressure [18] for standing devices have led to availability of several standing wheelchairs [19] and many other standing devices.  People should utilize such devices to stand several hours every day if possible.

Functional electrical stimulation (FES) can reverse muscle atrophy.  Many devices are available, including those designed to build muscles for standing and walking [20-27], new walking orthoses [28, 29] and neuroprostheses [30-32], and treadmills for gait training [33].   FES of innervated will reverse atrophy [34].  Lower extremity functional electrical stimulation (FES) for pedaling a bicycle against variable resistance not only increases muscle endurance, speed, and strength but also increases aerobic metabolism and endurance [35, 36].  Upper limb FES can restore upper limb muscles[37, 38].  FES can also be used to assist gait [39] and will suppress spasticity as well to reduce the amount of anti-spasticity drugs [40].

High intensity stimulation is required to reverse atrophy of denervated muscles [41].  Surface FES stimulates nerves that enter and they activate the deeper musculature.  In denervated muscle, FES cannot stimulate nerves to activate deeper muscles and hence are ineffective.  Very high currents are required to penetrate into and activate deeper muscles.  However, care must be taken to use large electrode so that the currents are spread out over a large area of skin [42-47].  Such stimulation can restore even denervated muscles.

Reversing Osteoporosis

Bone loss occurs after spinal cord injury [48].  The most significant bone losses occur in the lower extremities [49, 50].  Biering-Sorenson, et al. [51] studied 6 men and 2 women with “complete” SCI for up to 53 months, comparing upper and lower extremity bone, finding that certain areas showed rapid loss but other, including the spine and femoral shaft continued to decline slowly as long as 4 years after injury.  Frotzler, et al. [52] used quantitative CT to measure bone loss and found that bone loss reached a plateau in 15 months.  The bone loss did not seem to be due to testicular hormonal levels [53].

Mechanical loading and FES-induced muscle activity reduces but does not prevent bone loss. Dudley-Javorski, et al. [54] reported their experience with one patient who performed nearly 8,000 electrically stimulated soleus muscle contractions per month in one leg, resulting in significant increases in soleus muscle torque and fatigue index of the stimulated side compared to the unstimulated control side.  Bone mass density (BMD) of the untrained leg declined by 14% during the first year but fell only 7% in the trained leg.  Shields, et al. [55] had earlier shown that FES significantly improved BMD in one leg compared to the other untrained leg.  Others [56] found no effect of FES on BMD.

The bisphosphonate alendronate [57] prevents bone loss in patients with acute spinal cord injury [58].  In 31 age- and gender-matched patients randomized to the drug or placebo, treated patients had an average of 5.3% whole body BMD and 17.6% difference in hip BMD, confirming an earlier Brazilian study [59] reporting that the drug increased bone calcium.  Sniger & Garshick [60] had reported that alendronate increases bone density in people with chronic spinal cord injury.  As early as 1999, Lyles [61] and Harris, et al. [62] were already recommending alendronate for vertebral compression fractures in older women.  Alendronate prevents the hypercalciuria after spinal cord injury [63].

Bone loss increases risk of lower extremity fractures [64] and hip instability is common in patients after spinal cord injury [65].  Increasing BMD alone may not increase strength and may make bone more brittle. Dionyssoiotis, et al. [66] studied tibial strength in 50 patients with acute and chronic spinal cord injury, comparing those that had T4-7 levels and those with T8-12 levels.  Bone strength declined significantly over time in the lower thoracic and not the upper thoracic injuries.  The authors suggested that neurogenic factors may be involved in bone loss.  Maimoun, et al. [67, 68] had concluded that neurological factors were more important than mechanical or hormonal factors.

In summary, bone loss is a serious unsolved problem in spinal cord injury.  Mechanical loading and FES-induced muscle activity will reduce but does not completely prevent bone loss in acute spinal cord injury.  The bisphophonate alendronate prevents bone loss in acute spinal cord injury and may even restore bone mineral density in chronic spinal cord injury but may not normalize bone strength.  However, a combination of mechanical loading, FES-induced muscle activity, and alendronate may be necessary to restore bone mineral density and bone strength in people with spinal cord injury.

Reversible Surgery

Surgical therapies are frequently done to improve function and to increase independence in people with spinal cord injury. These include tendon transfers for the hand, the Mitrofanoff procedure and bladder augmentation to facilitate bladder care, colostomy and sphincterotomy to reduce the time required for take care of the bowel and bladder. I will discuss some of these procedures from the viewpoint of their reversibility.   If the procedure will provide significant function, independence, or better quality of life now, people should make the decision in favor of what they need today and not wait for tomorrow.  However, they need to understand if the surgery is not easily reversible.

Tendon surgery.  Tendon transfers take part of a tendon from a muscle and transfer the power of that muscle to another that is weak.  It is useful for restoring tenodesis or ability to use fingers to oppose the thumb to pick things up and to feed oneself.  It can be used to restore the triceps, which locks the elbow and allows a person independence to transfer on their own.  Although tendon transfers are reversible in theory, I know of few occasions in which reversals were done.

Mitrofanoff procedure.  Originally developed for children with spina bifida and other conditions that compromise bladder function, this procedure uses the appendix as a conduit to the bladder through the umbilicus, allowing people to catheterize themselves through their belly button. For quadriplegic women, it is a boon because it allows them to catheterize themselves without having to take their clothes off and lying down.  The surgeon may sew a piece of intestine to the bladder wall, so that the bladder can no longer contract, allowing people to reduce anti-cholinergic drugs for bladder spasticity.  The procedure itself should be reversible since it does not interfere with the bladder sphincter at all.

Colostomy.  A colostomy is a procedure where the colon is connected to an opening in the abdominal wall, allowing feces to come out into a bag.  It is a blessing for many people who spend hours every morning doing their bowel routines and for people with fecal incontinence.  Depending on how the procedure is carried out, it can be either temporary or permanent.  Many people have had temporary colostomies that have been reversed.

Sphincterotomy.  Many men with paralyzed bladder opt for a sphincterotomy, i.e. cutting the bladder sphincter so that the urine drains through a condom catheter to a bag.  The surgery is simple and it saves work required for intermittent catheterization.  However, the sphincterotomies are probably difficult to reverse and seldom done in practice.

Of these procedures, the colostomy and Mitrofanoff should be reversible if the surgeon takes care to minimize tissue removal.  Tendon surgeries should also be reversible.  Sphincterotomies may be less reversible although they should be reparable in theory.  If the surgeon knows that there is wish for reversal of procedure, they can take precautions to preserve tissues that may be required for reversal of the procedure.  This is something that should be discussed with the surgeon.

Locomotor Training

Scientists have long known that it was possible to train animals with transected spinal cords to walk [69-71], that noradrenergic and serotonergic agonists facilitate walking [72, 73], and the mammalian lumbar spinal cord is capable of great plasticity [74] and even learning [75, 76], providing a rational basis for locomotor training in people with spinal cord injury [73].  Training cats with transected spinal cords for 30 minutes per day and 5 days a week improves their stepping ability [75, 77].  Muir & Steeves [78] showed that phasic cutaneous input facilitates locomotor recovery after incomplete spinal cord injuries in chick.  De Leon, et al. [79] showed that the animals maintained walking functions after training ended.  Kim, et al. [79] found that serotonin agonists enhanced locomotor recovery in rats that received neural transplants [80]. Although treadmill training did not affect locomotor recovery in rats after spinal contusion injury [81] and enriched environment alone facilitated walking recovery[82], many scientists speculated that treadmill training would improve locomotor function after spinal cord injury.

Treadmill training improves walking in humans after spinal cord injury.  Wernig & Muller [83] first reported in 1992 that treadmill training restored walking in people with chronic spinal cord injury. By 1995, Wernig, et al. [84] had trained 89 people, 44 of whom had chronic incomplete spinal cord injury.  The 44 subjects with chronic spinal cord injury trained for 3-20 weeks at 0.5 to 18 years after injury and 33 were unable to walk or stand unassisted before training.  By the end of training, 25 of the 33 (75%) initially wheelchair bound subjects could walk independently, 7 improved but still needed help, and one did not improve.  Only 6 of the 44 people could do staircase walking before the therapy but 34 were able to do so after training.  In 1998, Wernig, et al. [85] reported that 31 of 35 subjects maintained their locomotor improvement, 3 showed further improvement, and one lost function.

Dietz, et al. [75] similarly found in 1995 that treadmill training with body weight support modulated electromyographic activity in leg muscles, similar to healthy subjects, except that activity in the gastrocnemius (the main antigravity muscle during gait) was significantly lower.  Dobkin, et al. [86] studied the effects of weight-supported locomotor training on complete and incomplete subjects with spinal cord injury[86] and showed the sensory input associated with rhythmic locomotion can enhance the output of lumbosacral neural circuits and contribute to stepping activity.  Behrman & Harkema [87] showed that treadmill training improved ability of people to perform stepping and the training either achieved or improved overground walking.

Based on the above studies, the U.S. National Institutes of Health commissioned a multicenter study to assess treadmill locomotor training.  Dobkins, et al. [88] compared weight-supported treadmill and over-ground walking training after acute incomplete spinal cord injury.  In 146 subjects recruited at 6 regional centers within 8 weeks after injury, all had FIM-locomotor scores of <4 and were randomized to treadmill or overground training. At 6 months, both groups showed substantial improvement:  35% of ASIA B, 92% of ASIA C, and all of ASIA D subjects walked independently. There was no difference between the two treatments.

Spinal Cord Stimulation

Many scientists speculated that humans have a central pattern generator (CPG) for locomotion in the human spinal cord [89-91] and proposed the use of spinal cord stimulation to activate locomotion [92].  Hadi, et al. [93] showed that destruction of interneurons neurons in the L2  spinal cord produced lasting loss of walking ability in rats, suggesting that this is where the mammalian CPG may be located.  Ribotta, et al. [80] showed that transplantation of loecus coreulus cells to provide serotonergic innervation of L1-L2 spinal cord segment restored well-defined locomotor patterns in rats.  The serotonin agonist 8-OH-DPAT induces locomotor movements in low thoracic transected mice [94].  Yakovenko, et al [95] showed that intraspinal stimulation of spinal cords of transected rats significantly increased locomotor scores.

Dimitrijevic, et al. [96, 97] reported evidence of a spinal central pattern generator and showed that stimulation of this center improved gait in people after spinal cord injury.  The center can be readily stimulated with epidural electrodes placed over the L2 spinal cord [98, 99].  The stimulation initiates extension of lower limb [100] and can produce stepping-like movements [101] in subjects with complete spinal cord injury.  In both complete and incomplete spinal cord injury, reorganization of the spinal cord circuitry provides alternative mechanisms of locomotor and motor control [102, 103].  In 2007, Mianssian, et al. [104] found that human lumbar cord circuitry can be activated by extrinsic tonic input to generate locomotor-like activity.  Early application both FES and CPG stimulation may be helpful in preventing disuse atrophy of both muscle and neurons.

CPG stimulation helps locomotor training.  Barriere, et al. [105] pointed out the important role of the central pattern generator in the recovery of voluntary locomotion. Herman, et al. [106-108] has shown that epidural stimulation of the T10/T12 central pattern generator in humans facilitates walking recovery in people with chronic spinal cord injury, improving walking speed and endurance while reducing the sense of effort by the subject.  In particular, Carhart, et al. [107] described a patient with chronic incomplete tetraplegia in whom partial weight-bearing therapy alone was insufficient to achieve functional ambulation.  However, application of the T10/T12 stimulation not only produced further improvements in treadmill walking but facilitated transfer of these gains to overground walking.  The participant initially reported a reduction in the sense of effort for overground walking from 8/10 to 3/10 (Borg scale) and was able to double his walking speed to 0.35 m/sec and distance to 325 m.

Spinal cord stimulation facilitates walking not by directly activating neurons that control walking but by lowering the threshold to activate walking and to recruit additional muscles that may not be under voluntary control.  The stimulation not only increases the efficiency and speed of walking but reduces both perceived and actual effort required for walking, including metabolic energy utilization during walking [106].  Recent studies suggest that the electrodes don’t even have to be placed epidurally but can activate the spinal cord when placed on skin overlying the lumbar cord [104, 109]. Note that rhythmic auditory stimulation likewise has strong entrainment effects on gait cadence, velocity, and stride length in patients with incomplete spinal cord injury [110].

Plasticity

Over half of the brain is devoted to processing sensory and motor signals coming from or going to the spinal cord.  What happens to the parts of the brain that are longer receiving and no longer having a place to send commands to?  Early studies by Goldberger, et al. [111-114] had shown that local neurons sprout to fill in synaptic sites vacated by injured axons.  Depending on the source of the sprouting axons, the neuron may become suppressed or hyperexcitable.

Jain, et al. [115] found new brainstem connections in adult monkeys after dorsal column transection, where face afferents from the trigeminal would grow into the cuneate nucleus, expanding the face region into the hand region of the somatosensory cortex. Kaas, et al. [116] reported that damage to sensory afferents in the spinal dorsal columns render the corresponding parts of the primary somatosensory inactive to tactile stimulation and initiate maladaptive neuronal circuitry, including hyperalgesia [117].  If some dorsal column afferents are present, they will activate larger portions of the somatosensory cortex.

The corticospinal tract (that directly connects the cortex to spinal cord) reorganizes after spinal cord injury. Diffusion tensor imaging show progressive degeneration and sprouting of spared fibers in the corticospinal tract [118].  Corticospinal evoked potentials revealed enhanced pathways targeting muscles rostral (above) to the spinal injury [119] and stimulating remaining pathways produces exaggerated motor responses.  Hayes, et al. [120] used magnetic transcranial stimulation to reinforce reflexes in patients after spinal cord injury.

The spinal cord proximal to the injury site also reorganizes.  Functional MRI studies of rats after midthoracic spinal cord injuries show that small sensory stimuli that would not normally activate spinal cord also activate neurons in the dorsal horn of spinal cord below the injury site [121]. People show exaggerated startle responses in muscles proximal to the injury site [122].  Hand motor evoked potentials in people with chronic complete thoracic spinal have longer central conduction times [123].

The spinal cord below the injury site also changes.  Except for loss of motoneurons [124] and second lesions in the lower spinal cord [125, 126], circuits in spinal cord below the injury site often show increased recurrent inhibition after injury [127].   Konya, et al. [128] found proliferation of endogenous neural stem cells, increased immunoreactivity of serotonin and synaptophysin, and faster neurite growth/sprouting after anastomoses of functional nerves with distal nerves.  Peripheral nerve injury induces more reorganization of spinal circuits below the injury site [129].

The brain and spinal cord above and below the injury site are plastic and reorganize after injury, often in response to a variety of inputs.  Exercise and other activities in the brain and spinal cord are likely to affect both brain and spinal cord after injury, including spasticity and neuropathic pain. Much of the recovery of locomotor and other functions occur solely because of this reorganization and not regeneration [130].

Education

Many studies indicate that one of the best predictor of quality of life after spinal cord injury is education level.  According to Smith, et al. [131], higher levels of education were associated with lower odds of FMD (frequent mental distress), FDS (frequent depressive symptoms), and poor or fair health in U.S. veterans with spinal cord injury. More education in the United States is associated with greater Internet use and higher quality of life [132].  In Canada, individuals with more formal education had better quality of life [133].  Likewise, education predicts quality of life quotients in Europe [134-136].  But there are other reasons for education.

Understanding of the mechanisms and treatments of spinal cord injury is essential for informed decisions concerning therapies.  In the coming years, many therapies are likely to be claimed beneficial for spinal cord injury.  Not all the therapies will be appropriate for everybody.  People must become expert on spinal cord injury and treatments.  You will not only help yourself but also become a better advocate for the cure by understanding what is needed.  There is a lot of learn and the earlier that you start, the better it will be.

Learning the normal anatomy and physiology of the spinal cord is the first step.  It would be useful for people to know the dermatomes and segmental representation of the muscle, how signals are conducted in the spinal cord, and how different sensations are represented in spinal cord tracts.  In addition to helping people evaluate their own recovery, it will allow them to understand their doctors and communicate.

Understanding the pathophysiology of spinal cord injury is the second step.  For example, it would be helpful for people to understand the mechanisms of spasticity and neuropathic pain, what causes syringomyelia, and autonomic dysreflexia.  Most people have little idea of why spinal cord injury causes all these problems.

Knowing what must be accomplished to restore function is the third step.  For example, it is important to understand regeneration.  A common misconception is that spinal nerve fibers or axons are like wires and that all one has to do is to reconnect the wires.  Axons are living parts of neurons.  When axons are injured, the part that has been separated from the cell dies.  Regeneration means regrowing axons back to their original connection.

Keeping up with the latest advances regarding therapies for spinal cord injury is important because our understanding of treatments is moving so quickly.  Stem cells are only the latest wave and it is important to know what they can and cannot do.  The cells alone are unlikely to facilitate regeneration and replace neurons.  They need to be applied in combination with growth factors, growth inhibitor blockers, and other treatments, as well as repetitive exercise to reverse learned non-use.

Education is the best guarantor of the cure.  If you don’t know the normal anatomy and physiology, don’t understand the pathophysiology and what must be done to restore function, and are not up on the latest information concerning therapies, you depend on the knowledge and understanding of others.  You don’t have to know and understand it all but the more you know, the more likely you will make the best decision.

Summary and Conclusions

What should a person do now to be ready for the cure?  First, people should prevent and reverse atrophy of muscle and bone.  Second, they should avoid surgical procedures that are irreversible.  Third, locomotor training can restore ambulation, particularly after incomplete injuries.  Fourth spinal cord stimulation may help locomotor training.  Fifth, the brain and spinal cord reorganizes after injury.  Finally education is important, not only because academic achievement improves quality of life after spinal cord injury but people also need to understand their injury and the therapies to make informed decisions.

Spasticity prevents muscle atrophy.  It is free exercise and people should avoid taking so much anti-spasticity drugs that their muscles are flaccid.  Standing exercises reflexes responsible for weight bearing and balance.  Electrical stimulation (FES) can reverse atrophy.  Normally, surface stimulation depends on muscle innervation to activate deeper muscles.  Higher intensity stimulation is required to activate deeper muscles and reverse atrophy of denervated muscles.

Osteoporosis or bone loss occurs after spinal cord injury.  Bone loss occurs primarily in parts of the body that are paralyzed.  Reinstatement of mechanical stress on bone, i.e. standing, is often not sufficient to rebuild bone.  Recent clinical trials suggest that the bisphosphonate alendronate prevents bone calcium loss but it is unclear that this drug restores bone strength.  Mechanical loading and FES-induced muscle activity probably should be combined with mechanical stress to rebuild bone.

Certain surgical procedures improve quality of life.  For example, tendon transfer can restore hand or arm function while tendon lengthening can reduce need for anti-spasticity medication.  The Mitrofanoff procedure allows people to catheterize themselves through their belly button.  Combined with augmentation, it reduces need for drugs to prevent bladder spasms.  A colostomy or sphincterotomy may reduce time and effort needed for bowel and bladder routines.  However, people should understand that these procedures are not easily reversible and they should discuss this with their surgeons.

Locomotor training can be beneficial, even in people with severe incomplete injuries who have not walked for many years after spinal cord injury.  A recent clinical trial showed that treadmill and overground training have similar benefits, restoring unassisted ambulation in over 90% of people during the first year after incomplete spinal cord injury.  Walking is programmed into the spinal cord and few spinal axons are required to initiate walking.  Spinal cord stimulation can reduce effort, speeds up, and increases efficiency of walking.

The brain and spinal cord undergoes extensive reorganization after spinal cord injury.  Spasticity, spasms, and neuropathic pain are a result of reorganization.  Exercise and training may reduce or alter spasticity and neuropathic pain.  Finally, education is important not only because formal educational achievement is one of the best predictor of quality of life after spinal cord injury but people need to learn as much as possible about their condition and the treatments that may help them.

References Cited

  1. Clarke JAL and Jackson JH (1867).  On a case of muscular atrophy, with disease of the spinal cord and medulla oblongata.  Printed by J.E. Adlard, London,.  {pp
  2. Boltshauser E, Isler W, Bucher HU and Friderich H (1981).  Permanent flaccid paraplegia in children with thoracic spinal cord injury.  Paraplegia 19: 227-34.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7290732
  3. Carter JG, Sokoll MD and Gergis SD (1981).  Effect of spinal cord transection on neuromuscular function in the rat.  Anesthesiology 55: 542-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7294409
  4. Scelsi R, Marchetti C, Poggi P, Lotta S and Lommi G (1982).  Muscle fiber type morphology and distribution in paraplegic patients with traumatic cord lesion. Histochemical and ultrastructural aspects of rectus femoris muscle.  Acta Neuropathol (Berl) 57: 243-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7136501
  5. Little JW and Halar EM (1985).  H-reflex changes following spinal cord injury.  Arch Phys Med Rehabil 66: 19-22.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3966862
  6. Boorman G, Becker WJ, Morrice BL and Lee RG (1992).  Modulation of the soleus H-reflex during pedalling in normal humans and in patients with spinal spasticity.  J Neurol Neurosurg Psychiatry 55: 1150-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1479394
  7. Robinson CJ, Kett NA and Bolam JM (1988).  Spasticity in spinal cord injured patients: 2. Initial measures and long-term effects of surface electrical stimulation.  Arch Phys Med Rehabil 69: 862-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3263102
  8. Little JW, Micklesen P, Umlauf R and Britell C (1989).  Lower extremity manifestations of spasticity in chronic spinal cord injury.  Am J Phys Med Rehabil 68: 32-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2917056
  9. Hinderer SR, Lehmann JF, Price R, White O, deLateur BJ and Deitz J (1990).  Spasticity in spinal cord injured persons: quantitative effects of baclofen and placebo treatments.  Am J Phys Med Rehabil 69: 311-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2264951
  10. Kofler M, Donovan WH, Loubser PG and Beric A (1992).  Effects of intrathecal baclofen on lumbosacral and cortical somatosensory evoked potentials.  Neurology 42: 864-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1565243
  11. Macdonell RA, Talalla A, Swash M and Grundy D (1989).  Intrathecal baclofen and the H-reflex.  J Neurol Neurosurg Psychiatry 52: 1110-2.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2795085
  12. Taube W, Gruber M and Gollhofer A (2008).  Spinal and supraspinal adaptations associated with balance training and their functional relevance.  Acta Physiol (Oxf) 193: 101-16.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18346210
  13. Mehrholz J, Kugler J and Pohl M (2008).  Locomotor training for walking after spinal cord injury.  Cochrane Database Syst Rev CD006676.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18425962
  14. King RB, Porter SL and Vertiz KB (2008).  Preventive skin care beliefs of people with spinal cord injury.  Rehabil Nurs 33: 154-62.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18686908
  15. Hoenig H, Murphy T, Galbraith J and Zolkewitz M (2001).  Case study to evaluate a standing table for managing constipation.  SCI Nurs 18: 74-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12035465
  16. Dunn RB, Walter JS, Lucero Y, Weaver F, Langbein E, Fehr L, Johnson P and Riedy L (1998).  Follow-up assessment of standing mobility device users.  Assist Technol 10: 84-93.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10339284
  17. Walter JS, Sola PG, Sacks J, Lucero Y, Langbein E and Weaver F (1999).  Indications for a home standing program for individuals with spinal cord injury.  J Spinal Cord Med 22: 152-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10685379
  18. Brown-Triolo DL, Roach MJ, Nelson K and Triolo RJ (2002).  Consumer perspectives on mobility: implications for neuroprosthesis design.  J Rehabil Res Dev 39: 659-69.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17943668
  19. Harrow JJ, Malassigne P, Nelson AL, Jensen RP, Amato M and Palacios PL (2007).  Design and evaluation of a stand-up motorized prone cart.  J Spinal Cord Med 30: 50-61.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17385270
  20. Yarkony GM, Jaeger RJ, Roth E, Kralj AR and Quintern J (1990).  Functional neuromuscular stimulation for standing after spinal cord injury.  Arch Phys Med Rehabil 71: 201-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2317138
  21. Gallien P, Brissot R, Eyssette M, Tell L, Barat M, Wiart L and Petit H (1995).  Restoration of gait by functional electrical stimulation for spinal cord injured patients.  Paraplegia 33: 660-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8584301
  22. Moynahan M, Mullin C, Cohn J, Burns CA, Halden EE, Triolo RJ and Betz RR (1996).  Home use of a functional electrical stimulation system for standing and mobility in adolescents with spinal cord injury.  Arch Phys Med Rehabil 77: 1005-13.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8857878
  23. Graupe D and Kohn KH (1998).  Functional neuromuscular stimulator for short-distance ambulation by certain thoracic-level spinal-cord-injured paraplegics.  Surg Neurol 50: 202-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9736079
  24. Faghri PD, Yount JP, Pesce WJ, Seetharama S and Votto JJ (2001).  Circulatory hypokinesis and functional electric stimulation during standing in persons with spinal cord injury.  Arch Phys Med Rehabil 82: 1587-95.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11689980
  25. Jacobs PL, Johnson B and Mahoney ET (2003).  Physiologic responses to electrically assisted and frame-supported standing in persons with paraplegia.  J Spinal Cord Med 26: 384-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14992341
  26. Mushahwar VK, Jacobs PL, Normann RA, Triolo RJ and Kleitman N (2007).  New functional electrical stimulation approaches to standing and walking.  J Neural Eng 4: S181-97.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17873417
  27. Graupe D, Cerrel-Bazo H, Kern H and Carraro U (2008).  Walking performance, medical outcomes and patient training in FES of innervated muscles for ambulation by thoracic-level complete paraplegics.  Neurol Res 30: 123-30.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18397602
  28. Kent HO (1992).  Vannini-Rizzoli stabilizing orthosis (boot): preliminary report on a new ambulatory aid for spinal cord injury.  Arch Phys Med Rehabil 73: 302-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1543438
  29. Middleton JW, Yeo JD, Blanch L, Vare V, Peterson K and Brigden K (1997).  Clinical evaluation of a new orthosis, the ‘walkabout’, for restoration of functional standing and short distance mobility in spinal paralysed individuals.  Spinal Cord 35: 574-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9300961
  30. Agarwal S, Triolo RJ, Kobetic R, Miller M, Bieri C, Kukke S, Rohde L and Davis JA, Jr. (2003).  Long-term user perceptions of an implanted neuroprosthesis for exercise, standing, and transfers after spinal cord injury.  J Rehabil Res Dev 40: 241-52.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14582528
  31. Fisher LE, Miller ME, Nogan SJ, Davis JA, Anderson JS, Murray LM, Tyler DJ and Triolo RJ (2006).  Preliminary evaluation of a neural prosthesis for standing after spinal cord injury with four contact nerve-cuff electrodes for quadriceps stimulation.  Conf Proc IEEE Eng Med Biol Soc 1: 3592-5.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17947042
  32. Forrest GP, Smith TC, Triolo RJ, Gagnon JP, DiRisio D, Miller ME, Murray L, Davis JA and Iqbal A (2007).  Energy cost of the case Western reserve standing neuroprosthesis.  Arch Phys Med Rehabil 88: 1074-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17678672
  33. Dietz V (2008).  Body weight supported gait training: from laboratory to clinical setting.  Brain Res Bull 76: 459-63.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18534251
  34. Block JE, Steinbach LS, Friedlander AL, Steiger P, Ellis W, Morris JM and Genant HK (1989).  Electrically-stimulated muscle hypertrophy in paraplegia: assessment by quantitative CT.  J Comput Assist Tomogr 13: 852-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2789239
  35. Pollack SF, Axen K, Spielholz N, Levin N, Haas F and Ragnarsson KT (1989).  Aerobic training effects of electrically induced lower extremity exercises in spinal cord injured people.  Arch Phys Med Rehabil 70: 214-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2784311
  36. Arnold PB, McVey PP, Farrell WJ, Deurloo TM and Grasso AR (1992).  Functional electric stimulation: its efficacy and safety in improving pulmonary function and musculoskeletal fitness.  Arch Phys Med Rehabil 73: 665-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1622323
  37. Betz RR, Mulcahey MJ, Smith BT, Triolo RJ, Weiss AA, Moynahan M, Keith MW and Peckham PH (1992).  Bipolar latissimus dorsi transposition and functional neuromuscular stimulation to restore elbow flexion in an individual with C4 quadriplegia and C5 denervation.  J Am Paraplegia Soc 15: 220-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1431869
  38. Ditunno JF, Jr., Stover SL, Freed MM and Ahn JH (1992).  Motor recovery of the upper extremities in traumatic quadriplegia: a multicenter study.  Arch Phys Med Rehabil 73: 431-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1580769
  39. Granat M, Keating JF, Smith AC, Delargy M and Andrews BJ (1992).  The use of functional electrical stimulation to assist gait in patients with incomplete spinal cord injury.  Disabil Rehabil 14: 93-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1600188
  40. Ragnarsson KT (1992).  Functional electrical stimulation and suppression of spasticity following spinal cord injury.  Bull N Y Acad Med 68: 351-64.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1586870
  41. Kern H, Hofer C, Modlin M, Mayr W, Vindigni V, Zampieri S, Boncompagni S, Protasi F and Carraro U (2008).  Stable muscle atrophy in long-term paraplegics with complete upper motor neuron lesion from 3- to 20-year SCI.  Spinal Cord 46: 293-304.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17955034
  42. Kern H, Hofer C, Strohhofer M, Mayr W, Richter W and Stohr H (1999).  Standing up with denervated muscles in humans using functional electrical stimulation.  Artif Organs 23: 447-52.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10378940
  43. Kern H, Boncompagni S, Rossini K, Mayr W, Fano G, Zanin ME, Podhorska-Okolow M, Protasi F and Carraro U (2004).  Long-term denervation in humans causes degeneration of both contractile and excitation-contraction coupling apparatus, which is reversible by functional electrical stimulation (FES): a role for myofiber regeneration?  J Neuropathol Exp Neurol 63: 919-31.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15453091
  44. Carraro U, Rossini K, Mayr W and Kern H (2005).  Muscle fiber regeneration in human permanent lower motoneuron denervation: relevance to safety and effectiveness of FES-training, which induces muscle recovery in SCI subjects.  Artif Organs 29: 187-91.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15725214
  45. Hofer C, Forstner C, Modlin M, Jager H, Mayr W and Kern H (2005).  In vivo assessment of conduction velocity and refractory period of denervated muscle fibers.  Artif Organs 29: 436-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15926977
  46. Kern H, Rossini K, Carraro U, Mayr W, Vogelauer M, Hoellwarth U and Hofer C (2005).  Muscle biopsies show that FES of denervated muscles reverses human muscle degeneration from permanent spinal motoneuron lesion.  J Rehabil Res Dev 42: 43-53.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16195962
  47. Modlin M, Forstner C, Hofer C, Mayr W, Richter W, Carraro U, Protasi F and Kern H (2005).  Electrical stimulation of denervated muscles: first results of a clinical study.  Artif Organs 29: 203-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15725217
  48. Giangregorio L and McCartney N (2006).  Bone loss and muscle atrophy in spinal cord injury: epidemiology, fracture prediction, and rehabilitation strategies.  J Spinal Cord Med 29: 489-500.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17274487
  49. Garland DE, Adkins RH and Stewart CA (2008).  Five-year longitudinal bone evaluations in individuals with chronic complete spinal cord injury.  J Spinal Cord Med 31: 543-50.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19086712
  50. Reiter AL, Volk A, Vollmar J, Fromm B and Gerner HJ (2007).  Changes of basic bone turnover parameters in short-term and long-term patients with spinal cord injury.  Eur Spine J 16: 771-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16830131
  51. Biering-Sorensen F, Bohr HH and Schaadt OP (1990).  Longitudinal study of bone mineral content in the lumbar spine, the forearm and the lower extremities after spinal cord injury.  Eur J Clin Invest 20: 330-5.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2114994
  52. Frotzler A, Berger M, Knecht H and Eser P (2008).  Bone steady-state is established at reduced bone strength after spinal cord injury: a longitudinal study using peripheral quantitative computed tomography (pQCT).  Bone 43: 549-55.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18567554
  53. Maimoun L, Lumbroso S, Paris F, Couret I, Peruchon E, Rouays-Mabit E, Rossi M, Leroux JL and Sultan C (2006).  The role of androgens or growth factors in the bone resorption process in recent spinal cord injured patients: a cross-sectional study.  Spinal Cord  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16568142
  54. Dudley-Javoroski S and Shields RK (2008).  Dose Estimation and Surveillance of Mechanical Loading Interventions for Bone Loss After Spinal Cord Injury.  Phys Ther  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18202080
  55. Shields RK, Dudley-Javoroski S and Law LA (2006).  Electrically induced muscle contractions influence bone density decline after spinal cord injury.  Spine 31: 548-53.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16508550
  56. Clark JM, Jelbart M, Rischbieth H, Strayer J, Chatterton B, Schultz C and Marshall R (2007).  Physiological effects of lower extremity functional electrical stimulation in early spinal cord injury: lack of efficacy to prevent bone loss.  Spinal Cord 45: 78-85.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16636686
  57. Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC and Liberman UA (2004).  Ten years’ experience with alendronate for osteoporosis in postmenopausal women.  N Engl J Med 350: 1189-99.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15028823
  58. Gilchrist NL, Frampton CM, Acland RH, Nicholls MG, March RL, Maguire P, Heard A, Reilly P and Marshall K (2007).  Alendronate prevents bone loss in patients with acute spinal cord injury: a randomized, double-blind, placebo-controlled study.  J Clin Endocrinol Metab 92: 1385-90.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17227802
  59. Moran de Brito CM, Battistella LR, Saito ET and Sakamoto H (2005).  Effect of alendronate on bone mineral density in spinal cord injury patients: a pilot study.  Spinal Cord 43: 341-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15700052
  60. Sniger W and Garshick E (2002).  Alendronate increases bone density in chronic spinal cord injury: a case report.  Arch Phys Med Rehabil 83: 139-40.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11782844
  61. Lyles KW (1999).  Management of patients with vertebral compression fractures.  Pharmacotherapy 19: 21S-24S.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9915558
  62. Harris ST, Gertz BJ, Genant HK, Eyre DR, Survill TT, Ventura JN, DeBrock J, Ricerca E and Chesnut CH, 3rd (1993).  The effect of short term treatment with alendronate on vertebral density and biochemical markers of bone remodeling in early postmenopausal women.  J Clin Endocrinol Metab 76: 1399-406.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8501142
  63. Atalay A and Turhan N (2008).  Treatment of immobilization hypercalciuria using weekly alendronate in two quadriplegic patients.  Int Urol Nephrol 40: 259-61.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17934791
  64. Freehafer AA and Mast WA (1965).  Lower Extremity Fractures in Patients with Spinal-Cord Injury.  J Bone Joint Surg Am 47: 683-94.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14299662
  65. Rink P and Miller F (1990).  Hip instability in spinal cord injury patients.  J Pediatr Orthop 10: 583-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2394810
  66. Dionyssiotis Y, Trovas G, Galanos A, Raptou P, Papaioannou N, Papagelopoulos P, Petropoulou K and Lyritis GP (2007).  Bone loss and mechanical properties of tibia in spinal cord injured men.  J Musculoskelet Neuronal Interact 7: 62-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17396008
  67. Maimoun L, Fattal C, Micallef JP, Peruchon E and Rabischong P (2006).  Bone loss in spinal cord-injured patients: from physiopathology to therapy.  Spinal Cord 44: 203-10.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16158075
  68. Maimoun L, Couret I, Mariano-Goulart D, Dupuy AM, Micallef JP, Peruchon E, Ohanna F, Cristol JP, Rossi M and Leroux JL (2005).  Changes in osteoprotegerin/RANKL system, bone mineral density, and bone biochemicals markers in patients with recent spinal cord injury.  Calcif Tissue Int 76: 404-11.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15812577
  69. Smith JL, Edgerton VR, Eldred E and Zernicke RF (1983).  The chronic spinalized cat: a model for neuromuscular plasticity.  Birth Defects Orig Artic Ser 19: 357-73.
  70. Barbeau H and Rossignol S (1987).  Recovery of locomotion after chronic spinalization in the adult cat.  Brain Res 412: 84-95.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3607464
  71. Edgerton VR, Roy RR, Hodgson JA, Prober RJ, de Guzman CP and de Leon R (1992).  Potential of adult mammalian lumbosacral spinal cord to execute and acquire improved locomotion in the absence of supraspinal input.  J Neurotrauma 9 Suppl 1: S119-28.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1588602
  72. Barbeau H, Chau C and Rossignol S (1993).  Noradrenergic agonists and locomotor training affect locomotor recovery after cord transection in adult cats.  Brain Res Bull 30: 387-93.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8457888
  73. Barbeau H and Rossignol S (1994).  Enhancement of locomotor recovery following spinal cord injury.  Curr Opin Neurol 7: 517-24.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7866583
  74. Harkema SJ (2001).  Neural plasticity after human spinal cord injury: application of locomotor training to the rehabilitation of walking.  Neuroscientist 7: 455-68.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11597104
  75. Hodgson JA, Roy RR, de Leon R, Dobkin B and Edgerton VR (1994).  Can the mammalian lumbar spinal cord learn a motor task?  Med Sci Sports Exerc 26: 1491-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7869884
  76. Rossignol S (2000).  Locomotion and its recovery after spinal injury.  Curr Opin Neurobiol 10: 708-16.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11240279
  77. de Leon RD, Hodgson JA, Roy RR and Edgerton VR (1998).  Locomotor capacity attributable to step training versus spontaneous recovery after spinalization in adult cats.  J Neurophysiol 79: 1329-40.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9497414
  78. Muir GD and Steeves JD (1995).  Phasic cutaneous input facilitates locomotor recovery after incomplete spinal injury in the chick.  J Neurophysiol 74: 358-68.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7472337
  79. De Leon RD, Hodgson JA, Roy RR and Edgerton VR (1999).  Retention of hindlimb stepping ability in adult spinal cats after the cessation of step training.  J Neurophysiol 81: 85-94.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9914269
  80. Ribotta MG, Provencher J, Feraboli-Lohnherr D, Rossignol S, Privat A and Orsal D (2000).  Activation of locomotion in adult chronic spinal rats is achieved by transplantation of embryonic raphe cells reinnervating a precise lumbar level.  J Neurosci 20: 5144-52.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10864971
  81. Fouad K, Metz GA, Merkler D, Dietz V and Schwab ME (2000).  Treadmill training in incomplete spinal cord injured rats.  Behav Brain Res 115: 107-13.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10996413
  82. Inman CG (2001).  Long term effects of locomotor training in spinal humans.  J Neurol Neurosurg Psychiatry 71: 6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11413253
  83. Wernig A and Muller S (1992).  Laufband locomotion with body weight support improved walking in persons with severe spinal cord injuries.  Paraplegia 30: 229-38.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1625890
  84. Wernig A, Muller S, Nanassy A and Cagol E (1995).  Laufband therapy based on ‘rules of spinal locomotion’ is effective in spinal cord injured persons.  Eur J Neurosci 7: 823-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7620630
  85. Wernig A, Nanassy A and Muller S (1998).  Maintenance of locomotor abilities following Laufband (treadmill) therapy in para- and tetraplegic persons: follow-up studies.  Spinal Cord 36: 744-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9848480
  86. Dobkin BH, Harkema S, Requejo P and Edgerton VR (1995).  Modulation of locomotor-like EMG activity in subjects with complete and incomplete spinal cord injury.  J Neurol Rehabil 9: 183-90.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11539274
  87. Behrman AL and Harkema SJ (2000).  Locomotor training after human spinal cord injury: a series of case studies.  Phys Ther 80: 688-700.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10869131
  88. Dobkin B, Apple D, Barbeau H, Basso M, Behrman A, Deforge D, Ditunno J, Dudley G, Elashoff R, Fugate L, Harkema S, Saulino M and Scott M (2006).  Weight-supported treadmill vs over-ground training for walking after acute incomplete SCI.  Neurology 66: 484-93.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16505299
  89. Duysens J and Van de Crommert HW (1998).  Neural control of locomotion; The central pattern generator from cats to humans.  Gait Posture 7: 131-141.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10200383
  90. Van de Crommert HW, Mulder T and Duysens J (1998).  Neural control of locomotion: sensory control of the central pattern generator and its relation to treadmill training.  Gait Posture 7: 251-263.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10200392
  91. Grillner S, Ekeberg, El Manira A, Lansner A, Parker D, Tegner J and Wallen P (1998).  Intrinsic function of a neuronal network – a vertebrate central pattern generator.  Brain Res Brain Res Rev 26: 184-97.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9651523
  92. Barbeau H, McCrea DA, O’Donovan MJ, Rossignol S, Grill WM and Lemay MA (1999).  Tapping into spinal circuits to restore motor function.  Brain Res Brain Res Rev 30: 27-51.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10407124
  93. Hadi B, Zhang YP, Burke DA, Shields CB and Magnuson DS (2000).  Lasting paraplegia caused by loss of lumbar spinal cord interneurons in rats: no direct correlation with motor neuron loss.  J Neurosurg 93: 266-75.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11012058
  94. Landry ES, Lapointe NP, Rouillard C, Levesque D, Hedlund PB and Guertin PA (2006).  Contribution of spinal 5-HT1A and 5-HT7 receptors to locomotor-like movement induced by 8-OH-DPAT in spinal cord-transected mice.  Eur J Neurosci 24: 535-46.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16836640
  95. Yakovenko S, Kowalczewski J and Prochazka A (2007).  Intraspinal stimulation caudal to spinal cord transections in rats. Testing the propriospinal hypothesis.  J Neurophysiol 97: 2570-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17215510
  96. Dimitrijevic MR, Gerasimenko Y and Pinter MM (1998).  Evidence for a spinal central pattern generator in humans.  Ann N Y Acad Sci 860: 360-76.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9928325
  97. Pinter MM and Dimitrijevic MR (1999).  Gait after spinal cord injury and the central pattern generator for locomotion.  Spinal Cord 37: 531-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10455527
  98. Murg M, Binder H and Dimitrijevic MR (2000).  Epidural electric stimulation of posterior structures of the human lumbar spinal cord: 1. muscle twitches – a functional method to define the site of stimulation.  Spinal Cord 38: 394-402.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10962598
  99. Pinter MM, Gerstenbrand F and Dimitrijevic MR (2000).  Epidural electrical stimulation of posterior structures of the human lumbosacral cord: 3. Control Of spasticity.  Spinal Cord 38: 524-31.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11035472
  100. Jilge B, Minassian K, Rattay F, Pinter MM, Gerstenbrand F, Binder H and Dimitrijevic MR (2004).  Initiating extension of the lower limbs in subjects with complete spinal cord injury by epidural lumbar cord stimulation.  Exp Brain Res 154: 308-26.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14586532
  101. Minassian K, Jilge B, Rattay F, Pinter MM, Binder H, Gerstenbrand F and Dimitrijevic MR (2004).  Stepping-like movements in humans with complete spinal cord injury induced by epidural stimulation of the lumbar cord: electromyographic study of compound muscle action potentials.  Spinal Cord  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15124000
  102. Dimitrijevic MR, Persy I, Forstner C, Kern H and Dimitrijevic MM (2005).  Motor control in the human spinal cord.  Artif Organs 29: 216-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15725220
  103. Kern H, McKay WB, Dimitrijevic MM and Dimitrijevic MR (2005).  Motor control in the human spinal cord and the repair of cord function.  Curr Pharm Des 11: 1429-39.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15853673
  104. Minassian K, Persy I, Rattay F, Pinter MM, Kern H and Dimitrijevic MR (2007).  Human lumbar cord circuitries can be activated by extrinsic tonic input to generate locomotor-like activity.  Hum Mov Sci 26: 275-95.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17343947
  105. Barriere G, Leblond H, Provencher J and Rossignol S (2008).  Prominent role of the spinal central pattern generator in the recovery of locomotion after partial spinal cord injuries.  J Neurosci 28: 3976-87.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18400897
  106. Herman R, He J, D’Luzansky S, Willis W and Dilli S (2002).  Spinal cord stimulation facilitates functional walking in a chronic, incomplete spinal cord injured.  Spinal Cord 40: 65-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11926417
  107. Carhart MR, He J, Herman R, D’Luzansky S and Willis WT (2004).  Epidural spinal-cord stimulation facilitates recovery of functional walking following incomplete spinal-cord injury.  IEEE Trans Neural Syst Rehabil Eng 12: 32-42.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15068185
  108. Huang H, He J, Herman R and Carhart MR (2006).  Modulation effects of epidural spinal cord stimulation on muscle activities during walking.  IEEE Trans Neural Syst Rehabil Eng 14: 14-23.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16562627
  109. Hofstoetter US, Minassian K, Hofer C, Mayr W, Rattay F and Dimitrijevic MR (2008).  Modification of reflex responses to lumbar posterior root stimulation by motor tasks in healthy subjects.  Artif Organs 32: 644-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18782137
  110. de l’Etoile SK (2008).  The effect of rhythmic auditory stimulation on the gait parameters of patients with incomplete spinal cord injury: an exploratory pilot study.  Int J Rehabil Res 31: 155-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18467930
  111. Murray M and Goldberger ME (1974).  Restitution of function and collateral sprouting in the cat spinal cord: the partially hemisected animal.  J. Comp. Neurol. 158: 19-36.
  112. Goldberger ME and Murray M (1974).  Restitution of function and collateral sprouting in the cat spinal cord: The deafferented animal.  J. Comp. Neurol. 158: 37-54.
  113. Goldberger ME (1974).  Functional recovery after lesions of the nervous system. IV. Structural correlates of recovery in adult subjects. Recovery of function and collateral sprouting in cat spinal cord.  Neurosci Res Program Bull 12: 235-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=4846478
  114. Goldberger ME (1965).  The extrapyramidal systems of the spinal cord: Results of combined spinal and cortical lesions in the macaque.  J. Comp. Neurol. 124: 161-174.
  115. Jain N, Florence SL, Qi HX and Kaas JH (2000).  Growth of new brainstem connections in adult monkeys with massive sensory loss.  Proc Natl Acad Sci U S A 97: 5546-50.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10779564
  116. Kaas JH, Qi HX, Burish MJ, Gharbawie OA, Onifer SM and Massey JM (2008).  Cortical and subcortical plasticity in the brains of humans, primates, and rats after damage to sensory afferents in the dorsal columns of the spinal cord.  Exp Neurol 209: 407-16.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17692844
  117. Hoschouer EL, Yin FQ and Jakeman LB (2008).  L1 cell adhesion molecule is essential for the maintenance of hyperalgesia after spinal cord injury.  Exp Neurol  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19059398
  118. Guleria S, Gupta RK, Saksena S, Chandra A, Srivastava RN, Husain M, Rathore R and Narayana PA (2008).  Retrograde Wallerian degeneration of cranial corticospinal tracts in cervical spinal cord injury patients using diffusion tensor imaging.  J Neurosci Res 86: 2271-80.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18335542
  119. Topka H, Cohen LG, Cole RA and Hallett M (1991).  Reorganization of corticospinal pathways following spinal cord injury.  Neurology 41: 1276-83.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1866018
  120. Hayes KC, Allatt RD, Wolfe DL, Kasai T and Hsieh J (1992).  Reinforcement of subliminal flexion reflexes by transcranial magnetic stimulation of motor cortex in subjects with spinal cord injury.  Electroencephalogr Clin Neurophysiol 85: 102-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1373362
  121. Endo T, Spenger C, Westman E, Tominaga T and Olson L (2008).  Reorganization of sensory processing below the level of spinal cord injury as revealed by fMRI.  Exp Neurol 209: 155-60.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17988666
  122. Kumru H, Vidal J, Kofler M, Benito J, Garcia A and Valls-Sole J (2008).  Exaggerated auditory startle responses in patients with spinal cord injury.  J Neurol 255: 703-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18286318
  123. Han DS, Li CM and Chang CW (2008).  Reorganization of the cortico-spinal pathway in patients with chronic complete thoracic spinal cord injury: a study of motor evoked potentials.  J Rehabil Med 40: 208-12.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18292923
  124. Aisen ML, Brown W and Rubin M (1992).  Electrophysiologic changes in lumbar spinal cord after cervical cord injury.  Neurology 42: 623-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1549226
  125. Beric A and Light JK (1992).  Function of the conus medullaris and cauda equina in the early period following spinal cord injury and the relationship to recovery of detrusor function.  J Urol 148: 1845-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1433618
  126. Light JK and Beric A (1992).  Detrusor function in suprasacral spinal cord injuries.  J Urol 148: 355-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1635134
  127. Shefner JM, Berman SA, Sarkarati M and Young RR (1992).  Recurrent inhibition is increased in patients with spinal cord injury.  Neurology 42: 2162-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1436529
  128. Konya D, Liao WL, Choi H, Yu D, Woodard MC, Newton KM, King AM, Pamir NM, Black PM, Frontera WR, Sabharwal S and Teng YD (2008).  Functional recovery in T13-L1 hemisected rats resulting from peripheral nerve rerouting: role of central neuroplasticity.  Regen Med 3: 309-27.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18462055
  129. Wang LH, Lu YJ, Bao L and Zhang X (2007).  Peripheral nerve injury induces reorganization of galanin-containing afferents in the superficial dorsal horn of monkey spinal cord.  Eur J Neurosci 25: 1087-96.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17331205
  130. Courtine G, Song B, Roy RR, Zhong H, Herrmann JE, Ao Y, Qi J, Edgerton VR and Sofroniew MV (2008).  Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury.  Nat Med 14: 69-74.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18157143
  131. Smith BM, LaVela SL and Weaver FM (2008).  Health-related quality of life for veterans with spinal cord injury.  Spinal Cord 46: 507-12.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18256674
  132. Drainoni ML, Houlihan B, Williams S, Vedrani M, Esch D, Lee-Hood E and Weiner C (2004).  Patterns of Internet use by persons with spinal cord injuries and relationship to health-related quality of life.  Arch Phys Med Rehabil 85: 1872-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15520984
  133. Dvorak MF, Fisher CG, Hoekema J, Boyd M, Noonan V, Wing PC and Kwon BK (2005).  Factors predicting motor recovery and functional outcome after traumatic central cord syndrome: a long-term follow-up.  Spine 30: 2303-11.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16227894
  134. Holtslag HR, van Beeck EF, Lindeman E and Leenen LP (2007).  Determinants of long-term functional consequences after major trauma.  J Trauma 62: 919-27.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17426549
  135. Valtonen K, Karlsson AK, Alaranta H and Viikari-Juntura E (2006).  Work participation among persons with traumatic spinal cord injury and meningomyelocele1.  J Rehabil Med 38: 192-200.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16702087
  136. Meerding WJ, Looman CW, Essink-Bot ML, Toet H, Mulder S and van Beeck EF (2004).  Distribution and determinants of health and work status in a comprehensive population of injury patients.  J Trauma 56: 150-61.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14749582

FAQ #3: Will the Cure Be for Chronic Spinal Cord Injury?

January 3, 2009

FAQ #3: Will the Cure Be for Chronic Spinal Cord Injury?
By Wise Young, Ph.D., M.D., Rutgers University
W. M Keck Center for Collaborative Neuroscience
604 Allison Road, Piscataway, NJ 08854-8082

Will a cure work for chronic spinal cord injury?  Many people are anxious that all the treatments that they hear about seem to be aimed at acute spinal cord injury.  When they look at their bodies, they ask how any therapy can restore a body that has been paralyzed and senseless for years, in some cases decades.  How will therapy restore muscle and bone?   Not surprisingly, many people with chronic spinal cord injury think that the cure is for the newly injured and not for those with chronic spinal cord injury.

I believe there will be effective restorative therapies for chronic spinal cord injury for the following reasons. First, much animal and human data indicate that regeneration of relatively few axons can restore function such as walking, bladder function, and sexual function. This is because the spinal cord contains much of the circuitry necessary to execute and control these functions. Only 10% of the axons in the spinal cord are necessary and sufficient to restore locomotor and other functions.  Second, axons continue to try to regrow for many years after injury. Treatments that provide a path for growth, that negate factors that inhibit growth, and that provide long-term stimulation of axonal growth can restore function.  Third, many people recover function years after injury.  These observations give me hope that there will be therapies that will restore function in chronic spinal cord injury.

Most of my reasons for hope do not stem from animal studies of spinal cord injury but from many years of observing people with spinal cord injury.  People can and do recover after injury, often years afterwards.  I have seen people recover when their spinal cords have been decompressed or an arteriovenous malformation has been obliterated, often after years of paralysis and sensory loss.  Sometimes the recovery is rapid, suggesting that connections were present but suppressed.  Other times, the recovery occurs over weeks, suggestive of remyelination.  The recovery may take years, suggestive of regeneration.

Before discussing these reasons for hope, I want to first deal with several misapprehensions that many people seem have about their spinal cord injury.  Over the years, many people have expressed surprise when I have told them that the spinal cord below the injury site is alive and kicking.  They think that the spinal cord below the injury site is “dead”.  Another common belief is that it is not possible to restore atrophic muscle and bone that have become flaccid and osteoporotic.  Finally, there is a general notion that the spinal cord is far too complex for it to be reparable with a dash of cells, a squirt of growth factors, and a sprinkle of growth inhibitor blockers.   These concerns are understandable.

Common Misapprehensions about Spinal Cord Injury

Many people are anxious that the therapies will not work for chronic spinal cord injury. Some believe that the spinal cord below the injury site is “dead” and cannot be revived.  Other think that chronic spinal cord injury is associated with many changes of the body that cannot be reversed, including atrophy of muscle and bone.  Finally, most people are concerned that the spinal cord is too complex to be repaired by transplanting some cells, splashing on some growth factors, blocking a few axonal growth inhibitors, and exercising.  Let me address these concerns first.

Isn’t the spinal cord dead below the injury site?  Christopher Reeve asked me once why his legs move whenever his respirator filled his lungs with air.  Aren’t they supposed to be paralyzed?  I answered that Penelope is there waiting for Odysseus to come home, referring of course to the Greek myth where Penelope is Odysseus’ wife waiting for him to come home from a long journey.  Many suitors are knocking on her door.  Like the neurons in the spinal cord below the injury site, she is impatient for her husband’s return.  Spasticity and spasms are proof that the spinal cord is alive and kicking. People who have flaccid paralysis below the injury site may have had some damage to the spinal cord below the injury site.  However, this does not necessarily mean that the spinal cord is “dead”.  It does mean that there is insufficient excitability to cause spasticity and spasms.

Can we reverse nerve, muscle and bone atrophy?  It takes time and a lot of work but activity can and will reverse the bone and muscle loss.  For example, recent studies suggest that even completely denervated muscles can be restored with intense electrical stimulation.  Astronauts who stay for prolonged periods of time in microgravity lose bone just like people in spinal cord injury but bone will return as the person spends time weight bearing in normal gravity.  Finally, the central nervous system is like muscle and bone in that it also undergoes atrophy when it is not active.  Called “learned non-use”, the central nervous system “forgets” its function.  Much evidence suggests that learned “non-use” could be reversed by intensive repetitive exercise.

Isn’t the spinal cord is too complex to repair and restore?  How can we hope to restore millions of connections between the brain and spinal cord?  It turns out that the spinal cord is not only much simpler but is much capable and plastic than we had ever imagined.  Your brain doesn’t control muscles directly when you walk.  The brain simply turns on the walking program that resides in the spinal cord and then modulates it to go faster slower, to turn, to slow down, to turn, etc.  The central pattern generator (CPG) resides in the L2 spinal cord and controls walking.  One does not need many axons to initiate and control walking.  That is why both humans and animals can walk with only 10% of the nerve fibers in their spinal cord.

In summary, the spinal cord below the injury site is alive and often kicking.  Flaccidity simply means insufficient excitability.  Although it takes time and a lot of work, atrophy of nerves, muscles, and bone can be reversed.  The spinal cord can learn and possess programs for movements, including walking.  It doesn’t take a lot to turn the programs on and control them.  That is why people with 10% of their spinal cord can walk.

The Ten Percent Rule

Less than ten percent of the spinal cord is necessary and sufficient to support complex functions such as walking.  We know from animal studies that rats and cats can walk with less than 10% of the spinal tracts crossing an injury site [1].  This is true for humans as well.  In the 1980’s, I use to do evoked potential monitoring [2, 3] for Fred Epstein, a neurosurgeon who operated on spinal cord tumors of kids.  He would often cut open the spinal cord and remove the tumor, leaving behind spinal cord that is thin that it is almost transparent.  On the Upper East Side of New York, there used to be bagel store where some Chinese guy would cut lox that is so thin that you could almost see through it.  That was what the spinal cord of these kids looked like and yet they would walk out of the hospital.

How do people walk with so little spinal cord?  The brain doesn’t directly control the muscles used for walking.  The spinal cord does [4].  All the movements for walking a programmed into the spinal cord [5].  To start walking, the brain sends a message to the spinal cord to tell it to walk [6].  A center in the L2 spinal cord called the central pattern generator (CPG) initiates and coordinates the muscles responsible for walking [7, 8].  The CPG is of course why chickens can continue to run around after their heads have been cut off [9].  It is also the reason why we can sleepwalk at nights.  You don’t need much of your brain to walk.  In fact, it is possible to stimulate the lower spinal cord at L2 and activate walking and the CPG is under sensory control [10].

Herman, et al. [11-13] reported in 1999 that subthreshold stimulus (not strong enough to activate walking by itself) made it easier for people with spinal cord injury to initiate and control walking.  This is of interest for locomotor training.  Herman describes a person who is just a household walker after years of overground locomotor training, normally taking over 160 seconds to walk ten meters.  However, when the L2 stimulator was turned out, at a level that does not activate walking, the person is able to walk 10 meters in less than half the time.  The walking recruited more muscles and the gait was more efficient.  After several months of training with the stimulator, the person is now able to walk more than a km at normal speeds.  Energy studies indicate that the walking pattern is much more efficient when the stimulator has been turned on.

Humans evolved tremendous redundancy of the spinal cord because of spinal cord injury because regeneration takes too long.  At one mm a day, regeneration may take a year or more to restore function.  No animal can survive his long without being able to escape, hunt, and procreate.  Therefore, animals (and humans) have evolved redundant spinal cords.  Such redundancy provides a major survival advantage because spinal cord injury is relatively common.  For example, although there are over a million cases of cervical whiplash every year in the United States, less than 10,000 result in spinal cord injury requiring hospitalization.  By having a redundant spinal cord, humans could survive even after 90% of their spinal cord has been damaged.  This is why a football player can keep playing after having gotten a “stinger” and people with incomplete spinal cord injury, ever severe ones destroying 90% of the spinal cord, will recover walking.

Axons Keep Trying to Grow

The first thing that I was taught in neuroscience as a graduate student was that the central nervous system cannot regenerate.  But, if you look at the injured spinal cord, this is not true.  Axons in the spinal cord not only can and do grow but continue to try growing throughout adult life.  This may sound like heresy but science is really about overturning dogmas and the dogma that the spinal cord cannot regenerate has been toppled many times over the past 20 years.  The spinal cord not only can grow and does so routinely but it continues to try to grow many years after spinal cord injury.  Let me explain.

After an injury, the spinal axons that have been damaged “die-back” a short distance and then start regrowing towards the injury site.  In most cases, they stop at the edge of the injury site, although some axons apparently will invade into the injury site itself.  In the first detailed and systematic study of axon regrowth in contused spinal cords [14], we found axonal growth into the injury site of over 70% of contused rat spinal cords at 6 weeks after injury.  Most of the axons did not grow out of the injury site but they have clearly grown up to and into the spinal cord.   Many axons, however, stop at the injury and appear to be waiting.

Ramon y Cajal [15] first described these waiting axons.   They have enlarged bulbous endings that he called “sterile terminal bulbs”.  He thought that these were just axons that had been damaged and could not grow.  The problem is that you can find these at 2 week, 2 years, and even 20 years after injury.  My friend Richard Bunge [16] once showed me a slide of a human spinal cord 20 years after injury.  The spinal cord was from a woman who had died 20 years after injury.  At the injury edge, thousands of axons with their bulbous endings were present, as if they were waiting.  This amazed me. Were these axons just sitting there for 20 years?  That seemed highly unlikely.

The answer to this question did not come to me until I saw a talk once by Jerry Silver.  He was trying to get axons to grow in culture dishes.  To mimic the inhibitory growth environment of the spinal cord, he and his students had coated a cell culture with laminin (which supports axonal growth) and put a drop of solution containing chondroitin-6-sulfate-proteogylan or CSPG (which stops axonal growth).  As the drop of CSPG solution dried, it left a concentration gradient of CSPG that was lowest at the center of the drop zone and highest at the drop edge.  Jerry then placed a dorsal root ganglion in the center of the drop zone and took videos of the dorsal root ganglion axons growing.

When an axon grows, it forms a growth cone at the tip.  In its fast growth mode, the growth cone is like a spearhead.  However, as axons grow in a progressively growth inhibitory environment, the growth cones tend to spread out.  They eventually stop and become bulbous terminals.  In his useful insight way, Jerry called these “frustrated” growth cones.  When viewed in on video, one can see that axons start growing, becoming frustrated, and then falling back, repeatedly trying over and over again.  The fact that these terminal bulbs are present in spinal cord 20 years after injury tells me that there is continued regrowth in the spinal cord, probably for the entire life of the individual.  Even if it did not, there are probably ways to kickstart the growth again.

Give Them a Path and They will Take it All the Way

In the 1980’s, Sam David and Alberto Aguayo [17, 18] literally stood the non-regeneration dogma on its head when they hypothesized that spinal axons can grow but that there are growth inhibitors in the spinal cord that stops growth.  To test the hypothesis, they excised a peripheral nerve, one end into the cervical spinal cord and the other end into the lumbar spinal cord of a rat.  Spinal axons grew into the nerve inserted into the spinal cord (on both sides) and all the way to the other end.  However, they would not re-enter the spinal cord on the other side.

In 1999, I heard Thomas Carlstedt [19] of the Royal National Orthopedic Hospital at Stanmore speak about his work inserting avulsed brachial plexus nerves back into the spinal cord.  Brachial plexus injuries cause avulsion of the spinal root from the cord.  He would expose the spinal cord and insert the avulsed nerve back into the spinal cord.  Several months later, all the patients recovered some movement in their paralyzed arm.  In fact, some of these patients had “breathing arms” because their arms would move as they breathed, suggesting that the axons that normally activate breathing have entered into the peripheral nerve to the arms.  To me, this is proof that if you give spinal axons a path to grow, they will take it and go all the way.

Giorgio Brunelli, et al. [20] used peripheral nerves to bridge from the spinal cord above the injury site to muscles below the injury site.  He started by using a branch of the ulnar nerve that innervates the little finger side of the hand and moving the nerve to the sciatic nerve of the leg, to innervate the leg muscles.  He has done this to a number of people but moved from this procedure to doing a nerve bridge from above the spinal cord to muscles below the injury site [21]. Brunelli et al. [22, 23] have shown that glutamatergic spinal axons from the spinal cord innervate muscle.

Shaochen Zhang [24] has done thousands of peripheral nerve grafts above the injury site to muscles below the injury site, not only from arms to the legs but from neck to arms, from upper arm and shoulder nerves to the hand, and from intercostal nerves to the bladder and legs.  Xiao, et al. [25-30] has been diverting the L2 or L3 ventral root to reinnervate the pudendal nerve (S2), which innervates the bladder.  This procedure restores bladder function in close to 80% of patients.  Scratching the dermatome for L2 can initiate micturition (bladder voiding).  Many patients were able to produce a 3-foot stream of urine.  The procedure seems to work in spinal cord injury and spina bifida.

To me, the finding that spinal axons will grow into peripheral nerves and connect cells at the end is proof that they can regenerate and that all you have to do is give them a path and they will take it all the way.  They will make synapses with the cells that they find at the end, including muscles.  But, even more amazing was the finding somatic motor nerves from the lumbar cord will reinnervate and make the bladder function again.  This is amazing because micturition (the act of urination) is a complex act that involves bladder contraction and relaxation of the bladder sphincter and ability to stop when the bladder is empty.  For a somatic nerve to mediate this complex response is amazing.

Recovery is Possible in Chronic Spinal Cord Injury

Recovery is the rule and not the exception after spinal cord injury.  Since most people have incomplete spinal cord injury, a majority of people recover substantial function.  Even those with so-called “complete” spinal cord injuries usually recover 1 or more segments.  This may come as a surprise to most people who are used to being told that people do not recover after spinal cord injury. Spontaneous recovery from spinal cord injury provide several insights into the mechanisms [31].  First, recovery is often slow and may take years. Second, repetitive training facilitates and accelerates the recovery.  Third, absence of function does not necessarily mean that the structures are absent. These will be discussed in turn below.

Most people continue to recover some function years after the original injury.  For example, Christopher Reeve, who was certified by many doctors to have a so-called “complete” spinal cord injury and did not receive any experimental regenerative therapy, begin recovering sensory about 2 years after injury, to the point that he had light touch sensation over 75% of his body [32-35].  His anal area was so sensitive that they had to use lidocaine cream during bowel procedures.  At 6 years, his wife Dana noticed that Christopher could move his left index finger.  It turns out that he has quite good control on his left index finger.  Christopher also found that he could move his legs slightly.  The time frame and nature of this recovery is consistent with the possibility of spontaneous regeneration after spinal cord injury [36].

Repetitive training can restore function even in people who have not functioned for years after injury. When a particular function has not been used for a long period of time, atrophy is not limited to bone and muscle.  It appears also to occur in the central nervous system.  Called “learned non-use”, this remarkable phenomena can be mimicked by denervating an animal’s arm by cutting the dorsal root, and then allowing the subject to stop using the arm.  After several months, the arm become effectively paralyzed.  However, intensive and repetitive exercise can restore function, even many years after injury [37].  Constraint-induced movement therapy [38] is now used to treat multiple sclerosis [39], stroke [40], and many other conditions [41].   Locomotor training is a formed of forced-use exercise [42-45] that can and has been used to restore locomotor function in people, often many years after their spinal cord injury.

Finally, neurologists have long assumed that absence of function means loss of the structure mediating the function.  However, central nervous system function can be suppressed for years without loss of structure.  For example, treating an arteriovenous malformation (AVM) or decompressing the spinal cord can result in rapid recovery of function.  I use to monitor evoked potentials of patients undergoing surgical or radiological procedures [3, 46-48].  One of the patients was a paraplegic athlete with thoracic spinal cord AVM. Although paralyzed for nearly 7 years, he recovered rapidly after the embolization and walked out of the hospital after embolization. Such rapid functional recovery could not have been due to regeneration or remyelination.  It was due to removing a cause that had suppressed function for many years.

Summary and Conclusions

Many people are concerned that the cure for spinal cord injury will apply to newly injured people and not to people with chronic spinal cord injury.  While these concerns are legitimate, it is important to dispose several common misapprehensions. First, the spinal cord is not “dead” below the injury site.  Injury disconnects the lower spinal cord from the brain and upper spinal cord. Spasticity and spasms is proof that the lower spinal cord is alive and kicking.  Second, neural, muscle, and bone atrophy can be reversed even after years of loss.  Finally, the spinal cord contains programs for complex functions such as walking.  Those should be preserved and the goal is to reconnect enough axons to initiate and modulate these programs.

About 10% of spinal cord tracts is necessary and sufficient to support complex functions, including walking.  Humans, for example, can walk even after damage to 90% of the spinal cord because the brain does not directly control walking.  All the movements for walking, for example, are programmed in the spinal cord.  The brain sends a message to the central pattern generator (CPG) in the spinal cord, telling it to walk. The CPG is located in the L2 lumbar cord and can be stimulated to initiate or facilitate walking of people after spinal cord injury.  Humans evolved redundancy of the spinal cord because regeneration is too slow to help an animal to survive after spinal cord injury.

Axons continue to try to grow after injury.  At the injury site, they die back a short distance and grow back to the lesion edge.  In contusion injuries, some axons grow into the injury site but many stop at the lesion edge.  Ramon y Cajal described axons at the injury site with terminal bulbs.  These axons with bulbous endings were present in human spinal cords even 20 years after injury.  These terminal bulbs are “frustrated” axons that are still trying to grow at the injury site, due to growth inhibitors that collect in the extracellular matrix surrounding the injury site.

If you give axons a path to grow, they will take it and grow all the way.   David & Aguayo first showed this in the 1980’s by inserting peripheral nerves into the spinal cord and showing that many axons from the spinal cord would grow into the nerve and continue all the way to the other end.  Thomas Carlstedt used this method to treat patients with avulsed brachial plexus, showing that axons from the spinal cord not only grew in the nerve by innervated muscle.  Giorgio Brunelli likewise showed that the axons that grew into the peripheral nerves were spinal axons rather than motoneurons and that they form glutamatergic synapses.  Finally, Zhang and Xiao in China diverted nerves from various parts of the spinal cord to innervate and control organs that they normally do not.

Recovery is possible in chronic spinal cord injury.  A majority of people recover substantially after spinal cord injury, particularly those with incomplete spinal cord injuries.  Even people with so-called “complete” spinal cord injuries continue to recover some function, often years after injury. Christopher Reeve is an example.  Likewise, intensive repetitive training can reverse learned non-use, including restoration of locomotion in people who have not walked for many years after spinal cord injury.  Finally, certain conditions in the spinal cord can suppress function for years and removal of the causes can result in rapid restoration of function, within days.

References

  1. Blight AR (1983).  Cellular morphology of chronic spinal cord injury in the cat: analysis of myelinated axons by line-sampling.  Neuroscience 10: 521-43.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=6633870
  2. Young W (1982).  Correlation of somatosensory evoked potentials and neurological findings in clinical spinal cord injury.  In:  Early Management of Cervical Spinal Injury (ed. Tator CH).  Raven Press, New York.
  3. Young W, Cohen A, Merkin H, Fisher B, Berenstein A and Ransohoff J (1982).  Somatosensory evoked potential changes in spinal injury and during intraoperative spinal manipulation.  J Am Paraplegia Soc 5: 44-8.  http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=0007186014
  4. Grillner S, Ekeberg, El Manira A, Lansner A, Parker D, Tegner J and Wallen P (1998).  Intrinsic function of a neuronal network – a vertebrate central pattern generator.  Brain Res Brain Res Rev 26: 184-97.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9651523
  5. Dimitrijevic MR and Larsson LE (1981).  Neural control of gait: clinical neurophysiological aspects.  Applied Neurophysiology 44: 152-159.
  6. Duysens J and Van de Crommert HW (1998).  Neural control of locomotion; The central pattern generator from cats to humans.  Gait Posture 7: 131-141.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10200383
  7. Dimitrijevic MR, Gerasimenko Y and Pinter MM (1998).  Evidence for a spinal central pattern generator in humans.  Ann N Y Acad Sci 860: 360-76.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9928325
  8. Pinter MM and Dimitrijevic MR (1999).  Gait after spinal cord injury and the central pattern generator for locomotion.  Spinal Cord 37: 531-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10455527
  9. Sholomenko GN and Delaney KR (1998).  Restitution of functional neural connections in chick embryos assessed in vitro after spinal cord transection in Ovo.  Exp Neurol 154: 430-51.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9878180
  10. Van de Crommert HW, Mulder T and Duysens J (1998).  Neural control of locomotion: sensory control of the central pattern generator and its relation to treadmill training.  Gait Posture 7: 251-263.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10200392
  11. Herman R, He J, D’Luzansky S, Willis W and Dilli S (2002).  Spinal cord stimulation facilitates functional walking in a chronic, incomplete spinal cord injured.  Spinal Cord 40: 65-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11926417
  12. Carhart MR, He J, Herman R, D’Luzansky S and Willis WT (2004).  Epidural spinal-cord stimulation facilitates recovery of functional walking following incomplete spinal-cord injury.  IEEE Trans Neural Syst Rehabil Eng 12: 32-42.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15068185
  13. Huang H, He J, Herman R and Carhart MR (2006).  Modulation effects of epidural spinal cord stimulation on muscle activities during walking.  IEEE Trans Neural Syst Rehabil Eng 14: 14-23.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16562627
  14. Beattie MS, Bresnahan JC, Komon J, Tovar CA, Van Meter M, Anderson DK, Faden AI, Hsu CY, Noble LJ, Salzman S and Young W (1997).  Endogenous repair after spinal cord contusion injuries in the rat.  Exp Neurol 148: 453-63.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9417825
  15. Cajal SR (1906).  Notas preventivas sobre la degeneración y regeneración de las vías nerviosas centrales.  Trab. Lab. Invest. Biol., Univ. Madrid 4: 295-301.
  16. Bunge RP, Puckett WR and Hiester ED (1997).  Observations on the pathology of several types of human spinal cord injury, with emphasis on the astrocyte response to penetrating injuries.  Adv Neurol 72: 305-15.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8993707
  17. David S and Aguayo AJ (1981).  Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats.  Science 214: 931-3.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=6171034
  18. David S and Aguayo AJ (1985).  Axonal regeneration after crush injury of rat central nervous system fibres innervating peripheral nerve grafts.  J Neurocytol 14: 1-12.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=4009210
  19. Carlstedt T, Anand P, Htut M, Misra P and Svensson M (2004).  Restoration of hand function and so called “breathing arm” after intraspinal repair of C5-T1 brachial plexus avulsion injury. Case report.  Neurosurg Focus 16: E7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15174827
  20. von Wild KR and Brunelli GA (2003).  Restoration of locomotion in paraplegics with aid of autologous bypass grafts for direct neurotisation of muscles by upper motor neurons–the future: surgery of the spinal cord?  Acta Neurochir Suppl 87: 107-12.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14518535
  21. Brunelli G (2005).  Research on the possibility of overcoming traumatic paraplegia and its first clinical results.  Curr Pharm Des 11: 1421-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15853672
  22. Brunelli G, Spano P, Barlati S, Guarneri B, Barbon A, Bresciani R and Pizzi M (2005).  Glutamatergic reinnervation through peripheral nerve graft dictates assembly of glutamatergic synapses at rat skeletal muscle.  Proc Natl Acad Sci U S A 102: 8752-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15937120
  23. Pizzi M, Brunelli G, Barlati S and Spano P (2006).  Glutamatergic innervation of rat skeletal muscle by supraspinal neurons: a new paradigm in spinal cord injury repair.  Curr Opin Neurobiol 16: 323-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16723220
  24. Zhang S, Wang Y and Johnston L (2008).  Restoration of function in complete spinal cord injury using peripheral nerve rerouting: a summary of procedures.  Surg Technol Int 17: 287-91.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18802915
  25. Xiao CG (2006).  Reinnervation for neurogenic bladder: historic review and introduction of a somatic-autonomic reflex pathway procedure for patients with spinal cord injury or spina bifida.  Eur Urol 49: 22-8; discussion 28-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16314037
  26. Xiao CG, Du MX, Li B, Liu Z, Chen M, Chen ZH, Cheng P, Xue XN, Shapiro E and Lepor H (2005).  An artificial somatic-autonomic reflex pathway procedure for bladder control in children with spina bifida.  J Urol 173: 2112-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15879861
  27. Dai CF and Xiao CG (2005).  Electrophysiological monitoring and identification of neural roots during somatic-autonomic reflex pathway procedure for neurogenic bladder.  Chin J Traumatol 8: 74-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15769303
  28. Xiao CG, Du MX, Dai C, Li B, Nitti VW and de Groat WC (2003).  An artificial somatic-central nervous system-autonomic reflex pathway for controllable micturition after spinal cord injury: preliminary results in 15 patients.  J Urol 170: 1237-41.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14501733
  29. Xiao CG, de Groat WC, Godec CJ, Dai C and Xiao Q (1999).  “Skin-CNS-bladder” reflex pathway for micturition after spinal cord injury and its underlying mechanisms.  J Urol 162: 936-42.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10458412
  30. Xiao CG and Godec CJ (1994).  A possible new reflex pathway for micturition after spinal cord injury.  Paraplegia 32: 300-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8058346
  31. Dobkin BH (2003).  Do electrically stimulated sensory inputs and movements lead to long-term plasticity and rehabilitation gains?  Curr Opin Neurol 16: 685-91.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14624077
  32. Kluger J (1999).  Will Christopher Reeve walk again?  Time 154: 85.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10661927
  33. Hughes L (1998).  Christopher Reeve.  Dillon Press, Parsippany, N.J.  {pp
  34. Oleksy WG (2000).  Christopher Reeve.  Lucent, San Diego, CA.  {pp
  35. Shute N (2002).  A super feeling. Are there signs of hope in Christopher Reeve’s modest recovery?  US News World Rep 133: 58.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12360833
  36. Kluger J (2004).  He never gave up. What actor and activist Christopher Reeve taught scientists about the treatment of spinal-cord injury.  Time 164: 77.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15554547
  37. Morris DM and Taub E (2001).  Constraint-induced therapy approach to restoring function after neurological injury.  Top Stroke Rehabil 8: 16-30.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14523735
  38. Taub E and Morris DM (2001).  Constraint-induced movement therapy to enhance recovery after stroke.  Curr Atheroscler Rep 3: 279-86.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11389792
  39. Mark VW, Taub E, Bashir K, Uswatte G, Delgado A, Bowman MH, Bryson CC, McKay S and Cutter GR (2008).  Constraint-Induced Movement therapy can improve hemiparetic progressive multiple sclerosis. Preliminary findings.  Mult Scler 14: 992-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18573826
  40. Wolf SL, Winstein CJ, Miller JP, Thompson PA, Taub E, Uswatte G, Morris D, Blanton S, Nichols-Larsen D and Clark PC (2008).  Retention of upper limb function in stroke survivors who have received constraint-induced movement therapy: the EXCITE randomised trial.  Lancet Neurol 7: 33-40.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18077218
  41. Taub E, Uswatte G and Pidikiti R (1999).  Constraint-Induced Movement Therapy: a new family of techniques with broad application to physical rehabilitation–a clinical review.  J Rehabil Res Dev 36: 237-51.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10659807
  42. Wernig A, Nanassy A and Muller S (2000).  Laufband (LB) therapy in spinal cord lesioned persons.  Prog Brain Res 128: 89-97.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11105671
  43. Wernig A, Nanassy A and Muller S (1998).  Maintenance of locomotor abilities following Laufband (treadmill) therapy in para- and tetraplegic persons: follow-up studies.  Spinal Cord 36: 744-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9848480
  44. Wernig A, Muller S, Nanassy A and Cagol E (1995).  Laufband therapy based on ‘rules of spinal locomotion’ is effective in spinal cord injured persons.  Eur J Neurosci 7: 823-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7620630
  45. Wernig A and Muller S (1992).  Laufband locomotion with body weight support improved walking in persons with severe spinal cord injuries.  Paraplegia 30: 229-38.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1625890
  46. Berenstein A, Young W, Ransohoff J, Benjamen V and Merkin H (1984).  Somatosensory evoked potentials (SEP) during spinal angiography and therapeutic transvascular embolization.  J. Neurosurgery 60: 777-785.
  47. Young W and Berenstein A (1985).  Somatosensory evoked potential monitoring of intraoperative procedures.  In:  Spinal Cord Monitoring (ed. Schramm J and Jones SJ).  Springer-Verlag, Berlin.
  48. Young W and Berenstein A (1985).  Intraoperative monitoring with somatosensory evoked potentials.  In:  Spinal Cord Monitoring (ed. Schramm J and Jones SJ).

FAQ #2: When will the Cure be Available for Spinal Cord Injury?

January 1, 2009

FAQ #2: When will the Cure be Available for Spinal Cord Injury?
Wise Young, Ph.D., M.D., Rutgers University
W. M. Keck Center for Collaborative Neuroscience
604 Allison Rd, Piscataway, NJ 08854-8082
First posted 23 December 2008, final version 3 January 2009

Introduction

When will a cure for spinal cord injury be available?  This is the second most frequently asked question, usually asked right after the first most frequently asked question, “Will there be a cure for spinal cord injury?” While I don’t have a crystal ball for the future, some therapies are already beginning to restore function in people with spinal cord injury with spinal cord injury, several regenerative therapies have begun clinical trials, and the first combination therapies will soon go into clinical trial.  If we work hard, the resources are available, and we are lucky, we should expect the first restorative therapies within 5 years and perhaps the first curative combination therapies within a decade.

First generation therapies for spinal cord injury are already restoring some function to some people with spinal cord injury.  Methylprednisolone (MP) was the first therapy to show any beneficial effects when given after spinal cord injury.  MP improves motor and sensory recovery by about 20% compared to control.  A second therapy is Fampridine (4-aminopyridine), which is restoring function to some people with demyelination. The third therapy is locomotor training for people with “incomplete” spinal cord injuries.

Second generation therapies are now or will soon be in clinical trial.  These include cell transplants (olfactory ensheathing glia, Schwann cells, bone marrow stem cells, neural stem cells, oligodendroglial progenitor cells, embryonic stem cells), nogo and nogo receptor blockers, chondroitinase, growth factors, lithium, and many others. These therapies are likely to stimulate modest regeneration in the spinal cord and restore more function to more people.

Third generation therapies will be combination therapies that will bring substantially more function to most people, fulfilling the definition of what many people may call “cures” for spinal cord injury.  The optimal combination will probably differ depending on the individual.  The combination therapies should include not only therapies that regenerate spinal axons but also remyelination and neuronal replacement, including motoneurons.

What can we learn from these experiences?  I will describe below eight examples of therapies for spinal cord injury, i.e. methyprednisolone, locomotor training, fampridine, cethrin, nogo antibody, and human embryonic stem cells, bone marrow stem cells, and combination therapy with cord blood mononuclear cells and lithium.  I chose these treatments because each have undergone or are going through clinical trial.  I will describe the development of each of the therapies to date, the lessons from this experience, and the probability of the first restorative therapies and combination therapies.

Methylprednisolone (MP)

MP was the first therapy shown to be effective for acute spinal cord injury.  In the 1970’s, neurosurgeons were using high doses of the anti-inflammatory glucocorticoid drug methylprednisolone (MP) to treat arachnoiditis [1] and head injury [2].  Some clinicians wondered if MP would be effective for acute spinal cord injury [3, 4].  In 1979, ten spinal cord injury centers joined to do the first double blind randomized clinical trial of high-dose and low-dose MP for acute spinal cord injury.

The first National Acute Spinal Cord Injury Study (NASCIS 1) randomized 300 patients to 1000 mg/day or 100 mg/day of intravenous MP for 10 days starting within 24 hours after injury. The trial found no significant difference between the two doses of MP [5].  However, in 1982, animal studies showed that much higher doses (30 mg/kg) were required to inhibit lipid peroxidation [6] and that very early treatment was necessary for to reduce extracellular calcium entry into cells and to prevent post-traumatic ischemia [7].  The opiate receptor blocker naloxone was beneficial in animal models [8, 9] and a phase 2 trial [10].

The second National Acute Spinal Cord Injury Study (NASCIS 2) therefore randomized 487 patients to placebo, high-dose MP (30 mg/kg bolus followed by 5.4 mg/kg/hour over 24 hours), and naloxone (5.4 mg/kg + 3.0 mg/kg/hour over 24 hours).  Starting in 1985, the trial proposed to segregate patients by the median treatment time, which was 8 hours, assess the effects of treatment timing.  NASCIS 2 [11] showed that high-dose MP improved motor and sensory recovery compared to placebo when treatment started within 8 hours but not when started later than 8 hours [12].  Naloxone had intermediate effects between MP and placebo.  MP was not associated with significant morbidity or mortality. From 1991-1993, <50% of people with acute spinal cord injury in Colorado received MP [13] and physicians tended to give the drug to more severely injured patients.

The third National Acute Spinal Cord Injury Study (NASCIS 3) randomized 499 patients with acute spinal cord injury and treated all within 8 hours with a 30 mg/kg MP bolus, followed by 5.4 mg/kg/hour for 24 hours (MP24), MP given for 48 hours (MP48), or tirilazad mesylate (TM) 2.5 mg bolus given every 6 hours for 48 hours (TM48).  The median treatment time was 3 hours.  All three treatment groups had similar outcomes when started within 3 hours but MP48 was better than either MP24 or TM48 when given more than 3 hours after injury [14, 15].  The treatments were not associated with significant mortality or morbidity except for an increase in severe pneumonia after MP48.

The NASCIS group recommended MP24 when it could be started within 3 hours, MP48 between 3-8 hours, and no MP if it could not be started within 8 hours after injury. Several randomized trials [16-19] have confirmed beneficial effects and safety of MP use in human acute spinal cord injury and related conditions [20, 21].  However, one small randomized trial [22] and several retrospective studies [23-27] suggested MP may be ineffective. One study suggested that MP Retrospective studies are biased because clinicians tend to give MP to more severely injured patients.  Nevertheless, criticisms of NASCIS mounted [28-36].  Today, MP is an option and not a standard treatment of acute spinal cord injury in the United States.

Locomotor Training

Most doctors believe that recovery of walking is unlikely after spinal cord injury and thus few encourage their patients to walk after injury.  In 1992, Wernig & Muller [37] reported that intensive treadmill training restored unassisted walking to 8 patients, starting at 5-20 months after spinal cord injury.  By 1995, Wernig et al. [38] had studied 89 patients (44 chronic, 45 acute) with spinal cord injury.  Of 44 chronic patients trained for 3-20 weeks, 33 were initially wheelchair-bound and could not stand or walk.  After training, 25 (76%) of the 33 wheelchair-bound patients achieved unassisted walking.  Of 11 patients who were walking before training, all had better speed and endurance.  In a 1998 followup [39], at 6-72 months after training, 31 of 35 chronic patients who recovered unassisted walking maintained, three improved, and one stopped walking.  Of 41 initially acute spinal cord injuries, 15 improved and one stopped walking.

In 1998, the National Institutes of Health (NIH) commissioned a multicenter study to compare weight-supported treadmill and overground walking training in spinal cord injury.  The Spinal Cord Injury Locomotor Trial or SCILT [40] showed that <10% of patients with ASIA B, 92% of those with ASIA C, and 100% of ASIA D recovered walking at >0.8 meter/second and over 260 meters in 6 minutes.  An ASIA (American Spinal Injury Association) B classification refers to an injury that preserves only sensation below the injury site, including anal sensation.  ASIA C indicate injuries that preserve anal sensation or sphincter function and motor function below the injury site but less than half of ten key muscles have strength grades exceeding 3 of 5 (0=paralyzed, 1=slight, 2=definite, 3=anti-gravity, 4=against resistance, 5=normal).  ASIA D indicates injuries with 5 or more key muscles with strength grades of 3 or more.  SCILT indicated no difference between training with weight-supported treadmill and overground walking.

Although intensive training can restore locomotion in animals after even severe spinal cord injuries [41-45], the finding that >90% of people with incomplete spinal cord injury can recover unassisted walking even without treadmill training nonetheless took many clinicians by surprise.  Despite initial resistance, this finding is transforming rehabilitation of spinal cord injury.  Motor incomplete patients can walk.  Many investigators are now examining the effects of treadmill training patients with ASIA A (complete) or B (sensory incomplete).  Others are assessing other training approaches, in combination with functional electrical stimulation [46], serotonin receptor agonists [47], and other methods of increasing motor control [48].

In summary, early studies in the 1990’s reported that weight-supported treadmill training could restore unassisted locomotion to people with chronic spinal cord injury.  In 1998, the NIH funded SCILT to study weight-supported treadmill training of patients with incomplete spinal cord injuries.  The study surprisingly showed that >90% of motor incomplete patients recovered unassisted locomotion, whether they were trained by treadmill or overground walking, suggesting that most people who have preserved motor function after injury can recover locomotion if they worked on it.  Many investigators are examining various adjuncts to locomotor training.

Fampridine (4-AP)

Trauma, ischemia, and inflammation demyelinate the spinal cord. 4-aminopyridine (4-AP or fampridine) blocks potassium channels on demyelinated axons, improves conduction, and increases neurotransmitter release [49].  In 1981, Bostock, et al. [50] reported that 4-AP improves conduction in demyelinated axons and Zangger, et al. [51] showed that it also facilitates L-DOPA induced spinal locomotor rhythms in spinal-injured animals.  In 1986, Eliasson, et al. [52] showed that 4-AP restores conduction in heat-injured nerve and spinal roots in animals.  In 1987, Bowe, et al. [53] confirmed that 4-AP improves conduction in demyelinated axons and Blight & Gruner [54] found that 4-AP improved vestibulospinal free fall responses in spinal-injured cats.  In 1989, Blight et al. studied the effects of 4-AP in dogs [55] and proposed clinical trials of 4-AP in spinal cord injury.

In 1993, Hansebout, et al. [56] did the a double-blind, crossover trial of 4-AP in eight patients, finding the drug improved motor and sensory function.  Hayes, et al. [57] confirmed the 4-AP effects on function [58] and motor evoked potentials [59] in patients with spinal cord injury.  In 1997, Segal & Brunnemann [60] found that 4-AP improves pulmonary function in quadriplegic humans with chronic spinal cord injury [60].  In 1997, Acorda Therapeutics licensed the use patent for 4-AP treatment of spinal cord injury. In 1998, Potter, et al. [61] did a randomized crossover trial of a sustained release 4-AP (Fampridine SR) made by Elan.  In 1999, Acorda partnered with Elan to develop Fampridine SR, including preclinical studies [62, 63], studies to assess pharmacokinetics of intravenous [64], intrathecal [65], oral [66] 4AP in humans and animals [67].

In 2001, van der Bruggen, et al. [68] found that 4-AP (0.5 mg/kg) did not improve neurological function of 20 patients with chronic incomplete spinal cord injury.  However, 4-AP improved motor evoked potentials patients with chronic spinal cord injury [69] and Grijalva, et al. [70] randomized 27 patients to 4-AP or placebo, and found that 30 mg/day 4AP for 12 weeks improved neurological function in 69% compared to 46% on placebo. In 2004, Deforge, et al. [71] found no difference between 4-AP (40 mg/day) or placebo in 15 people who were walking after spinal cord injury.

From 2005 to 2007, after a phase 2 [72], more pharmacokinetics [73, 74] and safety trials [75], Acorda did two large randomized placebo-controlled phase 3 trials involving over 800 patients with chronic spinal cord injury to assess Fampridine SR effects on spasticity.  Both trials [not yet published] showed no significant difference between Fampridine SR and placebo.  However, Acorda also did two phase 3 clinical trials that showed that Fampridine SR significantly improves walking performance in multiple sclerosis (MS).

In summary, over a decade of clinical trials yielded promising and conflicting results concerning 4-AP effects on chronic spinal cord injury.  The trials surprisingly revealed that people with spinal cord injury are susceptible to placebo.  Over 40% of patients responded to placebo and perhaps half of the patients responded to 4-AP.  Until better outcome measures can be found, it may be better to choose a condition that is more responsive to 4-AP and go back later to demonstrate efficacy for spinal cord injury.

Nogo-A Antibody

In 1990, Schwab, et al. stunned the world with his study showing that IN-1, an antibody against an as-yet-unidentified myelin component [76], stimulates regeneration of rat corticospinal tract [77].  The first demonstration of a treatment that regenerates the spinal cord, the work convinced many neuroscientists that Aguayo and David [78-80] were right in their proposal that there is something about central myelin that stops axonal growth.  Unfortunately, the IN-1 antibody was promiscuous and bound to many proteins.  It took ten years before Schwab and his colleagues were able to isolate and clone the gene for the protein, now named Nogo [81-86].  With the purified protein finally available, Novartis licensed the patent for Nogo antibody treatment of spinal cord injury and embarked on an intensive program to develop the first regenerative therapy for spinal cord injury.

Many investigators tried different approaches to using the discovery of myelin-based growth inhibitory proteins to regenerate the spinal cord injury.  For example, Huang, et al. [87] reported that vaccinating mice with spinal cord may have induced antibodies that stimulated spinal cord regeneration, an approach that was later validated when the nogo protein itself was available to determine whether the vaccination induced the antibodies against nogo [88, 89].  If vaccination will induce antibodies that can stimulate spinal cord regeneration, this would be a very powerful approach indeed.

Novartis developed specific nogo-A antibodies that improve behavioral outcome and corticospinal plasticity in rats after experimental stroke [90], stimulated corticospinal regeneration in marmosets [91], increased plasticity in many different preparations [92-94].  After demonstrating that the antibodies penetrated into the spinal cord when infused intrathecally [95] and showing that the anti-Nogo-A antibody stimulated sprouting of corticospinal axons in macaque monkeys [96] and the treatment restores serotonin projections in rats after spinal cord injury [97], the Nogo-A antibody was taken to clinical trial in patients with chronic spinal cord injury.

The Novartis phase 1 trial of Nogo-A-antibody (ATI355) was recently completed.  The phase 1 trial (ClinicalTrials.gov identifier NCT00406016) was an open-label multicenter study to assess feasibility, safety, and tolerability of continuous infusing five doses of ATI355 intrathecally into patients starting 4-14 days after injury.  Paraplegic and ASIA A tetraplegic patients were included.  Tetraplegic patients who require artificial respiration could receive treatment as late as 60 days after injury, as soon as they were weaned off the respirator.  Patient with complete anatomical transection or obstruction of the spinal canal, multiple spinal cord lesions, cauda equina injury, brachial or lumbar plexus injury, significant head injury and systemic disease were excluded.  A phase 2 trial has started, indicating that the phase 1 trial has shown safety and feasibility.

In summary, the development of the Nogo antibody has taken nearly 2 decades since the initial discovery that that something in myelin inhibits spinal axonal regeneration.  The treatment has been validated in many laboratory studies and completed phase 1, indicating feasibility and safety.  Upcoming phase 2 trials will optimize the therapy and outcome measures, to be followed by pivotal phase 3 studies to show efficacy.

Cethrin

In 2001, Strittmatter et al. [98-107] described the receptor for Nogo.  The receptor, like many others that stop axonal growth and cellular migration, inhibits axonal growth by activating the intracellular messenger rho with rho kinase [108].  The Strittmatter laboratory identified a 66-amino acid fragment of Nogo that blocks the Nogo receptor [109-112] and other Nogo receptor blockers [113-124].  They even showed that MP and Nogo-66 have a synergistic effect on regeneration [125].  Working with Biogen, they subsequently found that the soluble Nogo receptor protein itself tightly bind molecules that inhibit axonal growth [123] and improves recovery after spinal cord contusion [126].

In the meantime, after studies of rho activation patterns in the spinal cord [127], Lisa McKerracher proposed [128] a new approach to target rho to stimulate repair and regeneration after spinal cord injury.  She used the bacterial toxin C3 to inhibit rho, modifying it so that it entered cells.  She formed the company Bioaxone to develop the drug.  The resulting cell-permeable recombinant protein BA-210 prevented secondary damage and promoted function recovery in spinal cord injury [129].  BA-210 or Cethrin subsequently went to phase 1 clinical trial [130, 131].  Bioaxone was recently bought be Alseres Pharmaceuticals (formerly Boston Life Sciences).

The Cethrin trial (ClinicalTrials.gov identifier NCT00500812) was a Phase I/IIa dose-ranging study to evaluate the safety, tolerability, and pharmacokinetics of BA-210 and the neurological status of patients following administration of a single extradural application of Cethrin during surgery for acute thoracic and cervical Spinal Cord Injury.  All the patients were ASIA A (complete).  Carried out from February 2005 to October 2008, the final data collection of the trial will be in June 2009.   The trial compared 0.3, 1, 6, and 9 mg of BA-210 applied to the dura surface of the injured spinal cord, during surgery that exposed the spinal cord for decompression.

Presentations of the Cethrin phase 1 trial results suggest possible beneficial effects of Cethrin in recovery after spinal cord injury [132].  Of 37 patients entered into the trial, they found no serious adverse side effects.  All the patients were ASIA A on admission.  The six-month patient data indicated that 28% of the patients (10 of 36) improved by one or more ASIA grades as compared to reported literature results of 6.7% [133].  Five of the patients improved to ASIA C and two improved to ASIA D.  One patient died form acute respiratory distress syndrome.

A phase 2 trial will start soon to evaluate the safety and efficacy of Cethrin in adult subjects with acute cervical spinal cord injury [134].   The trial is a randomized, double blind, placebo controlled study that will use mean ASIA motor score change as the primary outcome measure.  Six experimental groups will be compared:  placebo, 1 mg, 3 mg, 6 mg, 12 mg, and 18 mg Cethrin.  All the treatments will be applied epidurally during surgery exposing the spinal cord for decompressive or other purposes during the first several weeks after spinal cord injury.

Olfactory Ensheathing Glia (OEG)

The olfactory nerve is the only part in the central nervous system that continuously regenerates in adult mammals.  Its regenerative ability has been attributed to olfactory ensheathing glial (OEG) cells that are born in the nasal mucosa and migrate to the olfactory bulb.  Doucette [135] suggested that OEG cells would facilitate regeneration in other parts of the central nervous system, including the spinal cord.  In 1996, Smale, et al. [136] used OEG cells to repair transected fornix in the rat.  In 1997, Li, et al. [137] used OEG cells to repair adult rat corticospinal tract.  In 1998, Ramon-Cueto, et al. [138] reported that OEG transplants promoted regeneration in transected rat spinal cords.

In 2000, Barnett, et al. [139, 140] reported that human OEG cells can remyelinate axons.  Imaizumi, et al. [141, 142] used pig OEG cells to promote regeneration and remyelination in the spinal cord.  Ramon-Cueto, et al. [143, 144] reported functional regeneration in rats after spinal cord transection.  Many investigators enthused about the promise of OEG cells to bridge the gap in spinal cord injury [145-151].  One company (Alexion) grew OEG from genetically modified pigs as a substitute for human cells.

In 2001, Lu, et al. [152] reported that transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats.  Shortly thereafter, in Portugal, Lima, et al. [153] began transplanting nasal mucosa into patients with chronic spinal cord injury and reported recovery of motor scores, as well as light touch and pinprick scores.  In total he transplanted nasal mucosa to over 160 patients with chronic spinal cord injury.  Several places, including Osaka University Medical School [154], want to continue the study.

In Brisbane, MacKay-Sim, et al. [155] successfully cultivated olfactory ensheathing cells from the nasal mucosa of 3 patients with chronic spinal cord injury and transplanted the cells into their spinal cords,  Compared with 3 patients matched for injury severity and other characteristics, the transplanted patients showed no adverse effects of the transplants. However, they also did not show any significant functional change or neuropathic pain at 3 years after the transplant.

In the largest published series to date, Huang, et al. [156] transplanted OEG isolated from olfactory bulbs of aborted fetuses into 171 patients with chronic spinal cord injury.  The patients showed significant increases in sensory scores but only modest improvements in motor function.  Dobkin, et al. [157] criticized the study, claiming that there were unreported complications and five patients did not show improvements.  Huang has denied these criticisms and published further studies suggesting that OEG transplants are safe and efficacious [158, 159].  He has transplanted OEG into over 1200 patients to date.

In summary, the discovery that OEG cells facilitate regeneration in animal spinal cords excited clinicians. Carlos Lima in Portugal transplanted autologous nasal mucosa into over 160 patients with chronic spinal cord injury with modest results.  McKay-Sim in Brisbane cultured nasal mucosa OEG cells and transplanted them into 3 patients who had no significant beneficial effects after 3 year.  Huang Beijing transplanted fetal OEG cells into more than 700 patients and find that they consistently restore significant sensory.

Human Embryonic Stem (HES) Cells

The 1977 disovery by Thomson, et al. [160] that pluripotent human embryonic stem (HES) cells can be isolated and cultivated indefinitely transformed stem cell research. The first study reporting efficacy of embryonic stem cells for spinal cord injury appeared in 1999 [172].  While several other cell transplants have reported to be beneficial for spinal cord injury, i.e. marrow stromal cells [162], fetal neural stem cells [163], and other cells [164-171], people thought that the only way to get cells for transplantation was to collect them from fetuses, blood, or bone marrow. HES cells can produce many cell types for transplants, including neural stem cells, which in turn can produce neurons, astrocytes, microglia, and oligodendroglia [161].

Geron helped fund the early work leading to the first successful cultivation of HES cells.  Working with Keirstead at UC Irvine [173-177], Geron has concentrated their attention on treating spinal cord injury with oligodendroglial progenitor cells derived from human embryonic stem cells [178-180].  However, after many announcements of clinical trials since 2005 [181], the first phase 1 trial of HES cells has not yet been approved by the FDA.

Many people assumed that the delays are due to opposition by the Bush Administration to clinical trials of HES cells in the United States, including a May 2008 hold by the FDA [182].  Some scientists are concerned that the first clinical trial of HES must be very carefully designed.  As Evan Snyder of the Burnham Institute pointed out, “The last thing we need is another Jesse Gelsinger, referring to the 18-year-old man who died during a gene therapy trial at the University of Pennsylvania in 1999.  After Gelsinger’s death, the FDA closed down many gene-therapy trials for several years.  Because it is the first time that human embryonic stem cells are being transplanted into human, the trial will be under a microscope and any adverse effect will be emphasized [183].

In statements to the public [184], Geron CEO Thomas Okarma has suggested that the company plans to study 40 people with acute spinal cord injury.  The trial will focus on patients who are “complete” (ASIA A) and within the first two weeks after injury.  It is not clear whether and how much immunosuppression will be used.  Geron scientists have reported that oligodendroglial cells differentiated from HES cells are not targets of innate and adaptive human effectors cells and are resistant to lysis by Neu5Gc antibodies [179]. However, Keirstead has suggeted that long-term immunosuppression may be necessary.

In summary, human embryonic stem cells have been the object of much hope and controversy.  Due to their pluripotency, many regard the cells to be a promising source of cells for transplantation.  Geron is one of the first companies to fund research leading to the first successful cultivation of human embryonic stem cells a decade ago.  The cells have not yet reached clinical trial stage. Geron chose to focus on spinal cord injury in their first clinical trials.  However, since 2005, despite repeated announcements, the first phase 1 trials have not yet been approved by the FDA.  The trial will likely study 40 patients with subacute spinal cord injury with oligodendroglial cells differentiated from a human embryonic stem cell line.  A major question is immune rejection of the cells and whether immunosuppression will be used.

Combination Therapies

Combination therapies achieve greater axonal growth than individual therapies [185].  To regenerate the spinal cord, therapies must address the following obstacles to regeneration.

  • Bridging the injury site.  The spinal cord injury site does not support regenerating axons for several reasons.  The injury site is disorganized, filled with inflammatory cells, lacks cellular adhesion molecules to guide axonal growth, and may contain factors the inhibit axonal growth.  Many laboratories are consequently transplanting cells or placing biomaterials to provide a bridge for axonal growth across the injury site.
  • Sustained source of growth factors.  Axons grow slowly, less than a mm a day.  They must grow long distances, as much as a meter, to reach their original targets.  To do so, there must be a sustained source of growth factors. Several neurotrophins, including NGF, NT-3, and GDNF are critical growth factors.  One way is to infuse the factors but a better way may be to stimulate either endogenous or transplanted cells to secrete growth factors.
  • Blocking growth inhibitors. Several factors block axonal growth in the spinal cord.  The best defined is the myelin-based factor Nogo.  Other include extracellular glycoproteins such as CSPG.  The former can be blocked by anti-Nogo-A antibodies, Nogo receptor blockers, rho inhibitors, and even soluble nogo receptor protein.  The latter can be digested by enzymes, including chondroitinase.

Individual therapies are being tested in clinical trials. To test combination therapies, we must have clinical trial networks that can test therapies rigorously and efficiently.  We have set up a clinical trial network to test spinal cord injury therapies in China.  Called the China Spinal Cord Injury Network (ChinaSCINet), this network currently has 25 centers in Mainland China, Hong Kong, and Taiwan, capable of randomizing many thousands of subjects per year.

ChinaSCINet is carrying out the first clinical trials of combination therapies of spinal cord injury, i.e. umbilical cord blood mononuclear cells (UCBMC) and lithium.  Many laboratories have reported beneficial effects of UCBMC on spinal cord injury [165-168, 170, 171, 186-188].  In 2004, Yick, et al. [189] reported that lithium stimulates regeneration in rat spinal cord. Subsequently, Su, et al. [190] found that lithium stimulates proliferation of neural stem cells in the spinal cord and Dill, et al. [191] showed that lithium promotes axon regeneration and recovery in rat spinal cord injury.

Lithium stimulates UCBMC cells to secrete NGF, NT-3, and GNDF and we therefore propose to carry out studies of lithium and UCBMC cells individually, in combination, and then with axonal growth inhibitor blockers such as anti-nogo-A antibody, nogo receptor protein, cethrin, and chondroitinase. UCBMC and lithium are attractive first therapies for clinical trial since both have been extensively used in humans for many years.  If UCBMC are effective, many cord blood banks are available to supply the cells.  Lithium is very low cost and can be taken orally.

Lessons Learned

What lessons have we learned from the above therapies for spinal cord injury?   Three lessons are clear:

  • Slow and Tortuous Process. Few therapies go through the development gauntlet without major hitches. The average time for therapy development exceeded a decade for all therapies described above. For example, development of MP required 13 years (1977 to 1990) from first preclinical discovery to NASCIS 2.  Weight-supported treadmill locomotor training required 14 years (1991-2005).  Fampridine (1987-now) and  Nogo-A antibody (1990-now) both are likely to take over 20 years to develop. The development of Cethrin began in 2003 and may complete clinical trials before 2013. OEG (1997-now) and embryonic stem cells (1997-now) both have taken over a decade already.
  • Rigorous proof-of-concept of treatment efficacy is required for companies, government, or foundations to invest millions of dollars into development of a therapy. In the case of companies, intellectual property protection is also necessary.  A large part of the development time for most of the therapies resulted from a prolonged period of research to establish proof-of-concept.  In certain cases, e.g. MP and locomotor training, the clinical trials and proof-of-concept research in animals proceeded in parallel.  However, both fampridine and nogo antibody therapies went through 10 years of extensive preclinical studies before the drugs was licensed.
  • Clinical Trials are Inherently Risky. A single mistake in clinical trial design can set a program by five or more years.  It is important to have systematic preclinical data before starting clinical trials.  For example, NASCIS 1 compared a ten-day course of 1000 mg/day and 100 mg/day without sufficient animal to indicate the optimal dose or timing of therapy, wasting over 5 years.  A wrong choice of outcome measures, such as the choice of spasticity as the primary outcome of the Fampridine trials added over five years to the development of fampridine for spinal cord injury.  Neither OEG nor HES cells have undergone any controlled clinical trials.

The development times for spinal cord injury therapies may have been particularly long because all of the therapies are the first in their class.  For example, MP was the first neuroprotective drug, weight-supported locomotor training the first major restorative rehabilitation treatment, fampridine was the first conduction enhancing drug, nogo antibody and cethrin are the first regenerative therapies, and OEG and HES transplants are both first of their class. Trailblazing is inherently time-consuming.

Clinical trial networks should reduce treatment development times because much time and expense of clinical trials must be spent on recruiting and train clinical trial centers. Having clinical trial networks that are ready and able to test therapies will not only improve the quality of clinical trials but should speed up and defray costs significantly. This will encourage companies to invest in spinal cord injury therapies.

Probability

How soon can we expect curative therapies of spinal cord injury?  To date, most spinal cord injury therapies have taken 10-20 years to complete clinical trials.  Establishment of clinical trial networks  and increased interest of pharmaceutical companies in spinal cord injury therapies may shorten the development time.  However, until significant new funding becomes available for spinal cord injury clinical trials, the rate of progress in developing therapies is unlikely to change significantly.

Fortunately, we are not starting from scratch and several promising therapies are already in the clinical trial pipeline.  Six of the 8 therapies described above are in or soon will be in clinical trials.  If each therapy has a 50% chance of success, we would have to be rather unlucky for all the trials will fail. In the case of 6 trials, the probability of all six trials failing is 1 in 64.  Clearly, it behooves us to have as many clinical trials going in parallel as possible.  The reason is that if one trial is successful, everybody wins.

The likelihood that a given clinical trial will be successful of course depends on the therapy and the amount of data supporting that particular therapy and clinical trial design.  If one rushes into a clinical trial without much preclinical data, one has a much greater risk of failure.  Since we have limited clinical trial funds and facilities, it would also increase the likelihood of successful clinical trials by focusing on those therapies that have the most supporting data.

The first successful clinical trial that restores function to people with subacute or chronic spinal cord injury will increase enthusiasm and funding for more clinical trials.  If any of the six therapies listed above, or dozens of therapies that are awaiting clinical trials, were to succeed, I believe that companies will begin investing in spinal cord injury therapies.   The first therapy is always the most difficult to get funded and moving.  Many of the therapies would also be the first of their classes, i.e. the first regenerative therapy, the first cell transplant therapy, the first remyelinative therapy.

Two types of clinical trial failures are harmful to the spinal cord injury community, the investigators, and the sponsors.  The first and worst are false negative trials, i.e. a trial that falsely indicates that treatment is ineffective, are particularly deleterious. Such trials may be underpowered, i.e. a trial that does not have enough subjects to establish significance.  It may also happen if the wrong outcome measure is chosen.  The second are inconclusive trials.  Inconclusive trials may result from poor followup and high drop out rates.

Finally, it is important to note that clinical trials that show that a treatment is ineffective are not “failures”.  Showing that a therapy does not work is just as important as showing that a therapy works.  It stops the waste of further time and resources on that particular therapy.  Thus, for example, many people believe that umbilical cord blood cells are beneficial for spinal cord injury.  In fact, several overseas clinics are offering and charging for umbilical cord blood treatment of spinal cord injury as if they have already been proven to be effective.  A rigorously conducted clinical trial that shows it is ineffective will stop wasteful practices.

Summary and Conclusions

Many people frequently ask how long it will take for a cure of spinal cord injury to be available.  In the last two decades, about a dozen therapies have gone to clinical trial.  To illustrate the course of therapy development, I described 8 therapies that have been through or are going into clinical trials for spinal cord injury.

  1. High-dose methylprednisolone (MP) is the first spinal cord injury treatment to be tested in a placebo-controlled randomized clinical trial.
  2. Weight-supported locomotor training is the first rehabilitation therapy that has been shown to restore function after spinal cord injury.
  3. Fampridine (4AP) is the first therapy that improves conduction in demyelinated axons but has not yet been shown to be effective in spinal cord injury.
  4. Nogo antibody is the first therapy shown to regenerate the spinal cord of rats and is currently in phase 2 clinical trials.
  5. Cethrin is a membrane-permeable recombinant bacterial toxin C3 that blocks rho, improves recovery in animals and humans, and is in phase 2 clinical trial.
  6. Olfactory ensheathing glia (OEG)  have been transplanted to >1200 patients with chronic spinal cord injury but has not yet been tested in a controlled trial.
  7. Human embryonic stem (HES) cells have been announced for clinical trial by Geron since 2005 and is still awaiting approval by the U.S. FDA.
  8. Combination therapies.  The China Spinal Cord Injury Network is now testing umbilical cord blood mononuclear cells and lithium alone and in combination.

The history of spinal cord injury therapy development teaches us three important lessons.  First, therapy development is slow and tortuous, with each therapy taking 10 or more years. Second, rigorous proof of concept is required before companies, government, or foundations will invest millions into developing a therapy. Finally, clinical trials are inherently risky.  A single mistake in trial design may set a program back by many years.

Development of curative therapies for spinal cord injury will require large clinical trial networks to test combination therapies systematically.  To regrow large numbers of axons across the injury site, therapies need to bridge the injury site with cells that support growing axons, provide a long-term source of growth factors, and block growth inhibitors in the spinal cord, as well as replace cells. We know that each of these is possible.

The China Spinal Cord Injury Network is beginning clinical trials of the first combination therapy: umbilical cord blood mononuclear cells and lithium.  Several groups had reported that cord blood cells are beneficial in animal models of spinal cord injury. Lithium enhances regeneration in the spinal cord, stimulates proliferation of cord blood cells and neural stem cells, and increases the production of neurotrophic factors.  If this combination is effective, we will add growth inhibitor blockers.

So, how long will it take?  Fortunately, we are not starting from scratch.  Six of the eight therapies described above are already in or will soon be in clinical trials.  Other therapies are achieving proof-of-concept and should reach clinical trial soon.  Even if each of these trials has only a 50% chance of success, the odds ratio that at least one will succeed in the next few years is high.  The time needed to develop curative combination therapies depends on funding and availability of clinical trial network.

References

  1. Savastano AA (1968).  Intrathecal steroid administration in postoperative arachnoiditis.  R I Med J 51: 337-8 passim.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=5240622
  2. Itani AL and Ducker TB (1976).  Effect of high and low doses of steroids on head injuries.  Surg Forum 27: 478-80.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=828324
  3. Ducker TB and Hamit HF (1969).  Experimental treatments of acute spinal cord injury.  J Neurosurg 30: 693-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=5819293
  4. Tator CH (1972).  Acute spinal cord injury: a review of recent studies of treatment and pathophysiology.  Can Med Assoc J 107: 143-5 passim.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=4557525
  5. Bracken MB, Collins WF, Freeman DF, Shepard MJ, Wagner FW, Silten RM, Hellenbrand KG, Ransohoff J, Hunt WE, Perot PL, Jr. and et al. (1984).  Efficacy of methylprednisolone in acute spinal cord injury.  Jama 251: 45-52.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=6361287
  6. Hall ED and Braughler JM (1982).  Effects of intravenous methylprednisolone on spinal cord lipid peroxidation and Na+ + K+)-ATPase activity. Dose-response analysis during 1st hour after contusion injury in the cat.  J Neurosurg 57: 247-53.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=6283042
  7. Young W and Flamm ES (1982).  Effect of high-dose corticosteroid therapy on blood flow, evoked potentials, and extracellular calcium in experimental spinal injury.  J Neurosurg 57: 667-73.  http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=0007131067
  8. Faden AI, Jacobs TP and Holaday JW (1981).  Opiate antagonist improves neurologic recovery after spinal injury.  Science 211: 493-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7455690
  9. Young W, Flamm ES, Demopoulos HB, Tomasula JJ and DeCrescito V (1981).  Effect of naloxone on posttraumatic ischemia in experimental spinal contusion.  J Neurosurg 55: 209-19.  http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=0007252544
  10. Flamm ES, Young W, Demopoulos HB, DeCrescito V and Tomasula JJ (1982).  Experimental spinal cord injury: treatment with naloxone.  Neurosurgery 10: 227-31.  http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=0007070619
  11. Bracken MB, Shepard MJ, Collins WF, Holford TR, Young W, Baskin DS, Eisenberg HM, Flamm E, Leo-Summers L, Maroon J and et al. (1990).  A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study.  N Engl J Med 322: 1405-11.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2278545
  12. Bracken MB and Holford TR (1993).  Effects of timing of methylprednisolone or naloxone administration on recovery of segmental and long-tract neurological function in NASCIS 2.  J Neurosurg 79: 500-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8410217
  13. Gerhart KA, Johnson RL, Menconi J, Hoffman RE and Lammertse DP (1995).  Utilization and effectiveness of methylprednisolone in a population-based sample of spinal cord injured persons.  Paraplegia 33: 316-21.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7644256
  14. Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings M, Herr DL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot PL, Jr., Piepmeier J, Sonntag VK, Wagner F, Wilberger JE, Winn HR and Young W (1997).  Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study.  Jama 277: 1597-604.  http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=0009168289
  15. Bracken MB and Holford TR (2002).  Neurological and functional status 1 year after acute spinal cord injury: estimates of functional recovery in National Acute Spinal Cord Injury Study II from results modeled in National Acute Spinal Cord Injury Study III.  J Neurosurg 96: 259-66.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11990832
  16. Otani K, Abe H, Kadoya S, Nakagawa H, Ikata T and Tominaga S (1996).  Beneficial effect of methylprednisolone sodium succinate in the treatment of acute spinal cord injury.  Sekitsui Sekuzui J. 7: 633-47.
  17. Sun T, Xu S and Huang H (1997).  [High-methylprednisolone treatment in acute cervical spinal cord injury without fracture and dislocation].  Zhonghua Wai Ke Za Zhi 35: 735-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10677995
  18. Pettersson K and Toolanen G (1998).  High-dose methylprednisolone prevents extensive sick leave after whiplash injury. A prospective, randomized, double-blind study.  Spine 23: 984-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9589535
  19. Bracken MB (2001).  Methylprednisolone and acute spinal cord injury: an update of the randomized evidence.  Spine 26: S47-54.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11805609
  20. Araujo AQ, Afonso CR, Leite AC and Dultra SV (1993).  Intravenous methylprednisolone in HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP).  Arq Neuropsiquiatr 51: 325-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8297234
  21. Defresne P, Meyer L, Tardieu M, Scalais E, Nuttin C, De Bont B, Loftus G, Landrieu P, Kadhim H and Sebire G (2001).  Efficacy of high dose steroid therapy in children with severe acute transverse myelitis.  J Neurol Neurosurg Psychiatry 71: 272-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11459911
  22. Pointillart V, Petitjean ME, Wiart L, Vital JM, Lassie P, Thicoipe M and Dabadie P (2000).  Pharmacological therapy of spinal cord injury during the acute phase.  Spinal Cord 38: 71-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10762178
  23. Galandiuk S, Raque G, Appel S and Polk HC, Jr. (1993).  The two-edged sword of large-dose steroids for spinal cord trauma.  Ann Surg 218: 419-25; discussion 425-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8215634
  24. Prendergast MR, Saxe JM, Ledgerwood AM, Lucas CE and Lucas WF (1994).  Massive steroids do not reduce the zone of injury after penetrating spinal cord injury.  J Trauma 37: 576-9; discussion 579-80.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7932887
  25. George ER, Scholten DJ, Buechler CM, Jordan-Tibbs J, Mattice C and Albrecht RM (1995).  Failure of methylprednisolone to improve the outcome of spinal cord injuries.  Am Surg 61: 659-63; discussion 663-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7618802
  26. Levy ML, Gans W, Wijesinghe HS, SooHoo WE, Adkins RH and Stillerman CB (1996).  Use of methylprednisolone as an adjunct in the management of patients with penetrating spinal cord injury: outcome analysis.  Neurosurgery 39: 1141-8; discussion 1148-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8938768
  27. Heary RF, Vaccaro AR, Mesa JJ, Northrup BE, Albert TJ, Balderston RA and Cotler JM (1997).  Steroids and gunshot wounds to the spine.  Neurosurgery 41: 576-83; discussion 583-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9310974
  28. Nesathurai S (1998).  Steroids and spinal cord injury: revisiting the NASCIS 2 and NASCIS 3 trials.  J Trauma 45: 1088-93.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9867054
  29. Coleman WP, Benzel D, Cahill DW, Ducker T, Geisler F, Green B, Gropper MR, Goffin J, Madsen PW, 3rd, Maiman DJ, Ondra SL, Rosner M, Sasso RC, Trost GR and Zeidman S (2000).  A critical appraisal of the reporting of the National Acute Spinal Cord Injury Studies (II and III) of methylprednisolone in acute spinal cord injury.  J Spinal Disord 13: 185-99.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10872756
  30. Hurlbert RJ (2000).  Methylprednisolone for acute spinal cord injury: an inappropriate standard of care.  J Neurosurg 93: 1-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10879751
  31. Short DJ, El Masry WS and Jones PW (2000).  High dose methylprednisolone in the management of acute spinal cord injury – a systematic review from a clinical perspective.  Spinal Cord 38: 273-86.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10822400
  32. Geisler FH, Coleman WP, Grieco G and Poonian D (2001).  Measurements and recovery patterns in a multicenter study of acute spinal cord injury.  Spine 26: S68-86.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11805613
  33. Hurlbert RJ (2001).  The role of steroids in acute spinal cord injury: an evidence-based analysis.  Spine 26: S39-46.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11805608
  34. Citerio G, Cormio M and Sganzerla EP (2002).  [Steroids in acute spinal cord injury. An unproven standard of care].  Minerva Anestesiol 68: 315-20.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12029237
  35. Hugenholtz H, Cass DE, Dvorak MF, Fewer DH, Fox RJ, Izukawa DM, Lexchin J, Tuli S, Bharatwal N and Short C (2002).  High-dose methylprednisolone for acute closed spinal cord injury–only a treatment option.  Can J Neurol Sci 29: 227-35.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12195611
  36. Hurlbert RJ and Moulton R (2002).  Why do you prescribe methylprednisolone for acute spinal cord injury? A Canadian perspective and a position statement.  Can J Neurol Sci 29: 236-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12195612
  37. Wernig A and Muller S (1992).  Laufband locomotion with body weight support improved walking in persons with severe spinal cord injuries.  Paraplegia 30: 229-38.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1625890
  38. Wernig A, Muller S, Nanassy A and Cagol E (1995).  Laufband therapy based on ‘rules of spinal locomotion’ is effective in spinal cord injured persons.  Eur J Neurosci 7: 823-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7620630
  39. Wernig A, Nanassy A and Muller S (1998).  Maintenance of locomotor abilities following Laufband (treadmill) therapy in para- and tetraplegic persons: follow-up studies.  Spinal Cord 36: 744-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9848480
  40. Dobkin B, Barbeau H, Deforge D, Ditunno J, Elashoff R, Apple D, Basso M, Behrman A, Harkema S, Saulino M and Scott M (2007).  The evolution of walking-related outcomes over the first 12 weeks of rehabilitation for incomplete traumatic spinal cord injury: the multicenter randomized Spinal Cord Injury Locomotor Trial.  Neurorehabil Neural Repair 21: 25-35.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17172551
  41. Barbeau H, McCrea DA, O’Donovan MJ, Rossignol S, Grill WM and Lemay MA (1999).  Tapping into spinal circuits to restore motor function.  Brain Res Brain Res Rev 30: 27-51.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10407124
  42. Fouad K, Metz GA, Merkler D, Dietz V and Schwab ME (2000).  Treadmill training in incomplete spinal cord injured rats.  Behav Brain Res 115: 107-13.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10996413
  43. Harkema SJ (2001).  Neural plasticity after human spinal cord injury: application of locomotor training to the rehabilitation of walking.  Neuroscientist 7: 455-68.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11597104
  44. Thota A, Carlson S and Jung R (2001).  Recovery of locomotor function after treadmill training of incomplete spinal cord injured rats.  Biomed Sci Instrum 37: 63-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11347446
  45. Kaegi S, Schwab ME, Dietz V and Fouad K (2002).  Electromyographic activity associated with spontaneous functional recovery after spinal cord injury in rats.  Eur J Neurosci 16: 249-58.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12169107
  46. Barbeau H, Ladouceur M, Mirbagheri MM and Kearney RE (2002).  The effect of locomotor training combined with functional electrical stimulation in chronic spinal cord injured subjects: walking and reflex studies.  Brain Res Brain Res Rev 40: 274-91.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12589926
  47. Hains BC, Everhart AW, Fullwood SD and Hulsebosch CE (2002).  Changes in serotonin, serotonin transporter expression and serotonin denervation supersensitivity: involvement in chronic central pain after spinal hemisection in the rat.  Exp Neurol 175: 347-62.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12061865
  48. Dimitrijevic MR, Persy I, Forstner C, Kern H and Dimitrijevic MM (2005).  Motor control in the human spinal cord.  Artif Organs 29: 216-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15725220
  49. Jankowska E, Lundberg A, Rudomin P and Sykova E (1977).  Effects of 4-aminopyridine on transmission in excitatory and inhibitory synapses in the spinal cord.  Brain Res 136: 387-92.
  50. Bostock H, Sears TA and Sherratt RM (1981).  The effects of 4-aminopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibres.  J Physiol 313: 301-15.
  51. Zangger P (1981).  The effect of 4-aminopyridine on the spinal locomotor rhythm induced by L-DOPA.  Brain Res 215: 211-23.
  52. Eliasson SG, Monafo WW and Meyr D (1986).  Potassium ion channel blockade restores conduction in heat-injured nerve and spinal nerve roots.  Exp Neurol 93: 128-37.
  53. Bowe CM, Kocsis JD, Targ EF and Waxman SG (1987).  Physiological effects of 4-aminopyridine on demyelinated mammalian motor and sensory fibers.  Ann Neurol 22: 264-8.
  54. Blight AR and Gruner JA (1987).  Augmentation by 4-aminopyridine of vestibulospinal free fall responses in chronic spinal-injured cats.  J Neurol Sci 82: 145-59.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2831307
  55. Blight AR, Toombs JP, Bauer MS and Widmer WR (1991).  The effects of 4-aminopyridine on neurological deficits in chronic cases of traumatic spinal cord injury in dogs: a phase I clinical trial.  J Neurotrauma 8: 103-19.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1870134
  56. Hansebout RR, Blight AR, Fawcett S and Reddy K (1993).  4-Aminopyridine in chronic spinal cord injury: a controlled, double-blind, crossover study in eight patients.  J Neurotrauma 10: 1-18.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8320728
  57. Hayes KC, Blight AR, Potter PJ, Allatt RD, Hsieh JT, Wolfe DL, Lam S and Hamilton JT (1993).  Preclinical trial of 4-aminopyridine in patients with chronic spinal cord injury.  Paraplegia 31: 216-24.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8493036
  58. Hayes KC, Potter PJ, Wolfe DL, Hsieh JT, Delaney GA and Blight AR (1994).  4-Aminopyridine-sensitive neurologic deficits in patients with spinal cord injury.  J Neurotrauma 11: 433-46.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7837283
  59. Qiao J, Hayes KC, Hsieh JT, Potter PJ and Delaney GA (1997).  Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury.  J Neurotrauma 14: 135-49.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9104931
  60. Segal JL and Brunnemann SR (1997).  4-Aminopyridine improves pulmonary function in quadriplegic humans with longstanding spinal cord injury.  Pharmacotherapy 17: 415-23.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9165545
  61. Potter PJ, Hayes KC, Hsieh JT, Delaney GA and Segal JL (1998).  Sustained improvements in neurological function in spinal cord injured patients treated with oral 4-aminopyridine: three cases.  Spinal Cord 36: 147-55.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9554012
  62. Shi R and Blight AR (1997).  Differential effects of low and high concentrations of 4-aminopyridine on axonal conduction in normal and injured spinal cord.  Neuroscience 77: 553-62.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9472411
  63. Shi R, Kelly TM and Blight AR (1997).  Conduction block in acute and chronic spinal cord injury: different dose-response characteristics for reversal by 4-aminopyridine.  Exp Neurol 148: 495-501.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9417828
  64. Donovan WH, Halter JA, Graves DE, Blight AR, Calvillo O, McCann MT, Sherwood AM, Castillo T, Parsons KC and Strayer JR (2000).  Intravenous infusion of 4-AP in chronic spinal cord injured subjects.  Spinal Cord 38: 7-15.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10762192
  65. Halter JA, Blight AR, Donovan WH and Calvillo O (2000).  Intrathecal administration of 4-aminopyridine in chronic spinal injured patients.  Spinal Cord 38: 728-32.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11175372
  66. Segal JL, Hayes KC, Brunnemann SR, Hsieh JT, Potter PJ, Pathak MS, Tierney DS and Mason D (2000).  Absorption characteristics of sustained-release 4-aminopyridine (fampridine SR) in patients with chronic spinal cord injury.  J Clin Pharmacol 40: 402-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10761168
  67. Hayes KC, Potter PJ, Hsieh JT, Katz MA, Blight AR and Cohen R (2004).  Pharmacokinetics and safety of multiple oral doses of sustained-release 4-aminopyridine (Fampridine-SR) in subjects with chronic, incomplete spinal cord injury.  Arch Phys Med Rehabil 85: 29-34.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14970964
  68. van der Bruggen MA, Huisman HB, Beckerman H, Bertelsmann FW, Polman CH and Lankhorst GJ (2001).  Randomized trial of 4-aminopyridine in patients with chronic incomplete spinal cord injury.  J Neurol 248: 665-71.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11569894
  69. Wolfe DL, Hayes KC, Hsieh JT and Potter PJ (2001).  Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury: a double-blinded, placebo-controlled crossover trial.  J Neurotrauma 18: 757-71.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11526982
  70. Grijalva I, Guizar-Sahagun G, Castaneda-Hernandez G, Mino D, Maldonado-Julian H, Vidal-Cantu G, Ibarra A, Serra O, Salgado-Ceballos H and Arenas-Hernandez R (2003).  Efficacy and safety of 4-aminopyridine in patients with long-term spinal cord injury: a randomized, double-blind, placebo-controlled trial.  Pharmacotherapy 23: 823-34.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12885095
  71. DeForge D, Nymark J, Lemaire E, Gardner S, Hunt M, Martel L, Curran D and Barbeau H (2004).  Effect of 4-aminopyridine on gait in ambulatory spinal cord injuries: a double-blind, placebo-controlled, crossover trial.  Spinal Cord 42: 674-85.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15356676
  72. Cardenas DD, Ditunno J, Graziani V, Jackson AB, Lammertse D, Potter P, Sipski M, Cohen R and Blight AR (2007).  Phase 2 trial of sustained-release fampridine in chronic spinal cord injury.  Spinal Cord 45: 158-68.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16773037
  73. Hayes KC, Katz MA, Devane JG, Hsieh JT, Wolfe DL, Potter PJ and Blight AR (2003).  Pharmacokinetics of an immediate-release oral formulation of Fampridine (4-aminopyridine) in normal subjects and patients with spinal cord injury.  J Clin Pharmacol 43: 379-85.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12723458
  74. Hayes KC, Potter PJ, Hansebout RR, Bugaresti JM, Hsieh JT, Nicosia S, Katz MA, Blight AR and Cohen R (2003).  Pharmacokinetic studies of single and multiple oral doses of fampridine-SR (sustained-release 4-aminopyridine) in patients with chronic spinal cord injury.  Clin Neuropharmacol 26: 185-92.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12897638
  75. Isoda WC and Segal JL (2003).  Effects of 4-aminopyridine on cardiac repolarization, PR interval, and heart rate in patients with spinal cord injury.  Pharmacotherapy 23: 133-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12587799
  76. Savio T and Schwab ME (1989).  Rat CNS white matter, but not gray matter, is nonpermissive for neuronal cell adhesion and fiber outgrowth.  J Neurosci 9: 1126-33.
  77. Schnell L and Schwab ME (1990).  Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors.  Nature 343: 269-72.  http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=2300171
  78. Aguayo AJ, David S and Bray GM (1981).  Influences of the glial environment on the elongation of axons after injury: transplantation studies in adult rodents.  J Exp Biol 95: 231-40.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7334319
  79. David S and Aguayo AJ (1981).  Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats.  Science 214: 931-3.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=6171034
  80. David S and Aguayo AJ (1985).  Axonal regeneration after crush injury of rat central nervous system fibres innervating peripheral nerve grafts.  J Neurocytol 14: 1-12.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=4009210
  81. Brosamle C, Huber AB, Fiedler M, Skerra A and Schwab ME (2000).  Regeneration of lesioned corticospinal tract fibers in the adult rat induced by a recombinant, humanized IN-1 antibody fragment.  J Neurosci 20: 8061-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11050127
  82. Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F and Schwab ME (2000).  Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1.  Nature 403: 434-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10667796
  83. Huber AB and Schwab ME (2000).  Nogo-A, a potent inhibitor of neurite outgrowth and regeneration.  Biol Chem 381: 407-19.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10937871
  84. Fouad K, Dietz V and Schwab ME (2001).  Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors.  Brain Res Brain Res Rev 36: 204-12.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11690617
  85. Merkler D, Metz GA, Raineteau O, Dietz V, Schwab ME and Fouad K (2001).  Locomotor recovery in spinal cord-injured rats treated with an antibody neutralizing the myelin-associated neurite growth inhibitor Nogo-A.  J Neurosci 21: 3665-73.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11331396
  86. Bareyre FM, Haudenschild B and Schwab ME (2002).  Long-lasting sprouting and gene expression changes induced by the monoclonal antibody IN-1 in the adult spinal cord.  J Neurosci 22: 7097-110.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12177206
  87. Huang DW, McKerracher L, Braun PE and David S (1999).  A therapeutic vaccine approach to stimulate axon regeneration in the adult mammalian spinal cord.  Neuron 24: 639-47.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10595515
  88. Merkler D, Oertle T, Buss A, Pinschewer DD, Schnell L, Bareyre FM, Kerschensteiner M, Buddeberg BS and Schwab ME (2003).  Rapid induction of autoantibodies against Nogo-A and MOG in the absence of an encephalitogenic T cell response: implication for immunotherapeutic approaches in neurological diseases.  Faseb J 17: 2275-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14563689
  89. Bourquin C, van der Haar ME, Anz D, Sandholzer N, Neumaier I, Endres S, Skerra A, Schwab ME and Linington C (2008).  DNA vaccination efficiently induces antibodies to Nogo-A and does not exacerbate experimental autoimmune encephalomyelitis.  Eur J Pharmacol 588: 99-105.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18495110
  90. Wiessner C, Bareyre FM, Allegrini PR, Mir AK, Frentzel S, Zurini M, Schnell L, Oertle T and Schwab ME (2003).  Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats.  J Cereb Blood Flow Metab 23: 154-65.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12571447
  91. Fouad K, Klusman I and Schwab ME (2004).  Regenerating corticospinal fibers in the Marmoset (Callitrix jacchus) after spinal cord lesion and treatment with the anti-Nogo-A antibody IN-1.  Eur J Neurosci 20: 2479-82.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15525289
  92. Schwab ME (2004).  Nogo and axon regeneration.  Curr Opin Neurobiol 14: 118-24.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15018947
  93. Buchli AD and Schwab ME (2005).  Inhibition of Nogo: a key strategy to increase regeneration, plasticity and functional recovery of the lesioned central nervous system.  Ann Med 37: 556-67.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16338758
  94. Liebscher T, Schnell L, Schnell D, Scholl J, Schneider R, Gullo M, Fouad K, Mir A, Rausch M, Kindler D, Hamers FP and Schwab ME (2005).  Nogo-A antibody improves regeneration and locomotion of spinal cord-injured rats.  Ann Neurol 58: 706-19.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16173073
  95. Weinmann O, Schnell L, Ghosh A, Montani L, Wiessner C, Wannier T, Rouiller E, Mir A and Schwab ME (2006).  Intrathecally infused antibodies against Nogo-A penetrate the CNS and downregulate the endogenous neurite growth inhibitor Nogo-A.  Mol Cell Neurosci 32: 161-73.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16697217
  96. Freund P, Wannier T, Schmidlin E, Bloch J, Mir A, Schwab ME and Rouiller EM (2007).  Anti-Nogo-A antibody treatment enhances sprouting of corticospinal axons rostral to a unilateral cervical spinal cord lesion in adult macaque monkey.  J Comp Neurol 502: 644-59.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17394135
  97. Mullner A, Gonzenbach RR, Weinmann O, Schnell L, Liebscher T and Schwab ME (2008).  Lamina-specific restoration of serotonergic projections after Nogo-A antibody treatment of spinal cord injury in rats.  Eur J Neurosci 27: 326-33.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18215231
  98. GrandPre T, Nakamura F, Vartanian T and Strittmatter SM (2000).  Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein.  Nature 403: 439-44.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10667797
  99. Fournier AE, GrandPre T and Strittmatter SM (2001).  Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration.  Nature 409: 341-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11201742
  100. Fournier AE and Strittmatter SM (2001).  Repulsive factors and axon regeneration in the CNS.  Curr Opin Neurobiol 11: 89-94.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11179877
  101. Fournier AE, Gould GC, Liu BP and Strittmatter SM (2002).  Truncated soluble Nogo receptor binds Nogo-66 and blocks inhibition of axon growth by myelin.  J Neurosci 22: 8876-83.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12388594
  102. Fournier AE, GrandPre T, Gould G, Wang X and Strittmatter SM (2002).  Nogo and the Nogo-66 receptor.  Prog Brain Res 137: 361-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12440378
  103. GrandPre T, Li S and Strittmatter SM (2002).  Nogo-66 receptor antagonist peptide promotes axonal regeneration.  Nature 417: 547-51.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12037567
  104. Liu BP, Fournier A, GrandPre T and Strittmatter SM (2002).  Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor.  Science 297: 1190-3.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12089450
  105. Strittmatter SM (2002).  Modulation of axonal regeneration in neurodegenerative disease: focus on Nogo.  J Mol Neurosci 19: 117-21.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12212768
  106. Wang X, Chun SJ, Treloar H, Vartanian T, Greer CA and Strittmatter SM (2002).  Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon-myelin and synaptic contact.  J Neurosci 22: 5505-15.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12097502
  107. Barton WA, Liu BP, Tzvetkova D, Jeffrey PD, Fournier AE, Sah D, Cate R, Strittmatter SM and Nikolov DB (2003).  Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins.  Embo J 22: 3291-302.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12839991
  108. Fournier AE, Takizawa BT and Strittmatter SM (2003).  Rho kinase inhibition enhances axonal regeneration in the injured CNS.  J Neurosci 23: 1416-23.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12598630
  109. Kim JE, Li S, GrandPre T, Qiu D and Strittmatter SM (2003).  Axon regeneration in young adult mice lacking Nogo-A/B.  Neuron 38: 187-99.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12718854
  110. Lee DH, Strittmatter SM and Sah DW (2003).  Targeting the Nogo receptor to treat central nervous system injuries.  Nat Rev Drug Discov 2: 872-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14668808
  111. Li S and Strittmatter SM (2003).  Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury.  J Neurosci 23: 4219-27.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12764110
  112. McGee AW and Strittmatter SM (2003).  The Nogo-66 receptor: focusing myelin inhibition of axon regeneration.  Trends Neurosci 26: 193-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12689770
  113. Hu F and Strittmatter SM (2004).  Regulating axon growth within the postnatal central nervous system.  Semin Perinatol 28: 371-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15693393
  114. Kim JE, Liu BP, Park JH and Strittmatter SM (2004).  Nogo-66 receptor prevents raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury.  Neuron 44: 439-51.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15504325
  115. Lee JK, Kim JE, Sivula M and Strittmatter SM (2004).  Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity.  J Neurosci 24: 6209-17.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15240813
  116. Li S, Liu BP, Budel S, Li M, Ji B, Walus L, Li W, Jirik A, Rabacchi S, Choi E, Worley D, Sah DW, Pepinsky B, Lee D, Relton J and Strittmatter SM (2004).  Blockade of Nogo-66, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein by soluble Nogo-66 receptor promotes axonal sprouting and recovery after spinal injury.  J Neurosci 24: 10511-20.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15548666
  117. Li W, Walus L, Rabacchi SA, Jirik A, Chang E, Schauer J, Zheng BH, Benedetti NJ, Liu BP, Choi E, Worley D, Silvian L, Mo W, Mullen C, Yang W, Strittmatter SM, Sah DW, Pepinsky B and Lee DH (2004).  A neutralizing anti-Nogo66 receptor monoclonal antibody reverses inhibition of neurite outgrowth by central nervous system myelin.  J Biol Chem 279: 43780-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15297463
  118. Hu F, Liu BP, Budel S, Liao J, Chin J, Fournier A and Strittmatter SM (2005).  Nogo-A interacts with the Nogo-66 receptor through multiple sites to create an isoform-selective subnanomolar agonist.  J Neurosci 25: 5298-304.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15930377
  119. Li S, Kim JE, Budel S, Hampton TG and Strittmatter SM (2005).  Transgenic inhibition of Nogo-66 receptor function allows axonal sprouting and improved locomotion after spinal injury.  Mol Cell Neurosci 29: 26-39.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15866044
  120. McGee AW, Yang Y, Fischer QS, Daw NW and Strittmatter SM (2005).  Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor.  Science 309: 2222-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16195464
  121. Cafferty WB and Strittmatter SM (2006).  The Nogo-Nogo receptor pathway limits a spectrum of adult CNS axonal growth.  J Neurosci 26: 12242-50.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17122049
  122. Marklund N, Fulp CT, Shimizu S, Puri R, McMillan A, Strittmatter SM and McIntosh TK (2006).  Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat.  Exp Neurol 197: 70-83.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16321384
  123. Lauren J, Hu F, Chin J, Liao J, Airaksinen MS and Strittmatter SM (2007).  Characterization of myelin ligand complexes with neuronal Nogo-66 receptor family members.  J Biol Chem 282: 5715-25.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17189258
  124. Hu F and Strittmatter SM (2008).  The N-terminal domain of Nogo-A inhibits cell adhesion and axonal outgrowth by an integrin-specific mechanism.  J Neurosci 28: 1262-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18234903
  125. Ji B, Li M, Budel S, Pepinsky RB, Walus L, Engber TM, Strittmatter SM and Relton JK (2005).  Effect of combined treatment with methylprednisolone and soluble Nogo-66 receptor after rat spinal cord injury.  Eur J Neurosci 22: 587-94.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16101740
  126. Wang X, Baughman KW, Basso DM and Strittmatter SM (2006).  Delayed Nogo receptor therapy improves recovery from spinal cord contusion.  Ann Neurol 60: 540-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16958113
  127. Dubreuil CI, Winton MJ and McKerracher L (2003).  Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system.  J Cell Biol 162: 233-43.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12860969
  128. McKerracher L and Higuchi H (2006).  Targeting Rho to stimulate repair after spinal cord injury.  J Neurotrauma 23: 309-17.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16629618
  129. Lord-Fontaine S, Yang F, Diep Q, Dergham P, Munzer S, Tremblay P and McKerracher L (2008).  Local Inhibition of Rho Signaling by Cell-Permeable Recombinant Protein BA-210 Prevents Secondary Damage and Promotes Functional Recovery following Acute Spinal Cord Injury.  J Neurotrauma 25: 1309-22.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19061375
  130. Pitts C (2005).  Data Safety Monitoring Board recommends continuation of BioAxone’s phase I/IIa clinical trial with its lead product Cethrin (R) (BA-210) in acute spinal cord injury.   http://www.newswire.ca/en/releases/archive/June2005/06/c8025.html
  131. Baptiste DC and Fehlings MG (2007).  Update on the treatment of spinal cord injury.  Prog Brain Res 161: 217-33.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17618980
  132. Anonymous (2007).  Boston Life Sciences, Inc. Announces Presentation of Cethrin Phase I/IIa 6-Month Results at 75th Annual Meeting of the American Association of Neurological Surgeons.   http://www.bio-medicine.org/medicine-technology/Boston-Life-Sciences–Inc–Announces-Presentation-of-Cethrin-Phase-0AI-IIa-6-Month-Results-at-75th-Annual-Meeting-of-the-American-0AAssociation-of-Neu-996-2/
  133. Burns AS, Lee BS, Ditunno JF, Jr. and Tessler A (2003).  Patient selection for clinical trials: the reliability of the early spinal cord injury examination.  J Neurotrauma 20: 477-82.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12803979
  134. Baptiste DC and Fehlings MG (2006).  Pharmacological approaches to repair the injured spinal cord.  J Neurotrauma 23: 318-34.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16629619
  135. Doucette R (1995).  Olfactory ensheathing cells: potential for glial cell transplantation into areas of CNS injury.  Histol Histopathol 10: 503-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7599444
  136. Smale KA, Doucette R and Kawaja MD (1996).  Implantation of olfactory ensheathing cells in the adult rat brain following fimbria-fornix transection.  Exp Neurol 137: 225-33.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8635537
  137. Li Y, Field PM and Raisman G (1997).  Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells.  Science 277: 2000-2.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9302296
  138. Ramon-Cueto A, Plant GW, Avila J and Bunge MB (1998).  Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants.  J Neurosci 18: 3803-15.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9570810
  139. Barnett SC, Alexander CL, Iwashita Y, Gilson JM, Crowther J, Clark L, Dunn LT, Papanastassiou V, Kennedy PG and Franklin RJ (2000).  Identification of a human olfactory ensheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons.  Brain 123 ( Pt 8): 1581-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10908188
  140. Smith PM, Sim FJ, Barnett SC and Franklin RJ (2001).  SCIP/Oct-6, Krox-20, and desert hedgehog mRNA expression during CNS remyelination by transplanted olfactory ensheathing cells.  Glia 36: 342-53.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11746771
  141. Imaizumi T, Lankford KL, Burton WV, Fodor WL and Kocsis JD (2000).  Xenotransplantation of transgenic pig olfactory ensheathing cells promotes axonal regeneration in rat spinal cord.  Nat Biotechnol 18: 949-53.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10973214
  142. Imaizumi T, Lankford KL and Kocsis JD (2000).  Transplantation of olfactory ensheathing cells or Schwann cells restores rapid and secure conduction across the transected spinal cord.  Brain Res 854: 70-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10784108
  143. Ramon-Cueto A (2000).  Olfactory ensheathing glia transplantation into the injured spinal cord.  Prog Brain Res 128: 265-72.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11105686
  144. Ramon-Cueto A, Cordero MI, Santos-Benito FF and Avila J (2000).  Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia.  Neuron 25: 425-35.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10719896
  145. Bartolomei JC and Greer CA (2000).  Olfactory ensheathing cells: bridging the gap in spinal cord injury.  Neurosurgery 47: 1057-69.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11063098
  146. Franklin RJ and Barnett SC (2000).  Olfactory ensheathing cells and CNS regeneration: the sweet smell of success?  Neuron 28: 15-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11086978
  147. Bunge MB (2001).  Bridging areas of injury in the spinal cord.  Neuroscientist 7: 325-39.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11488398
  148. Kwon BK and Tetzlaff W (2001).  Spinal cord regeneration: from gene to transplants.  Spine 26: S13-22.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11805602
  149. Raisman G (2001).  Olfactory ensheathing cells – another miracle cure for spinal cord injury?  Nat Rev Neurosci 2: 369-75.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11331921
  150. Ramon-Cueto A and Santos-Benito FF (2001).  Cell therapy to repair injured spinal cords: olfactory ensheathing glia transplantation.  Restor Neurol Neurosci 19: 149-56.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12082235
  151. Treloar HB, Bartolomei JC, Lipscomb BW and Greer CA (2001).  Mechanisms of axonal plasticity: lessons from the olfactory pathway.  Neuroscientist 7: 55-63.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11486344
  152. Lu J, Feron F, Ho SM, Mackay-Sim A and Waite PM (2001).  Transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats.  Brain Res 889: 344-57.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11166728
  153. Lima C, Pratas-Vital J, Escada P, Hasse-Ferreira A, Capucho C and Peduzzi JD (2006).  Olfactory mucosa autografts in human spinal cord injury: a pilot clinical study.  J Spinal Cord Med 29: 191-203; discussion 204-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16859223
  154. Iwatsuki K, Yoshimine T, Kishima H, Aoki M, Yoshimura K, Ishihara M, Ohnishi Y and Lima C (2008).  Transplantation of olfactory mucosa following spinal cord injury promotes recovery in rats.  Neuroreport 19: 1249-52.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18695502
  155. Mackay-Sim A, Feron F, Cochrane J, Bassingthwaighte L, Bayliss C, Davies W, Fronek P, Gray C, Kerr G, Licina P, Nowitzke A, Perry C, Silburn PA, Urquhart S and Geraghty T (2008).  Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial.  Brain 131: 2376-86.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18689435
  156. Huang H, Chen L, Wang H, Xiu B, Li B, Wang R, Zhang J, Zhang F, Gu Z, Li Y, Song Y, Hao W, Pang S and Sun J (2003).  Influence of patients’ age on functional recovery after transplantation of olfactory ensheathing cells into injured spinal cord injury.  Chin Med J (Engl) 116: 1488-91.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14570607
  157. Dobkin BH, Curt A and Guest J (2006).  Cellular transplants in China: observational study from the largest human experiment in chronic spinal cord injury.  Neurorehabil Neural Repair 20: 5-13.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16467274
  158. Huang H, Chen L, Wang H, Xi H, Gou C, Zhang J, Zhang F and Liu Y (2006).  Safety of fetal olfactory ensheathing cell transplantation in patients with chronic spinal cord injury. A 38-month follow-up with MRI.  Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 20: 439-43.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16683452
  159. Huang H, Wang H, Chen L, Gu Z, Zhang J, Zhang F, Song Y, Li Y, Tan K, Liu Y and Xi H (2006).  Influence factors for functional improvement after olfactory ensheathing cell transplantation for chronic spinal cord injury.  Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 20: 434-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16683451
  160. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS and Jones JM (1998).  Embryonic stem cell lines derived from human blastocysts.  Science 282: 1145-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9804556
  161. McDonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, Gottlieb DI and Choi DW (1999).  Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord.  Nat Med 5: 1410-2.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10581084
  162. Dezawa M, Hoshino M, Nabeshima Y and Ide C (2005).  Marrow stromal cells: implications in health and disease in the nervous system.  Curr Mol Med 5: 723-32.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16305495
  163. Weible MW, 2nd and Chan-Ling T (2007).  Phenotypic characterization of neural stem cells from human fetal spinal cord: synergistic effect of LIF and BMP4 to generate astrocytes.  Glia 55: 1156-68.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17597119
  164. Saporta S, Kim JJ, Willing AE, Fu ES, Davis CD and Sanberg PR (2003).  Human umbilical cord blood stem cells infusion in spinal cord injury: engraftment and beneficial influence on behavior.  J Hematother Stem Cell Res 12: 271-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12857368
  165. Zhao ZM, Li HJ, Liu HY, Lu SH, Yang RC, Zhang QJ and Han ZC (2004).  Intraspinal transplantation of CD34+ human umbilical cord blood cells after spinal cord hemisection injury improves functional recovery in adult rats.  Cell Transplant 13: 113-22.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15129757
  166. Kuh SU, Cho YE, Yoon DH, Kim KN and Ha Y (2005).  Functional recovery after human umbilical cord blood cells transplantation with brain-derived neutrophic factor into the spinal cord injured rat.  Acta Neurochir (Wien) 147: 985-92.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16010451
  167. Nishio Y, Koda M, Kamada T, Someya Y, Yoshinaga K, Okada S, Harada H, Okawa A, Moriya H and Yamazaki M (2006).  The use of hemopoietic stem cells derived from human umbilical cord blood to promote restoration of spinal cord tissue and recovery of hindlimb function in adult rats.  J Neurosurg Spine 5: 424-33.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17120892
  168. Dasari VR, Spomar DG, Gondi CS, Sloffer CA, Saving KL, Gujrati M, Rao JS and Dinh DH (2007).  Axonal remyelination by cord blood stem cells after spinal cord injury.  J Neurotrauma 24: 391-410.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17376002
  169. Lim JH, Byeon YE, Ryu HH, Jeong YH, Lee YW, Kim WH, Kang KS and Kweon OK (2007).  Transplantation of canine umbilical cord blood-derived mesenchymal stem cells in experimentally induced spinal cord injured dogs.  J Vet Sci 8: 275-82.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17679775
  170. Chen CT, Foo NH, Liu WS and Chen SH (2008).  Infusion of human umbilical cord blood cells ameliorates hind limb dysfunction in experimental spinal cord injury through anti-inflammatory, vasculogenic and neurotrophic mechanisms.  Pediatr neonatol 49: 77-83.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18947003
  171. Cho SR, Yang MS, Yim SH, Park JH, Lee JE, Eom YW, Jang IK, Kim HE, Park JS, Kim HO, Lee BH, Park CI and Kim YJ (2008).  Neurally induced umbilical cord blood cells modestly repair injured spinal cords.  Neuroreport 19: 1259-63.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18695504
  172. Gage FH (2000).  Mammalian neural stem cells.  Science 287: 1433-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10688783
  173. Faulkner J and Keirstead HS (2005).  Human embryonic stem cell-derived oligodendrocyte progenitors for the treatment of spinal cord injury.  Transpl Immunol 15: 131-42.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16412957
  174. Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K and Steward O (2005).  Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury.  J Neurosci 25: 4694-705.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15888645
  175. Nistor GI, Totoiu MO, Haque N, Carpenter MK and Keirstead HS (2005).  Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation.  Glia 49: 385-96.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15538751
  176. Cloutier F, Siegenthaler MM, Nistor G and Keirstead HS (2006).  Transplantation of human embryonic stem cell-derived oligodendrocyte progenitors into rat spinal cord injuries does not cause harm.  Regen Med 1: 469-79.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17465839
  177. Coutts M and Keirstead HS (2008).  Stem cells for the treatment of spinal cord injury.  Exp Neurol 209: 368-77.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17950280
  178. Zhang YW, Denham J and Thies RS (2006).  Oligodendrocyte progenitor cells derived from human embryonic stem cells express neurotrophic factors.  Stem Cells Dev 15: 943-52.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17253955
  179. Okamura RM, Lebkowski J, Au M, Priest CA, Denham J and Majumdar AS (2007).  Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells.  J Neuroimmunol 192: 134-44.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17996308
  180. Puceat M and Ballis A (2007).  Embryonic stem cells: from bench to bedside.  Clin Pharmacol Ther 82: 337-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17637781
  181. Keim B (2007).  The Company Who Cried Clinical Trial: Geron’s Unfulfilled Stem Cell Promises.  blog.wired.com.  http://blog.wired.com/wiredscience/2007/07/the-company-who.html
  182. Anonymous (2008).  FDA’s delay of Geron ESC trial raises concerns.  {May 15, 2008.  http://www.fiercebiotech.com/story/fda-s-delay-of-geron-esc-trial-raises-concerns/2008-05-15?utm_medium=rss&utm_source=rss&cmp-id=OTC-RSS-FB0
  183. Philipkoski K (2005).  Race to Human Stem-Cell Trials.  Wired Magazine.  http://www.wired.com/medtech/health/news/2005/04/67266
  184. Smith A (2008).  Human stem cell tests could be near.  CNNMoney.com.  http://money.cnn.com/2008/02/11/news/companies/geron/index.htm?postversion=2008021212
  185. Lu P and Tuszynski MH (2008).  Growth factors and combinatorial therapies for CNS regeneration.  Exp Neurol 209: 313-20.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17927983
  186. Kao CH, Chen SH, Chio CC and Lin MT (2008).  Human umbilical cord blood-derived CD34+ cells may attenuate spinal cord injury by stimulating vascular endothelial and neurotrophic factors.  Shock 29: 49-55.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17666954
  187. Dasari VR, Spomar DG, Li L, Gujrati M, Rao JS and Dinh DH (2008).  Umbilical cord blood stem cell mediated downregulation of fas improves functional recovery of rats after spinal cord injury.  Neurochem Res 33: 134-49.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17703359
  188. Kang KS, Kim SW, Oh YH, Yu JW, Kim KY, Park HK, Song CH and Han H (2005).  A 37-year-old spinal cord-injured female patient, transplanted of multipotent stem cells from human UC blood, with improved sensory perception and mobility, both functionally and morphologically: a case study.  Cytotherapy 7: 368-73.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16162459
  189. Yick LW, So KF, Cheung PT and Wu WT (2004).  Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury.  J Neurotrauma 21: 932-43.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15307905
  190. Su H, Chu TH and Wu W (2007).  Lithium enhances proliferation and neuronal differentiation of neural progenitor cells in vitro and after transplantation into the adult rat spinal cord.  Exp Neurol 206: 296-307.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17599835
  191. Dill J, Wang H, Zhou F and Li S (2008).  Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS.  J Neurosci 28: 8914-28.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18768685

FAQ #1: Will There Be A Cure For Spinal Cord Injury?

December 22, 2008

FAQ #1:  Will There Be A Cure for Spinal Cord Injury?
By Wise Young PhD MD, Rutgers University,
W. M. Keck Center for Collaborative Neuroscience
604 Allison Rd, Piscataway, NJ 08854-8082
First posted 22 December 2008

Will there be a cure for spinal cord injury?  This is the most frequently asked and often first question asked by people and families after spinal cord injury.  I answer yes to this question for the following reasons.

  • People and animals often recover substantially after “incomplete” spinal cord injury.  Animals can walk with only 5-10% of their axons [1].  A large majority (>90%) of people with even slight initial preservation of function at the lowest level of their spinal cord, i.e. anal sensation and sphincter control, recover ability to walk [2].  Examination of their spinal cords may indicate that they have only 10% of their spinal cord tracts remaining at the injury site.  The spinal cord is capable of tremendous plasticity.  Thus, depending on what the person has, regenerating and remyelinating even a small proportion of the axons in the spinal cord may be sufficient to restore substantial function to people with spinal cord injury.
  • The spinal cord can regenerate.  For over a century, scientists have reported that spinal cords of some animals and even mammals can regenerate under certain circumstances.  For example, lamprey [3], tadpoles [4], goldfish [5], and many other animals are able to regenerate their spinal cords.  For a long time, people thought that this was because these animals are evolutionarily primitive and that mammalian axons cannot regrow.  However, Aguayo, et al. [6-8] found that spinal axons can regrow in peripheral nerve but certain factors in the spinal cord inhibit growth [9].
  • Many therapies regenerate the spinal cords.  Over 100 individual therapies have been reported to stimulate axonal regeneration in the spinal cord. Please note that the following is by no means an exhaustive list of curative therapies of spinal cord injury.  I only cite representative recent publications supporting each therapy.  The point is that *many* therapies have been reported to regenerate the spinal cord.
    • Nogo and Nogo receptor blockers.  Nogo is a myelin-based protein that activates axonal receptors that act through rho and rho kinase to stop axonal growth.  Many ways of blocking Nogo or its receptors have been shown to increase regeneration:
      • Binding of Nogo with antibodies [10, 11] or soluble Nogo receptor protein [12]  stimulate regeneration.  The former is currently in clinical trial by Novartis.  The latter is being developed for clinical trial by Biogen.
      • Blocking Nogo receptor with a 66-amino acid fragment of Nogo [13].  The fragment apparently binds the nogo receptor and prevents further activation.
      • Blocking Lingo co-receptor also stimulates regeneration [14, 15].  .  Lingo is a co-receptor of the Nogo receptor.  This is being developed by Biogen.
      • Blocking rho kinase and rho (“rhok and rho”).  Rho kinase blockers stimulate regeneration in the spinal cord.  A modified version of a bacterial toxin that blocks rho, named Cethrin, has been reported to stimulate regeneration and functional recover in animals and in clinical trials  [23-27]
    • Chondroitinase.  The extracellular space contains glycoproteins that inhibit axonal growth.  These include chondroitin-6-sulfate proteoglycans (CSPG), which impedes axonal guidance and growth [28, 29].  Chondroitinase ABC is a bacterial enzyme that break down CSPG [30], allows regeneration [31, 32], and improves locomotor recovery [33].
    • Cyclic nucleotides.  Cyclic nucleotides convert neuronal growth cone responses from repulsion to attraction [34].  An increase in intracellular cAMP in axons will stimulate axons to grow and ignore growth inhibitors such as Nogo and CSPG [35, 36].   In zebrafish, where regeneration can occur but not of all neurons, cAMP application is helpful [37].  Several treatments are available to increase cAMP levels in neurons.  One is rolipram, a phosphodiesterase 4 (PDE4) inhibitor localized to the central nervous system.  Dibutyryl cAMP will enter the cells and directly increase cAMP.  The combination of Schwann cell transplant, rolipram, and dibutyryl-cAMP strongly stimulate regeneration [38, 39].
    • Combination Neurotrophins.  Several neurotrophins are known to stimulate regeneration in the spinal cord, even in the presence of growth inhibitors.  These include nerve growth factor (NGF), neurotrophin-3 (NT3), and glial-derived neurotrophic factor (GDNF).  Much evidence point to the importance of NT-3 [40-42] in combination with other factors [43-46].  BDNF may have undesirable effects [47].  A sustained source of these neurotrophins, however, is required for long-distance regeneration.   Fibroblast growth factor (FGF-2) [48] and FGF-1 [49] apparently improved regeneration.  This may be through stimulation of endogenous neural stem cells in the spinal cord [50].
    • Cellular Adhesion Molecules.  A number of cell adhesion molecules play a major role in axonal regeneration [51].  The most interesting one is L1, a member of the IgG superfamily of cell adhesion molecules, that bind to L1 expressed by other growing axons and stimulate the axons to grow in bundles, a process called fasciculation.  Increasing L1 expressing in the spinal cord stimulates regeneration [52].  Elimination of L1 reduces sensor fiber sprouting in mice [53] perhaps through manipulation of semaphorins [54].  Another regenerative CAM is N-CAM [55] but increasing CHL1 cellular adhesion may inhibit recovery [56].
    • Cell Transplants.  Many cell transplants have been reported to improve recovery after spinal cord injury
      • Olfactory Ensheathing Glia.  These cells are born in the nasal mucosa and migrate in the olfactory nerve to the olfactory bulb, facilitating growth and connection of olfactory axons.  The olfactory nerve is the only nerve in the body that continuously regenerates throughout adult life and its ability to do so is believe to be due to the presence of OEG cells.  These cells also express L1 and neurotrophins. Astrocytes do not respond to exposure to olfactory ensheathing glia with GFAP or CSPG secretion.  Transplantation of these cells improves recovery after spinal cord injury [57-69] and ventral root repair [70, 71], although one group suggests that Schwann cells may be better in a direct comparison [72, 73].
      • Umbilical cord blood mononuclear cells.  Several groups have reported the umbilical cord blood mononuclear cells, particularly CD34+ cells, stimulate regeneration and improve recovery in animals after spinal cord injury [74-79].  The mechanisms of action were not clear.   Human umbilical cord blood-derived CD34+ cells may attenuate spinal cord injury by stimulating vascular endothelial and other neurotrophic factors [80] and downregulated FAS [81]. Cord blood cells may even myelinated axons [82].  We recently found that cord blood mononuclear cells secrete neurotrophins and that lithium strongly boosts neurotrophin production by these cells.   One study suggest that myeloid cells are essential for peripheral nerve regeneration [83].  Cord blood cells are already being used for multiple neurological applications [84].
      • Mesenchymal stem cells.  These are pluripotent stem cells that can be isolated from bone marrow and other tissues.  Several groups have now reported that these cells are beneficial in spinal cord injury [85-87].   These cells may act through similar mechanisms as umbilical cord blood mononuclear cells production of neurotrophins and provision of a hospitable environment for axonal growth.  Mesenchymal cells can be isolated from human umbilical cord and have been reported to have beneficial effects in animal spinal cord injury models [88, 89] and stroke [90].  Carvalho, et al. [91], however, found that CD45+/CD34+ mesenchymal stem cells do not improve neurological recovery in Wistar rats after spinal cord contusion.
      • Astrocytes.  Several studies [92, 93] suggest that certain types of astrocytes facilitate regeneration in the spinal cord.  As opposed to astrocytes that react to injury and surround the injury site, these astrocytes provide a conducive pathway for axonal growth in the spinal cord [94]. Neural stem cells produce these astrocytes and this may account for beneficial effects of neural stem cell transplants into injured spinal cords.  Glial precursor cells likewise may be beneficial [95].
      • Neural stem cells.  These can be obtained from embryonic stem cells, aborted fetuses, or even autologous from the hippocampus or subventricular zones [96].  Many groups have suggested that these cells alone [97, 98], after differentiation [99] or genetic manipulation [100] or in combination with other cells such as olfactory ensheathing glia [101] or Schwann cells [41, 42] are beneficial for spinal cord injury.  One of the main questions that has not yet been answered is how will the transplanted cells interact with neural stem cells that may already be present in the spinal cord [102].
      • Oligodendroglial progenitor cells.  Many groups have transplanted oligodendroglial progenitor cells (O2A) to the spinal cord and have found significant improvement of function [103].  Whether this is due to the remyelination observed or regeneration of axons is not clear.  Keirstead, et al. [93-95] are planning to go to clinical trial with oligodendroglial progenitor cells derived from human embryonic stem cells with Geron.
    • Purine nucleotides.  Several purine nucleotides have been reported to stimulate regeneration of the spinal cord.  These include cGMP and adenosine [34] and the modified guanosine analog AIT-082 [104, 105].  The mechanism is not well understood but may be related to increased cAMP levels and other mechanisms described above.  Several groups have reported the beneficial effects of inosine on regeneration of the spinal cord [106].
    • Ephrins.  The ephrins are guidance molecules that play a role in telling axons whether they have grown into the right places in the central nervous system [107].  Injury upregulated certain ephrins and blockade of these ephrins stimulates regeneration in mammalian spinal cords [107-111].   In particular, EphA4 blocking peptide enhances corticospinal tract regeneration [112].  EphA4-deficient mice regenerate axons and show less astrocytic gliosis [113].
    • Biomaterials.  Many different biomaterials have been reported to support regeneration in spinal cord injury.  For example, self-assembling peptides form a scaffold that can be used to bridge injured rat spinal cords [114, 115] and inhibit glial scar formation and promote axonal elongation [116].  Many types of hydrogels [117-120], other gels [121], poly-lactic-coglycolic acid [122-124], poly-lactic acid [125-127], and other synthetic materials [128] have been tried.  Natural materials such chitosan [129], agarose [130, 131], and alginate [132] have been used.  Plasma, fibrin glue, laminin, and collagen are popular [133-138].  Many types of configurations have been used with and without embedded biological factors [139] or drugs [140].  Many invetigators seeded biomaterials with Schwann cells [141, 142], neural stem cells [143], bone marrow stromal cells [144].
    • Therapeutic vaccines.  Many investigators have vaccinated animals with various putative substances in the hopes of stimulating them to produce antibodies against axonal growth inhibitors, such as Nogo.  For example, Huang, et al. [145] immunized rats with their own spinal cords and found that this stimulated extensive regeneration of large numbers of corticospinal axons.  Vaccination with p472 (a peptide derived from Nogo A [146] and Nogo-66 [10] promotes axonal regeneration and motor recovery after spinal cord injury. DNA vaccination efficiently induces antibodies to Nogo-A without exacerbating experimental autoimmune encephalomyelitis [147, 148] and can stimulate retinal ganglion cell regeneration [149].  DNA vaccines of other known inhibitors, such a MAG and OMGP have been tried as well [150, 151].
    • Electrical Stimulation.  Many early studies suggest that electrical currents stimulate regeneration [152-160].  Electrical stimulation is often used to enhance regeneration and reinnervation by peripheral nerves [161, 162].  A recent clinical trial of oscillating currents [163] suggests improved function in humans [164].
    • Other Therapies.  Many other therapies have been reported to be beneficial for regeneration:
      • Artemin.  This factor promotes re-entry of multiple classes of sensory fiber into the spinal cord and re-establishment of synaptic function and behavior improvements [165].  Incidentally, olfactory ensheathing glia express artemin [166].
      • Erythropoietin.  This hematopoietic hormone is a potent inducer of immune system [167], is neuroprotective [168], reduces oxidative stress [169], enhances regeneration in the spinal cord [170], and has been reported to improve recovery after spinal cord injury[171].
      • Bone Morphogenetic Protein (BMP) inhibitors.  BMP’s are potent inhibitors of axons regeneration [107].  BMP-2/4 are elevated in oligodendroglial cells.  Intrathecal administration of Noggin, a soluble BMP antagonist, results in enhanced locomotor recovery and significant regrowth of the corticospinal tract after spinal cord contusion [172].  BMP, however, is used to treat glial-restricted precursor cells to create astrocytes that support axonal regeneration [93].
      • Methylprednisolone (MP).  While MP has long been regarded to be an inhibitor of axonal growth, if it is applied for too long, it apparently reduces CSPG expression by astrocytes and enhances axonal growth in injured spinal cord as a result [173].
      • Polysialic acid.  Induced expression of these molecules increased the number of axons growing into the lesion cavity by 20-fold [174].
      • Granulocyte colony-stimulating factor (G-CSF).  Pan, et al. [175] reported that G-CSF inhibits programmed cell death and stimulates neuronal progenitor differentiation, that the combination of G-CSF and neural stem cell transplants enhances regeneration in transected rat spinal cords.
  • Neuronal replacement therapies.  Injuries to the spinal cord, particularly to the cervical and lumbosacral enlargement, damage neurons.  When motoneurons are damaged, the muscles they innervate may undergo atrophy.  Most muscles are innervated by many motoneurons and therefore will survive even after severe injuries.  However, cauda equina and peripheral nerve injuries will eliminate all or most of the motor innervations of a muscle and cause the muscle to undergo atrophy.  Likewise, injuries to the conus may cause severe damage to sacral motor centers controlling bowel, bladder, and sexual functions.  In such situations, motoneuronal replacement may be required.  If you had asked me a decade ago whether neuronal replacement therapies were possible, I would have said that it was unlikely.  However, the discovery of stem cells has changed this situation considerably.
    • Neural stem cell transplants.  Scientists who receive their education more than a decade ago were taught that we were born with the neurons that we die with.  In other words, no new neurons are supposed to be created after birth.  This situation changed when many groups discovered that the brain and spinal cord contain neural stem cells that continue to make many thousands of neurons every day.  Therefore, replacement of neurons by endogenous neural stem cells is not only possible but also likely.
    • Embryonic stem cells.  Kerr, et al. [176, 177] has shown that neural stem cells derived from embryonic stem cells are able to replace motoneurons in the spinal cord of animals that have had viral induced motoneuronal death.  When the cell transplants were combined with some of regenerative therapies described above, the neurons not only received input from descending tracts but grew their axons out of ventral roots to re-innervate muscle.   However, some researchers have found that embryonic stem cells do not replace neurons [178].
    • Stimulation of endogenous stem cells.  Lithium drug has long been used to treat manic depression.  Recent studies suggest that this drug may be acting through stimulation of endogenous neural stem cells [179], stimulates spinal cord regeneration [180, 181], supports retinal ganglion survival and axon regeneration [182], and may even reduce neuropathic pain [183].  A recent study [184, 185] suggests that this drug remarkably stops progression of amyotrophic lateral sclerosis.  Although the mechanisms are not well understood, one possible mechanism is through stimulation of endogenous neural stem cells in the spinal cord.
  • Many therapies stimulate remyelination of spinal axons.  Trauma damages not only axons and neurons but also oligodendroglia responsible for myelinating axons in the spinal cord.  Remyelination decreases with age [186].  In addition, oligodendroglia undergo apoptosis in the spinal cord when exposed to pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha).  Furthermore, regenerating axons are naked and need to be myelinated in order to function optimally.  Fortunately, many therapies remyelinate the spinal cord.
    • Oligodendroglial progenitors.  These are cells that make oligodendroglia and can be derived from embryonic stem cells or neural stem cells.  Many investigators have shown that these cells will remyelinate the spinal cord [187]. Geron is planning a clinical trial to assess the effects of pre-differentiated oligodendroglia progenitor cells derived from human embryonic stem cells [188].
    • Schwann cells.  These are of course the cells that myelinate peripheral axons.  Schwann cells sometimes invade into the spinal cord injury site and, when they do invade, will remyelinate most of the spinal axons.   Transplanted Schwann cells were the first transplanted cells to remyelinate axons of the central nervous system [189].  The Schwann cells can also be genetically modified to express molecules that facilitate myelination [55].   However, they have been reported to be non-contributory to regeneration [190].
    • Olfactory ensheathing glia.  In addition to facilitating regeneration [191], OEG cells not only stimulate myelination [192, 193] but themselves can myelinate axons [194, 195] like Schwann cells. These cells can be obtained from adult olfactory bulb and nasal mucosa [196] and fetal olfactory bulb.  The first would be autografts and the latter would be heterografts.
    • Mesenchymal stem cells.  These have been reported to stimulate remyelination in rats [197].  Likewise, bone marrow cells have been reported to stimulate remyelination of the spinal cord [85, 198-201].
    • Myelination antibodies.  Several IgM antibodies have been reported to stimulate remyelination in the spinal cord.  The mechanism is not well understood but these antibodies appear to working as signalling antibodies that stimulate remyelination to occur in the spinal cord [202-204].
  • Combination therapies are necessary for significant regeneration.  It has become clear that combination therapies are necessary for the cure of spinal cord injury.  No single therapy can address all the obstacles to regeneration and neuronal replacement in the spinal cord.  In order for rivers of axons to cross the spinal cord injury site, therapies will need to address at least three obstacles:
    • Bridge the injury site.  Shortly after injury, the injury site is often filled with inflammatory cells and is bereft of cellular adhesion molecules that may help guide and facilitate axonal growth.  In chronic spinal cord injury, the injury site is often walled off by astrocytes that may consider the injury site to be “outside” of the central nervous system.  The extracellular matrix may be filled with CSPG.  To get around this, it is often useful to transplant cells that can “bridge” the gap and allow axons to growth through the injury site.  Many cells can serve this purpose, including astrocytes, olfactory ensheathing glia, umbilical cord blood mononuclear cells, mesenchymal stem cells, and others.
    • Sustained source of growth factors.  Axonal regeneration is very slow, probably no faster than a millimeter per day.  Therefore, a source of sustained growth factor is necessary for long-distance and long-term growth.  These include cells that secrete neurotrophins and a means of stimulating them to do so for long periods.  We recently discovered that lithium stimulates umbilical cord blood mononuclear cells to secrete three of the most important neurotrophins and therefore have proposed a clinical trial to test the effects of combination umbilical cord blood mononuclear cell transplants and lithium.
    • Block growth inhibitors.  At least two known proteins are known to inhibit axonal growth in the spinal cord.  The first is Nogo and several therapies are known to block Nogo, including antibodies against Nogo, Nogo receptor blockers, and blockers of rho [26] or rho kinase that mediate the effects of Nogo.  The second is CSPG and chondroitinase is known to break down CSPG and allow regeneration.  An alternative is a molecule called decorin, which inhibits CSPG production and may allow axonal growth to occur in chronic spinal cord injury [205, 206].

One legitimate question that might be asked is why we don’t have a cure for spinal cord injury already, given all these treatments that regenerate and remyelinate the spinal cords of animals?  Scientists design their experiments to show the possibilities of therapies, choosing models and outcome measures that maximally reflect the benefits of the therapies.  In the clinical situation, different obstacles to regeneration and recovery may be present, such as learned non-use, atrophy, spasticity, and pain.  Of course, animals aren’t being told by their doctors that they won’t walk.  They keep trying.  Animal models of spinal cord differ from the human situation in one important respect.  The distances that axons have to regrow in a rat are much shorter than those in the human.  Finally, few of these therapies have been tried in clinical trials.  When they have been applied, it is often in situations that mitigated against showing the therapeutic efficacy, e.g. using cells that are not immune-matched for transplantation, not addressing all the obstacles to regeneration, not including rehabilitation in the clinical trial protocol, and not providing credible documentation of patient recovery.

In summary, there are many reasons to be optimistic that there will be not just one but many “cures” for spinal cord injury.  I defined a cure as a treatment that would make it so that an observer who did not know you wouldn’t be able to tell that you have spinal cord injury.  I believe that there will be a cure because much data indicate that the spinal cord can regenerate and many therapies restore function in animal studies.  One or more of these will be shown to be successful in people in the coming years, hopefully sooner rather than later.  At the present, we don’t have the clinical trial infrastructure to test all the therapies that have shown promise in animal models.  It is likely that some combination of the therapies will provide cures.  However, we must be aware that the translation of findings from animal studies to human clinical trials will not necessarily be smooth and there will be bumps along the way.

References

  1. Blight AR (1983).  Cellular morphology of chronic spinal cord injury in the cat: analysis of myelinated axons by line-sampling.  Neuroscience 10: 521-43.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=6633870
  2. Ditunno JF, Scivoletto G, Patrick M, Biering-Sorensen F, Abel R and Marino R (2008).  Validation of the walking index for spinal cord injury in a US and European clinical population.  Spinal Cord 46: 181-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17502878
  3. Lurie DI and Selzer ME (1991).  Preferential regeneration of spinal axons through the scar in hemisected lamprey spinal cord.  J Comp Neurol 313: 669-79.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1783686
  4. Tseng AS and Levin M (2008).  Tail regeneration in Xenopus laevis as a model for understanding tissue repair.  J Dent Res 87: 806-16.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18719206
  5. Takeda A, Nakano M, Goris RC and Funakoshi K (2008).  Adult neurogenesis with 5-HT expression in lesioned goldfish spinal cord.  Neuroscience 151: 1132-41.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18222047
  6. David S and Aguayo AJ (1985).  Axonal regeneration after crush injury of rat central nervous system fibres innervating peripheral nerve grafts.  J Neurocytol 14: 1-12.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=4009210
  7. Richardson PM, Issa VM and Aguayo AJ (1984).  Regeneration of long spinal axons in the rat.  J Neurocytol 13: 165-82.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=6707710
  8. Aguayo AJ, David S and Bray GM (1981).  Influences of the glial environment on the elongation of axons after injury: transplantation studies in adult rodents.  J Exp Biol 95: 231-40.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7334319
  9. Xie F and Zheng B (2008).  White matter inhibitors in CNS axon regeneration failure.  Exp Neurol 209: 302-12.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17706966
  10. Yu P, Huang L, Zou J, Yu Z, Wang Y, Wang X, Xu L, Liu X, Xu XM and Lu PH (2008).  Immunization with recombinant Nogo-66 receptor (NgR) promotes axonal regeneration and recovery of function after spinal cord injury in rats.  Neurobiol Dis  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18930141
  11. Freund P, Wannier T, Schmidlin E, Bloch J, Mir A, Schwab ME and Rouiller EM (2007).  Anti-Nogo-A antibody treatment enhances sprouting of corticospinal axons rostral to a unilateral cervical spinal cord lesion in adult macaque monkey.  J Comp Neurol 502: 644-59.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17394135
  12. MacDermid VE, McPhail LT, Tsang B, Rosenthal A, Davies A and Ramer MS (2004).  A soluble Nogo receptor differentially affects plasticity of spinally projecting axons.  Eur J Neurosci 20: 2567-79.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15548200
  13. Wang X, Baughman KW, Basso DM and Strittmatter SM (2006).  Delayed Nogo receptor therapy improves recovery from spinal cord contusion.  Ann Neurol 60: 540-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16958113
  14. Mi S, Hu B, Hahm K, Luo Y, Kam Hui ES, Yuan Q, Wong WM, Wang L, Su H, Chu TH, Guo J, Zhang W, So KF, Pepinsky B, Shao Z, Graff C, Garber E, Jung V, Wu EX and Wu W (2007).  LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis.  Nat Med 13: 1228-33.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17906634
  15. Fu QL, Hu B, Wu W, Pepinsky RB, Mi S and So KF (2008).  Blocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection.  Invest Ophthalmol Vis Sci 49: 975-85.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18326721
  16. Gopalakrishnan SM, Teusch N, Imhof C, Bakker MH, Schurdak M, Burns DJ and Warrior U (2008).  Role of Rho kinase pathway in chondroitin sulfate proteoglycan-mediated inhibition of neurite outgrowth in PC12 cells.  J Neurosci Res 86: 2214-26.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18438921
  17. Kubo T and Yamashita T (2007).  Rho-ROCK inhibitors for the treatment of CNS injury.  Recent Patents CNS Drug Discov 2: 173-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18221230
  18. Kubo T, Hata K, Yamaguchi A and Yamashita T (2007).  Rho-ROCK inhibitors as emerging strategies to promote nerve regeneration.  Curr Pharm Des 13: 2493-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17692017
  19. Hata K, Fujitani M, Yasuda Y, Doya H, Saito T, Yamagishi S, Mueller BK and Yamashita T (2006).  RGMa inhibition promotes axonal growth and recovery after spinal cord injury.  J Cell Biol 173: 47-58.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16585268
  20. Mueller BK, Mack H and Teusch N (2005).  Rho kinase, a promising drug target for neurological disorders.  Nat Rev Drug Discov 4: 387-98.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15864268
  21. Monnier PP, Sierra A, Schwab JM, Henke-Fahle S and Mueller BK (2003).  The Rho/ROCK pathway mediates neurite growth-inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar.  Mol Cell Neurosci 22: 319-30.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12691734
  22. Fournier AE, Takizawa BT and Strittmatter SM (2003).  Rho kinase inhibition enhances axonal regeneration in the injured CNS.  J Neurosci 23: 1416-23.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12598630
  23. Dergham P, Ellezam B, Essagian C, Avedissian H, Lubell WD and McKerracher L (2002).  Rho signaling pathway targeted to promote spinal cord repair.  J Neurosci 22: 6570-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12151536
  24. Ellezam B, Dubreuil C, Winton M, Loy L, Dergham P, Selles-Navarro I and McKerracher L (2002).  Inactivation of intracellular Rho to stimulate axon growth and regeneration.  Prog Brain Res 137: 371-80.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12440379
  25. Dubreuil CI, Winton MJ and McKerracher L (2003).  Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system.  J Cell Biol 162: 233-43.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12860969
  26. McKerracher L and Higuchi H (2006).  Targeting Rho to stimulate repair after spinal cord injury.  J Neurotrauma 23: 309-17.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16629618
  27. Baptiste DC and Fehlings MG (2007).  Update on the treatment of spinal cord injury.  Prog Brain Res 161: 217-33.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17618980
  28. Wang H, Katagiri Y, McCann TE, Unsworth E, Goldsmith P, Yu ZX, Tan F, Santiago L, Mills EM, Wang Y, Symes AJ and Geller HM (2008).  Chondroitin-4-sulfation negatively regulates axonal guidance and growth.  J Cell Sci 121: 3083-91.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18768934
  29. Vahidi B, Park JW, Kim HJ and Jeon NL (2008).  Microfluidic-based strip assay for testing the effects of various surface-bound inhibitors in spinal cord injury.  J Neurosci Methods 170: 188-96.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18314199
  30. Iseda T, Okuda T, Kane-Goldsmith N, Mathew M, Ahmed S, Chang YW, Young W and Grumet M (2008).  Single, high-dose intraspinal injection of chondroitinase reduces glycosaminoglycans in injured spinal cord and promotes corticospinal axonal regrowth after hemisection but not contusion.  J Neurotrauma 25: 334-49.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18373483
  31. Shields LB, Zhang YP, Burke DA, Gray R and Shields CB (2008).  Benefit of chondroitinase ABC on sensory axon regeneration in a laceration model of spinal cord injury in the rat.  Surg Neurol 69: 568-77; discussion 577.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18486695
  32. Nakamae T, Tanaka N, Nakanishi K, Kamei N, Sasaki H, Hamasaki T, Yamada K, Yamamoto R, Mochizuki Y and Ochi M (2008).  Chondroitinase ABC promotes corticospinal axon growth in organotypic cocultures.  Spinal Cord  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18542086
  33. Tester NJ and Howland DR (2008).  Chondroitinase ABC improves basic and skilled locomotion in spinal cord injured cats.  Exp Neurol 209: 483-96.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17936753
  34. Song H, Ming G, He Z, Lehmann M, McKerracher L, Tessier-Lavigne M and Poo M (1998).  Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides.  Science 281: 1515-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9727979
  35. Hannila SS and Filbin MT (2007).  The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury.  Exp Neurol  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17720160
  36. Hannila SS and Filbin MT (2008).  The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury.  Exp Neurol 209: 321-32.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17720160
  37. Bhatt DH, Otto SJ, Depoister B and Fetcho JR (2004).  Cyclic AMP-induced repair of zebrafish spinal circuits.  Science 305: 254-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15247482
  38. Pearse DD, Pereira FC, Marcillo AE, Bates ML, Berrocal YA, Filbin MT and Bunge MB (2004).  cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury.  Nat Med 10: 610-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15156204
  39. Bunge MB (2008).  Novel combination strategies to repair the injured mammalian spinal cord.  J Spinal Cord Med 31: 262-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18795474
  40. Zhang HT, Gao ZY, Chen YZ and Wang TH (2008).  Temporal changes in the level of neurotrophins in the spinal cord and associated precentral gyrus following spinal hemisection in adult Rhesus monkeys.  J Chem Neuroanat  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18692128
  41. Zhang X, Zeng Y, Zhang W, Wang J, Wu J and Li J (2007).  Co-transplantation of neural stem cells and NT-3-overexpressing Schwann cells in transected spinal cord.  J Neurotrauma 24: 1863-77.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18159998
  42. Guo JS, Zeng YS, Li HB, Huang WL, Liu RY, Li XB, Ding Y, Wu LZ and Cai DZ (2007).  Cotransplant of neural stem cells and NT-3 gene modified Schwann cells promote the recovery of transected spinal cord injury.  Spinal Cord 45: 15-24.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16773039
  43. Sharma HS (2007).  Neurotrophic factors in combination: a possible new therapeutic strategy to influence pathophysiology of spinal cord injury and repair mechanisms.  Curr Pharm Des 13: 1841-74.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17584113
  44. Kamei N, Tanaka N, Oishi Y, Hamasaki T, Nakanishi K, Sakai N and Ochi M (2007).  BDNF, NT-3, and NGF released from transplanted neural progenitor cells promote corticospinal axon growth in organotypic cocultures.  Spine 32: 1272-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17515814
  45. Iarikov DE, Kim BG, Dai HN, McAtee M, Kuhn PL and Bregman BS (2007).  Delayed transplantation with exogenous neurotrophin administration enhances plasticity of corticofugal projections after spinal cord injury.  J Neurotrauma 24: 690-702.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17439351
  46. Hendriks WT, Ruitenberg MJ, Blits B, Boer GJ and Verhaagen J (2004).  Viral vector-mediated gene transfer of neurotrophins to promote regeneration of the injured spinal cord.  Prog Brain Res 146: 451-76.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14699980
  47. Bretzner F, Liu J, Currie E, Roskams AJ and Tetzlaff W (2008).  Undesired effects of a combinatorial treatment for spinal cord injury–transplantation of olfactory ensheathing cells and BDNF infusion to the red nucleus.  Eur J Neurosci 28: 1795-807.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18973595
  48. Furukawa S and Furukawa Y (2007).  [FGF-2-treatment improves locomotor function via axonal regeneration in the transected rat spinal cord].  Brain Nerve 59: 1333-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18095482
  49. Lee MJ, Chen CJ, Cheng CH, Huang WC, Kuo HS, Wu JC, Tsai MJ, Huang MC, Chang WC and Cheng H (2008).  Combined treatment using peripheral nerve graft and FGF-1: changes to the glial environment and differential macrophage reaction in a complete transected spinal cord.  Neurosci Lett 433: 163-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18291581
  50. Kwiecien JM and Avram R (2008).  Long-distance axonal regeneration in the filum terminale of adult rats is regulated by ependymal cells.  J Neurotrauma 25: 196-204.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18352833
  51. Zhang Y, Yeh J, Richardson PM and Bo X (2008).  Cell adhesion molecules of the immunoglobulin superfamily in axonal regeneration and neural repair.  Restor Neurol Neurosci 26: 81-96.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18820404
  52. Chen J, Wu J, Apostolova I, Skup M, Irintchev A, Kugler S and Schachner M (2007).  Adeno-associated virus-mediated L1 expression promotes functional recovery after spinal cord injury.  Brain 130: 954-69.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17438016
  53. Deumens R, Lubbers M, Jaken RJ, Meijs MF, Thurlings RM, Honig WM, Schachner M, Brook GA and Joosten EA (2007).  Mice lacking L1 have reduced CGRP fibre in-growth into spinal transection lesions.  Neurosci Lett 420: 277-81.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17540505
  54. Chaudhry N, de Silva U and Smith GM (2006).  Cell adhesion molecule L1 modulates nerve-growth-factor-induced CGRP-IR fiber sprouting.  Exp Neurol 202: 238-49.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16860320
  55. Papastefanaki F, Chen J, Lavdas AA, Thomaidou D, Schachner M and Matsas R (2007).  Grafts of Schwann cells engineered to express PSA-NCAM promote functional recovery after spinal cord injury.  Brain 130: 2159-74.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17626035
  56. Jakovcevski I, Wu J, Karl N, Leshchyns’ka I, Sytnyk V, Chen J, Irintchev A and Schachner M (2007).  Glial scar expression of CHL1, the close homolog of the adhesion molecule L1, limits recovery after spinal cord injury.  J Neurosci 27: 7222-33.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17611275
  57. Lopez-Vales R, Fores J, Navarro X and Verdu E (2007).  Chronic transplantation of olfactory ensheathing cells promotes partial recovery after complete spinal cord transection in the rat.  Glia 55: 303-11.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17096411
  58. Raisman G (2007).  Repair of spinal cord injury by transplantation of olfactory ensheathing cells.  C R Biol 330: 557-60.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17631453
  59. Richter MW and Roskams AJ (2007).  Olfactory ensheathing cell transplantation following spinal cord injury: Hype or hope?  Exp Neurol  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17643431
  60. Zhang J, Wang B, Xiao Z, Zhao Y, Chen B, Han J, Gao Y, Ding W, Zhang H and Dai J (2008).  Olfactory ensheathing cells promote proliferation and inhibit neuronal differentiation of neural progenitor cells through activation of Notch signaling.  Neuroscience 153: 406-13.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18400409
  61. Yuan TF (2008).  Olfactory ensheathing cells transplantation for spinal cord injury treatment: still a long way to go.  Med Hypotheses 71: 153-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18316162
  62. Wu J, Sun TS, Ren JX and Wang XZ (2008).  Ex vivo non-viral vector-mediated neurotrophin-3 gene transfer to olfactory ensheathing glia: effects on axonal regeneration and functional recovery after implantation in rats with spinal cord injury.  Neurosci Bull 24: 57-65.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18369383
  63. Shyu WC, Liu DD, Lin SZ, Li WW, Su CY, Chang YC, Wang HJ, Wang HW, Tsai CH and Li H (2008).  Implantation of olfactory ensheathing cells promotes neuroplasticity in murine models of stroke.  J Clin Invest 118: 2482-95.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18596986
  64. Richter MW and Roskams AJ (2008).  Olfactory ensheathing cell transplantation following spinal cord injury: hype or hope?  Exp Neurol 209: 353-67.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17643431
  65. Richter M, Westendorf K and Roskams AJ (2008).  Culturing olfactory ensheathing cells from the mouse olfactory epithelium.  Methods Mol Biol 438: 95-102.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18369752
  66. Radtke C, Sasaki M, Lankford KL, Vogt PM and Kocsis JD (2008).  Potential of olfactory ensheathing cells for cell-based therapy in spinal cord injury.  J Rehabil Res Dev 45: 141-52.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18566933
  67. Mackay-Sim A, Feron F, Cochrane J, Bassingthwaighte L, Bayliss C, Davies W, Fronek P, Gray C, Kerr G, Licina P, Nowitzke A, Perry C, Silburn PA, Urquhart S and Geraghty T (2008).  Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial.  Brain 131: 2376-86.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18689435
  68. Kubasak MD, Jindrich DL, Zhong H, Takeoka A, McFarland KC, Munoz-Quiles C, Roy RR, Edgerton VR, Ramon-Cueto A and Phelps PE (2008).  OEG implantation and step training enhance hindlimb-stepping ability in adult spinal transected rats.  Brain 131: 264-76.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18056162
  69. Iwatsuki K, Yoshimine T, Kishima H, Aoki M, Yoshimura K, Ishihara M, Ohnishi Y and Lima C (2008).  Transplantation of olfactory mucosa following spinal cord injury promotes recovery in rats.  Neuroreport 19: 1249-52.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18695502
  70. Barnett SC and Riddell JS (2007).  Olfactory ensheathing cell transplantation as a strategy for spinal cord repair–what can it achieve?  Nat Clin Pract Neurol 3: 152-61.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17342191
  71. Li Y, Yamamoto M, Raisman G, Choi D and Carlstedt T (2007).  An experimental model of ventral root repair showing the beneficial effect of transplanting olfactory ensheathing cells.  Neurosurgery 60: 734-40; discussion 740-1.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17415211
  72. Pearse DD, Sanchez AR, Pereira FC, Andrade CM, Puzis R, Pressman Y, Golden K, Kitay BM, Blits B, Wood PM and Bunge MB (2007).  Transplantation of Schwann cells and/or olfactory ensheathing glia into the contused spinal cord: Survival, migration, axon association, and functional recovery.  Glia 55: 976-1000.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17526000
  73. Li Y, Li D and Raisman G (2007).  Transplanted Schwann cells, not olfactory ensheathing cells, myelinate optic nerve fibres.  Glia 55: 312-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17099888
  74. Cho SR, Yang MS, Yim SH, Park JH, Lee JE, Eom YW, Jang IK, Kim HE, Park JS, Kim HO, Lee BH, Park CI and Kim YJ (2008).  Neurally induced umbilical cord blood cells modestly repair injured spinal cords.  Neuroreport 19: 1259-63.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18695504
  75. Chen CT, Foo NH, Liu WS and Chen SH (2008).  Infusion of human umbilical cord blood cells ameliorates hind limb dysfunction in experimental spinal cord injury through anti-inflammatory, vasculogenic and neurotrophic mechanisms.  Pediatr neonatol 49: 77-83.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18947003
  76. Lim JH, Byeon YE, Ryu HH, Jeong YH, Lee YW, Kim WH, Kang KS and Kweon OK (2007).  Transplantation of canine umbilical cord blood-derived mesenchymal stem cells in experimentally induced spinal cord injured dogs.  J Vet Sci 8: 275-82.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17679775
  77. Nishio Y, Koda M, Kamada T, Someya Y, Yoshinaga K, Okada S, Harada H, Okawa A, Moriya H and Yamazaki M (2006).  The use of hemopoietic stem cells derived from human umbilical cord blood to promote restoration of spinal cord tissue and recovery of hindlimb function in adult rats.  J Neurosurg Spine 5: 424-33.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17120892
  78. Kuh SU, Cho YE, Yoon DH, Kim KN and Ha Y (2005).  Functional recovery after human umbilical cord blood cells transplantation with brain-derived neutrophic factor into the spinal cord injured rat.  Acta Neurochir (Wien) 147: 985-92.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16010451
  79. Zhao ZM, Li HJ, Liu HY, Lu SH, Yang RC, Zhang QJ and Han ZC (2004).  Intraspinal transplantation of CD34+ human umbilical cord blood cells after spinal cord hemisection injury improves functional recovery in adult rats.  Cell Transplant 13: 113-22.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15129757
  80. Kao CH, Chen SH, Chio CC and Lin MT (2008).  Human umbilical cord blood-derived CD34+ cells may attenuate spinal cord injury by stimulating vascular endothelial and neurotrophic factors.  Shock 29: 49-55.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17666954
  81. Dasari VR, Spomar DG, Li L, Gujrati M, Rao JS and Dinh DH (2008).  Umbilical cord blood stem cell mediated downregulation of fas improves functional recovery of rats after spinal cord injury.  Neurochem Res 33: 134-49.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17703359
  82. Dasari VR, Spomar DG, Gondi CS, Sloffer CA, Saving KL, Gujrati M, Rao JS and Dinh DH (2007).  Axonal remyelination by cord blood stem cells after spinal cord injury.  J Neurotrauma 24: 391-410.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17376002
  83. Barrette B, Hebert MA, Filali M, Lafortune K, Vallieres N, Gowing G, Julien JP and Lacroix S (2008).  Requirement of myeloid cells for axon regeneration.  J Neurosci 28: 9363-76.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18799670
  84. Harris DT (2008).  Cord Blood Stem Cells: A Review of Potential Neurological Applications.  Stem Cell Rev  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18679834
  85. Parr AM, Tator CH and Keating A (2007).  Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury.  Bone Marrow Transplant 40: 609-19.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17603514
  86. Parr AM, Kulbatski I and Tator CH (2007).  Transplantation of adult rat spinal cord stem/progenitor cells for spinal cord injury.  J Neurotrauma 24: 835-45.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17518538
  87. Parr AM and Tator CH (2007).  Intrathecal epidermal growth factor and fibroblast growth factor-2 exacerbate meningeal proliferative lesions associated with intrathecal catheters.  Neurosurgery 60: 926-33; discussion 926-33.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17460529
  88. Yang CC, Shih YH, Ko MH, Hsu SY, Cheng H and Fu YS (2008).  Transplantation of human umbilical mesenchymal stem cells from Wharton’s jelly after complete transection of the rat spinal cord.  PLoS ONE 3: e3336.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18852872
  89. Wu J, Feng D and Yang T (2007).  [Effect of transplanting marrow mesenchymal stem cells via subarachnoid space on spinal cord injury and T cell subpopulation in rats].  Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 21: 492-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17578289
  90. Andrews EM, Tsai SY, Johnson SC, Farrer JR, Wagner JP, Kopen GC and Kartje GL (2008).  Human adult bone marrow-derived somatic cell therapy results in functional recovery and axonal plasticity following stroke in the rat.  Exp Neurol 211: 588-92.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18440506
  91. Carvalho KA, Vialle EN, Moreira GH, Cunha RC, Simeoni RB, Francisco JC, Guarita-Souza LC, Oliveira L, Zocche L and Olandoski M (2008).  Functional outcome of bone marrow stem cells (CD45(+)/CD34(-)) after cell therapy in chronic spinal cord injury in Wistar rats.  Transplant Proc 40: 845-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18455033
  92. White RE and Jakeman LB (2008).  Don’t fence me in: Harnessing the beneficial roles of astrocytes for spinal cord repair.  Restor Neurol Neurosci 26: 197-214.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18820411
  93. Davies JE, Proschel C, Zhang N, Noble M, Mayer-Proschel M and Davies SJ (2008).  Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury.  J Biol 7: 24.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18803859
  94. Imaizumi T, Lankford KL, Kocsis JD and Hashi K (2001).  [The role of transplanted astrocytes for the regeneration of CNS axons].  No To Shinkei 53: 632-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11517487
  95. Kulbatski I, Mothe AJ, Parr AM, Kim H, Kang CE, Bozkurt G and Tator CH (2008).  Glial precursor cell transplantation therapy for neurotrauma and multiple sclerosis.  Prog Histochem Cytochem 43: 123-76.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18706353
  96. Pfeifer K, Vroemen M, Caioni M, Aigner L, Bogdahn U and Weidner N (2006).  Autologous adult rodent neural progenitor cell transplantation represents a feasible strategy to promote structural repair in the chronically injured spinal cord.  Regen Med 1: 255-66.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17465808
  97. Okano H (2006).  Adult neural stem cells and central nervous system repair.  Ernst Schering Res Found Workshop 215-28.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16903425
  98. Okano H, Kaneko S, Okada S, Iwanami A, Nakamura M and Toyama Y (2007).  Regeneration-based therapies for spinal cord injuries.  Neurochem Int 51: 68-73.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17544171
  99. Kim BG, Hwang DH, Lee SI, Kim EJ and Kim SU (2007).  Stem cell-based cell therapy for spinal cord injury.  Cell Transplant 16: 355-64.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17658126
  100. Tang BL and Low CB (2007).  Genetic manipulation of neural stem cells for transplantation into the injured spinal cord.  Cell Mol Neurobiol 27: 75-85.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17151948
  101. Ao Q, Wang AJ, Chen GQ, Wang SJ, Zuo HC and Zhang XF (2007).  Combined transplantation of neural stem cells and olfactory ensheathing cells for the repair of spinal cord injuries.  Med Hypotheses 69: 1234-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17548168
  102. Meletis K, Barnabe-Heider F, Carlen M, Evergren E, Tomilin N, Shupliakov O and Frisen J (2008).  Spinal cord injury reveals multilineage differentiation of ependymal cells.  PLoS Biol 6: e182.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18651793
  103. Lee KH, Yoon DH, Park YG and Lee BH (2005).  Effects of glial transplantation on functional recovery following acute spinal cord injury.  J Neurotrauma 22: 575-89.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15892602
  104. Jiang S, Khan MI, Middlemiss PJ, Lu Y, Werstiuk ES, Crocker CE, Ciccarelli R, Caciagli F and Rathbone MP (2004).  AIT-082 and methylprednisolone singly, but not in combination, enhance functional and histological improvement after acute spinal cord injury in rats.  Int J Immunopathol Pharmacol 17: 353-66.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15461869
  105. Rathbone MP, Middlemiss PJ, Gysbers JW, Andrew C, Herman MA, Reed JK, Ciccarelli R, Di Iorio P and Caciagli F (1999).  Trophic effects of purines in neurons and glial cells.  Prog Neurobiol 59: 663-90.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10845757
  106. Bohnert DM, Purvines S, Shapiro S and Borgens RB (2007).  Simultaneous application of two neurotrophic factors after spinal cord injury.  J Neurotrauma 24: 846-63.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17518539
  107. Bolsover S, Fabes J and Anderson PN (2008).  Axonal guidance molecules and the failure of axonal regeneration in the adult mammalian spinal cord.  Restor Neurol Neurosci 26: 117-30.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18820406
  108. Du J, Fu C and Sretavan DW (2007).  Eph/ephrin signaling as a potential therapeutic target after central nervous system injury.  Curr Pharm Des 13: 2507-18.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17692019
  109. Niclou SP, Ehlert EM and Verhaagen J (2006).  Chemorepellent axon guidance molecules in spinal cord injury.  J Neurotrauma 23: 409-21.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16629626
  110. Willson CA, Irizarry-Ramirez M, Gaskins HE, Cruz-Orengo L, Figueroa JD, Whittemore SR and Miranda JD (2002).  Upregulation of EphA receptor expression in the injured adult rat spinal cord.  Cell Transplant 11: 229-39.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12075988
  111. Miranda JD, White LA, Marcillo AE, Willson CA, Jagid J and Whittemore SR (1999).  Induction of Eph B3 after spinal cord injury.  Exp Neurol 156: 218-22.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10192794
  112. Fabes J, Anderson P, Brennan C and Bolsover S (2007).  Regeneration-enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord.  Eur J Neurosci 26: 2496-505.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17970742
  113. Goldshmit Y, Galea MP, Wise G, Bartlett PF and Turnley AM (2004).  Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice.  J Neurosci 24: 10064-73.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15537875
  114. Guo J, Su H, Zeng Y, Liang YX, Wong WM, Ellis-Behnke RG, So KF and Wu W (2007).  Reknitting the injured spinal cord by self-assembling peptide nanofiber scaffold.  Nanomedicine 3: 311-21.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17964861
  115. Ellis-Behnke RG, Liang YX, Tay DK, Kau PW, Schneider GE, Zhang S, Wu W and So KF (2006).  Nano hemostat solution: immediate hemostasis at the nanoscale.  Nanomedicine 2: 207-15.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17292144
  116. Tysseling-Mattiace VM, Sahni V, Niece KL, Birch D, Czeisler C, Fehlings MG, Stupp SI and Kessler JA (2008).  Self-assembling nanofibers inhibit glial scar formation and promote axon elongation after spinal cord injury.  J Neurosci 28: 3814-23.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18385339
  117. Hejcl A, Lesny P, Pradny M, Michalek J, Jendelova P, Stulik J and Sykova E (2008).  Biocompatible hydrogels in spinal cord injury repair.  Physiol Res  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18481908
  118. Horn EM, Beaumont M, Shu XZ, Harvey A, Prestwich GD, Horn KM, Gibson AR, Preul MC and Panitch A (2007).  Influence of cross-linked hyaluronic acid hydrogels on neurite outgrowth and recovery from spinal cord injury.  J Neurosurg Spine 6: 133-40.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17330580
  119. Sykova E, Jendelova P, Urdzikova L, Lesny P and Hejcl A (2006).  Bone marrow stem cells and polymer hydrogels–two strategies for spinal cord injury repair.  Cell Mol Neurobiol 26: 1113-29.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16633897
  120. Jain A, Kim YT, McKeon RJ and Bellamkonda RV (2006).  In situ gelling hydrogels for conformal repair of spinal cord defects, and local delivery of BDNF after spinal cord injury.  Biomaterials 27: 497-504.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16099038
  121. Rochkind S, Shahar A, Fliss D, El-Ani D, Astachov L, Hayon T, Alon M, Zamostiano R, Ayalon O, Biton IE, Cohen Y, Halperin R, Schneider D, Oron A and Nevo Z (2006).  Development of a tissue-engineered composite implant for treating traumatic paraplegia in rats.  Eur Spine J 15: 234-45.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16292587
  122. Moore MJ, Friedman JA, Lewellyn EB, Mantila SM, Krych AJ, Ameenuddin S, Knight AM, Lu L, Currier BL, Spinner RJ, Marsh RW, Windebank AJ and Yaszemski MJ (2006).  Multiple-channel scaffolds to promote spinal cord axon regeneration.  Biomaterials 27: 419-29.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16137759
  123. Moore K, MacSween M and Shoichet M (2006).  Immobilized concentration gradients of neurotrophic factors guide neurite outgrowth of primary neurons in macroporous scaffolds.  Tissue Eng 12: 267-78.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16548685
  124. Huang YC, Huang YY, Huang CC and Liu HC (2005).  Manufacture of porous polymer nerve conduits through a lyophilizing and wire-heating process.  J Biomed Mater Res B Appl Biomater 74: 659-64.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15909301
  125. Hurtado A, Moon LD, Maquet V, Blits B, Jerome R and Oudega M (2006).  Poly (D,L-lactic acid) macroporous guidance scaffolds seeded with Schwann cells genetically modified to secrete a bi-functional neurotrophin implanted in the completely transected adult rat thoracic spinal cord.  Biomaterials 27: 430-42.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16102815
  126. Deng QY, Li SR, Cai WQ and Su BY (2006).  Poly-lactic acid and agarose gelatin play an active role in the recovery of spinal cord injury.  Neurosci Bull 22: 73-78.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17687401
  127. Patist CM, Mulder MB, Gautier SE, Maquet V, Jerome R and Oudega M (2004).  Freeze-dried poly(D,L-lactic acid) macroporous guidance scaffolds impregnated with brain-derived neurotrophic factor in the transected adult rat thoracic spinal cord.  Biomaterials 25: 1569-82.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14697859
  128. Carone TW and Hasenwinkel JM (2006).  Mechanical and morphological characterization of homogeneous and bilayered poly(2-hydroxyethyl methacrylate) scaffolds for use in CNS nerve regeneration.  J Biomed Mater Res B Appl Biomater  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16447165
  129. Yu LM, Kazazian K and Shoichet MS (2007).  Peptide surface modification of methacrylamide chitosan for neural tissue engineering applications.  J Biomed Mater Res A 82: 243-55.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17295228
  130. Stokols S and Tuszynski MH (2006).  Freeze-dried agarose scaffolds with uniaxial channels stimulate and guide linear axonal growth following spinal cord injury.  Biomaterials 27: 443-51.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16099032
  131. Stokols S, Sakamoto J, Breckon C, Holt T, Weiss J and Tuszynski MH (2006).  Templated agarose scaffolds support linear axonal regeneration.  Tissue Eng 12: 2777-87.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17518647
  132. Prang P, Muller R, Eljaouhari A, Heckmann K, Kunz W, Weber T, Faber C, Vroemen M, Bogdahn U and Weidner N (2006).  The promotion of oriented axonal regrowth in the injured spinal cord by alginate-based anisotropic capillary hydrogels.  Biomaterials 27: 3560-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16500703
  133. Takenaga M, Ohta Y, Tokura Y, Hamaguchi A, Suzuki N, Nakamura M, Okano H and Igarashi R (2007).  Plasma as a scaffold for regeneration of neural precursor cells after transplantation into rats with spinal cord injury.  Cell Transplant 16: 57-65.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17436855
  134. Petter-Puchner AH, Froetscher W, Krametter-Froetscher R, Lorinson D, Redl H and van Griensven M (2007).  The long-term neurocompatibility of human fibrin sealant and equine collagen as biomatrices in experimental spinal cord injury.  Exp Toxicol Pathol 58: 237-45.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17118635
  135. Cheng H, Huang YC, Chang PT and Huang YY (2007).  Laminin-incorporated nerve conduits made by plasma treatment for repairing spinal cord injury.  Biochem Biophys Res Commun 357: 938-44.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17466943
  136. Taylor SJ and Sakiyama-Elbert SE (2006).  Effect of controlled delivery of neurotrophin-3 from fibrin on spinal cord injury in a long term model.  J Control Release 116: 204-10.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16919351
  137. Taylor SJ, Rosenzweig ES, McDonald JW, 3rd and Sakiyama-Elbert SE (2006).  Delivery of neurotrophin-3 from fibrin enhances neuronal fiber sprouting after spinal cord injury.  J Control Release  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16797770
  138. Wang SS, Hu YY, Luo ZJ, Chen LW, Liu HL, Meng GL, Lu R and Xu XZ (2005).  [Morphology research of the rat sciatic nerve bridged by collage-heparin sulfate scaffold].  Zhonghua Wai Ke Za Zhi 43: 531-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15938914
  139. Wong DY, Leveque JC, Brumblay H, Krebsbach PH, Hollister SJ and Lamarca F (2008).  Macro-architectures in spinal cord scaffold implants influence regeneration.  J Neurotrauma 25: 1027-37.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18721107
  140. Willerth SM and Sakiyama-Elbert SE (2007).  Approaches to neural tissue engineering using scaffolds for drug delivery.  Adv Drug Deliv Rev 59: 325-38.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17482308
  141. Tabesh H, Amoabediny G, Nik NS, Heydari M, Yosefifard M, Siadat SO and Mottaghy K (2008).  The role of biodegradable engineered scaffolds seeded with Schwann cells for spinal cord regeneration.  Neurochem Int  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19084565
  142. Novikova LN, Pettersson J, Brohlin M, Wiberg M and Novikov LN (2008).  Biodegradable poly-beta-hydroxybutyrate scaffold seeded with Schwann cells to promote spinal cord repair.  Biomaterials 29: 1198-206.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18083223
  143. Potter W, Kalil RE and Kao WJ (2008).  Biomimetic material systems for neural progenitor cell-based therapy.  Front Biosci 13: 806-21.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17981590
  144. Itosaka H, Kuroda S, Shichinohe H, Yasuda H, Yano S, Kamei S, Kawamura R, Hida K and Iwasaki Y (2008).  Fibrin matrix provides a suitable scaffold for bone marrow stromal cells transplanted into injured spinal cord: A novel material for CNS tissue engineering.  Neuropathology  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18992011
  145. Huang DW, McKerracher L, Braun PE and David S (1999).  A therapeutic vaccine approach to stimulate axon regeneration in the adult mammalian spinal cord.  Neuron 24: 639-47.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10595515
  146. Hauben E, Ibarra A, Mizrahi T, Barouch R, Agranov E and Schwartz M (2001).  Vaccination with a Nogo-A-derived peptide after incomplete spinal-cord injury promotes recovery via a T-cell-mediated neuroprotective response: comparison with other myelin antigens.  Proc Natl Acad Sci U S A 98: 15173-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11752461
  147. Bourquin C, van der Haar ME, Anz D, Sandholzer N, Neumaier I, Endres S, Skerra A, Schwab ME and Linington C (2008).  DNA vaccination efficiently induces antibodies to Nogo-A and does not exacerbate experimental autoimmune encephalomyelitis.  Eur J Pharmacol 588: 99-105.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18495110
  148. Merkler D, Oertle T, Buss A, Pinschewer DD, Schnell L, Bareyre FM, Kerschensteiner M, Buddeberg BS and Schwab ME (2003).  Rapid induction of autoantibodies against Nogo-A and MOG in the absence of an encephalitogenic T cell response: implication for immunotherapeutic approaches in neurological diseases.  Faseb J 17: 2275-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14563689
  149. Ellezam B, Bertrand J, Dergham P and McKerracher L (2003).  Vaccination stimulates retinal ganglion cell regeneration in the adult optic nerve.  Neurobiol Dis 12: 1-10.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12609484
  150. Xu G, Nie DY, Chen JT, Wang CY, Yu FG, Sun L, Luo XG, Ahmed S, David S and Xiao ZC (2004).  Recombinant DNA vaccine encoding multiple domains related to inhibition of neurite outgrowth: a potential strategy for axonal regeneration.  J Neurochem 91: 1018-23.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15525355
  151. Nie DY, Xu G, Ahmed S and Xiao ZC (2007).  DNA vaccine and the CNS axonal regeneration.  Curr Pharm Des 13: 2500-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17692018
  152. Sisken BF, Walker J and Orgel M (1993).  Prospects on clinical applications of electrical stimulation for nerve regeneration.  J Cell Biochem 51: 404-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8496243
  153. Moriarty LJ and Borgens RB (2001).  An oscillating extracellular voltage gradient reduces the density and influences the orientation of astrocytes in injured mammalian spinal cord.  J Neurocytol 30: 45-57.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11577245
  154. Borgens RB (1999).  Electrically mediated regeneration and guidance of adult mammalian spinal axons into polymeric channels.  Neuroscience 91: 251-64.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10336075
  155. Borgens RB and Bohnert DM (1997).  The responses of mammalian spinal axons to an applied DC voltage gradient.  Exp Neurol 145: 376-89.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9217074
  156. Borgens RB, Blight AR and McGinnis ME (1990).  Functional recovery after spinal cord hemisection in guinea pigs: the effects of applied electric fields.  J Comp Neurol 296: 634-53.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2358555
  157. Borgens RB, Blight AR and McGinnis ME (1987).  Behavioral recovery induced by applied electric fields after spinal cord hemisection in guinea pig.  Science 238: 366-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3659920
  158. Borgens RB, Blight AR, Murphy DJ and Stewart L (1986).  Transected dorsal column axons within the guinea pig spinal cord regenerate in the presence of an applied electric field.  J Comp Neurol 250: 168-80.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3489013
  159. Borgens RB, Blight AR and Murphy DJ (1986).  Axonal regeneration in spinal cord injury: a perspective and new technique.  J Comp Neurol 250: 157-67.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3745509
  160. Borgens RB, Roederer E and Cohen MJ (1981).  Enhanced spinal cord regeneration in lamprey by applied electric fields.  Science 213: 611-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7256258
  161. Vivo M, Puigdemasa A, Casals L, Asensio E, Udina E and Navarro X (2008).  Immediate electrical stimulation enhances regeneration and reinnervation and modulates spinal plastic changes after sciatic nerve injury and repair.  Exp Neurol 211: 180-93.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18316076
  162. Ruggieri MR, Braverman AS, D’Andrea L, McCarthy J and Barbe MF (2008).  Functional reinnervation of the canine bladder after spinal root transection and immediate somatic nerve transfer.  J Neurotrauma 25: 214-24.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18352835
  163. Hamid S and Hayek R (2008).  Role of electrical stimulation for rehabilitation and regeneration after spinal cord injury: an overview.  Eur Spine J 17: 1256-69.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18677518
  164. Shapiro S, Borgens R, Pascuzzi R, Roos K, Groff M, Purvines S, Rodgers RB, Hagy S and Nelson P (2005).  Oscillating field stimulation for complete spinal cord injury in humans: a phase 1 trial.  J Neurosurg Spine 2: 3-10.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15658119
  165. Wang R, King T, Ossipov MH, Rossomando AJ, Vanderah TW, Harvey P, Cariani P, Frank E, Sah DW and Porreca F (2008).  Persistent restoration of sensory function by immediate or delayed systemic artemin after dorsal root injury.  Nat Neurosci 11: 488-96.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18344995
  166. Lipson AC, Widenfalk J, Lindqvist E, Ebendal T and Olson L (2003).  Neurotrophic properties of olfactory ensheathing glia.  Exp Neurol 180: 167-71.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12684030
  167. Yuan R, Maeda Y, Li W, Lu W, Cook S and Dowling P (2008).  Erythropoietin: a potent inducer of peripheral immuno/inflammatory modulation in autoimmune EAE.  PLoS ONE 3: e1924.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18382691
  168. Yoo JY, Won YJ, Lee JH, Kim JU, Sung IY, Hwang SJ, Kim MJ and Hong HN (2008).  Neuroprotective effects of erythropoietin posttreatment against kainate-induced excitotoxicity in mixed spinal cultures.  J Neurosci Res  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18711747
  169. Yazihan N, Uzuner K, Salman B, Vural M, Koken T and Arslantas A (2008).  Erythropoietin improves oxidative stress following spinal cord trauma in rats.  Injury  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18635178
  170. Toth C, Martinez JA, Liu WQ, Diggle J, Guo GF, Ramji N, Mi R, Hoke A and Zochodne DW (2008).  Local erythropoietin signaling enhances regeneration in peripheral axons.  Neuroscience 154: 767-83.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18456410
  171. Vitellaro-Zuccarello L, Mazzetti S, Madaschi L, Bosisio P, Fontana E, Gorio A and De Biasi S (2008).  Chronic erythropoietin-mediated effects on the expression of astrocyte markers in a rat model of contusive spinal cord injury.  Neuroscience 151: 452-66.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18065151
  172. Matsuura I, Taniguchi J, Hata K, Saeki N and Yamashita T (2008).  BMP inhibition enhances axonal growth and functional recovery after spinal cord injury.  J Neurochem  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18221366
  173. Liu WL, Lee YH, Tsai SY, Hsu CY, Sun YY, Yang LY, Tsai SH and Yang WC (2008).  Methylprednisolone inhibits the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycans in reactivated astrocytes.  Glia 56: 1390-400.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18618653
  174. Zhang Y, Ghadiri-Sani M, Zhang X, Richardson PM, Yeh J and Bo X (2007).  Induced expression of polysialic acid in the spinal cord promotes regeneration of sensory axons.  Mol Cell Neurosci 35: 109-19.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17363265
  175. Pan HC, Cheng FC, Lai SZ, Yang DY, Wang YC and Lee MS (2008).  Enhanced regeneration in spinal cord injury by concomitant treatment with granulocyte colony-stimulating factor and neuronal stem cells.  J Clin Neurosci 15: 656-64.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18406145
  176. Kerr DA, Llado J, Shamblott MJ, Maragakis NJ, Irani DN, Crawford TO, Krishnan C, Dike S, Gearhart JD and Rothstein JD (2003).  Human embryonic germ cell derivatives facilitate motor recovery of rats with diffuse motor neuron injury.  J Neurosci 23: 5131-40.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12832537
  177. Harper JM, Krishnan C, Darman JS, Deshpande DM, Peck S, Shats I, Backovic S, Rothstein JD and Kerr DA (2004).  Axonal growth of embryonic stem cell-derived motoneurons in vitro and in motoneuron-injured adult rats.  Proc Natl Acad Sci U S A 101: 7123-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15118094
  178. Yang J, Li C and Zhai R (2007).  [Experimental study on transplantation of embryonic stem cells in treating spinal cord injury].  Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 21: 487-91.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17578288
  179. Su H, Chu TH and Wu W (2007).  Lithium enhances proliferation and neuronal differentiation of neural progenitor cells in vitro and after transplantation into the adult rat spinal cord.  Exp Neurol 206: 296-307.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17599835
  180. Dill J, Wang H, Zhou F and Li S (2008).  Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS.  J Neurosci 28: 8914-28.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18768685
  181. Yick LW, So KF, Cheung PT and Wu WT (2004).  Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury.  J Neurotrauma 21: 932-43.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15307905
  182. Huang X, Wu DY, Chen G, Manji H and Chen DF (2003).  Support of retinal ganglion cell survival and axon regeneration by lithium through a Bcl-2-dependent mechanism.  Invest Ophthalmol Vis Sci 44: 347-54.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12506095
  183. Shimizu T, Shibata M, Wakisaka S, Inoue T, Mashimo T and Yoshiya I (2000).  Intrathecal lithium reduces neuropathic pain responses in a rat model of peripheral neuropathy.  Pain 85: 59-64.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10692603
  184. Fornai F, Longone P, Ferrucci M, Lenzi P, Isidoro C, Ruggieri S and Paparelli A (2008).  Autophagy and amyotrophic lateral sclerosis: The multiple roles of lithium.  Autophagy 4: 527-30.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18367867
  185. Fornai F, Longone P, Cafaro L, Kastsiuchenka O, Ferrucci M, Manca ML, Lazzeri G, Spalloni A, Bellio N, Lenzi P, Modugno N, Siciliano G, Isidoro C, Murri L, Ruggieri S and Paparelli A (2008).  Lithium delays progression of amyotrophic lateral sclerosis.  Proc Natl Acad Sci U S A 105: 2052-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18250315
  186. Siegenthaler MM, Ammon DL and Keirstead HS (2008).  Myelin pathogenesis and functional deficits following SCI are age-associated.  Exp Neurol 213: 363-71.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18644369
  187. Imaizumi T, Lankford KL, Burton WV, Fodor WL and Kocsis JD (2000).  Xenotransplantation of transgenic pig olfactory ensheathing cells promotes axonal regeneration in rat spinal cord.  Nat Biotechnol 18: 949-53.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10973214
  188. Coutts M and Keirstead HS (2008).  Stem cells for the treatment of spinal cord injury.  Exp Neurol 209: 368-77.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17950280
  189. Hill CE, Moon LD, Wood PM and Bunge MB (2006).  Labeled Schwann cell transplantation: cell loss, host Schwann cell replacement, and strategies to enhance survival.  Glia 53: 338-43.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16267833
  190. Vroemen M, Caioni M, Bogdahn U and Weidner N (2007).  Failure of Schwann cells as supporting cells for adult neural progenitor cell grafts in the acutely injured spinal cord.  Cell Tissue Res 327: 1-13.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16941122
  191. Santos-Benito FF and Ramon-Cueto A (2003).  Olfactory ensheathing glia transplantation: a therapy to promote repair in the mammalian central nervous system.  Anat Rec B New Anat 271: 77-85.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12619089
  192. Au E, Richter MW, Vincent AJ, Tetzlaff W, Aebersold R, Sage EH and Roskams AJ (2007).  SPARC from olfactory ensheathing cells stimulates Schwann cells to promote neurite outgrowth and enhances spinal cord repair.  J Neurosci 27: 7208-21.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17611274
  193. Boyd JG, Doucette R and Kawaja MD (2005).  Defining the role of olfactory ensheathing cells in facilitating axon remyelination following damage to the spinal cord.  Faseb J 19: 694-703.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15857884
  194. Barnett SC, Alexander CL, Iwashita Y, Gilson JM, Crowther J, Clark L, Dunn LT, Papanastassiou V, Kennedy PG and Franklin RJ (2000).  Identification of a human olfactory ensheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons.  Brain 123 ( Pt 8): 1581-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10908188
  195. Smith PM, Sim FJ, Barnett SC and Franklin RJ (2001).  SCIP/Oct-6, Krox-20, and desert hedgehog mRNA expression during CNS remyelination by transplanted olfactory ensheathing cells.  Glia 36: 342-53.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11746771
  196. Feron F, Perry C, Cochrane J, Licina P, Nowitzke A, Urquhart S, Geraghty T and Mackay-Sim A (2005).  Autologous olfactory ensheathing cell transplantation in human spinal cord injury.  Brain 128: 2951-60.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16219671
  197. Keilhoff G, Stang F, Goihl A, Wolf G and Fansa H (2006).  Transdifferentiated mesenchymal stem cells as alternative therapy in supporting nerve regeneration and myelination.  Cell Mol Neurobiol 26: 1235-52.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16779672
  198. Kocsis JD, Akiyama Y, Lankford KL and Radtke C (2002).  Cell transplantation of peripheral-myelin-forming cells to repair the injured spinal cord.  J Rehabil Res Dev 39: 287-98.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12051471
  199. Akiyama Y, Radtke C and Kocsis JD (2002).  Remyelination of the rat spinal cord by transplantation of identified bone marrow stromal cells.  J Neurosci 22: 6623-30.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12151541
  200. Akiyama Y, Radtke C, Honmou O and Kocsis JD (2002).  Remyelination of the spinal cord following intravenous delivery of bone marrow cells.  Glia 39: 229-36.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12203389
  201. Inoue M, Honmou O, Oka S, Houkin K, Hashi K and Kocsis JD (2003).  Comparative analysis of remyelinating potential of focal and intravenous administration of autologous bone marrow cells into the rat demyelinated spinal cord.  Glia 44: 111-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14515327
  202. Warrington AE and Rodriguez M (2008).  Remyelination-promoting human IgMs: developing a therapeutic reagent for demyelinating disease.  Curr Top Microbiol Immunol 318: 213-39.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18219820
  203. Ciric B, Van Keulen V, Paz Soldan M, Rodriguez M and Pease LR (2004).  Antibody-mediated remyelination operates through mechanism independent of immunomodulation.  J Neuroimmunol 146: 153-61.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14698858
  204. Ciric B, Howe CL, Paz Soldan M, Warrington AE, Bieber AJ, Van Keulen V, Rodriguez M and Pease LR (2003).  Human monoclonal IgM antibody promotes CNS myelin repair independent of Fc function.  Brain Pathol 13: 608-16.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14655764
  205. Davies JE, Tang X, Bournat JC and Davies SJ (2006).  Decorin promotes plasminogen/plasmin expression within acute spinal cord injuries and by adult microglia in vitro.  J Neurotrauma 23: 397-408.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16629625
  206. Davies JE, Tang X, Denning JW, Archibald SJ and Davies SJ (2004).  Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes axon growth across adult rat spinal cord injuries.  Eur J Neurosci 19: 1226-42.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15016081

Ten Frequently Asked Questions Concerning Cure of Spinal Cord Injury

December 21, 2008

Ten Frequently Asked Questions Concerning Cure of Spinal Cord Injury
By Wise Young, Ph.D., M.D., Rutgers University
W. M. Keck Center for Collaborative Neuroscience
Revised 20 December 2008 from 21 July 2004

Many questions recur repeatedly on CareCure every few days.  On 21 July 2004, I posted a summary of answers to the ten most frequently asked questions on CareCure (Link) .  That thread received over 450 responses and over 80,000 page-views. Here, I update some of responses to the questions and will expand each of the answers with sequential articles to follow.

1. Will there be a cure for spinal cord injury?

The answer to this question depends on one’s definition of a cure. If a “cure” requires complete eradication of spinal cord injury, I think that it would unlikely in my lifetime.  If a cure means complete restoration of all functions to pre-injury levels for all people with spinal cord injury, I think that this would also be unlikely.  Not only are we unlikely to be able to reverse aging but we may not be able to reverse all changes in the body due to spinal cord injury.  On the other hand, I believe that there will be therapies that will restore sufficient function to a person with severe spinal cord injury so that a casual third-party observer would not be able to tell that the person had spinal cord injury.  This is a reasonably practical definition of a cure for me and I think that will happen.

2. When will a cure be available?

First generation therapies are already restoring function to people with spinal cord injury, including weight-supported treadmill ambulation training, decompression and untethering of a spinal cord, and Fampridine.  Preliminary data suggest that olfactory ensheathing glia transplants may restore some sensory function but only modest motor function, perhaps because the cells are not HLA-matched and are immune-rejected after a few weeks.  Second generation therapies are in or soon-to-be started clinical trial, including umbilical cord blood mononuclear cells, Schwann cells, and embryonic stem cells.  Several therapies such as Nogo receptor blockers and Nogo antibodies, glial-derived neurotrophic factor, cethrin, and other treatments are already in or are close to clinical trial.  Finally, third generation therapies include combination cell transplants, growth factors, and growth inhibitor blockers.  These should be in clinical trial in the next few years. The timing of clinical trials depends on availability of funding for clinical trials. With sufficient funding, I think that one or more of these clinical trials will yield the first therapies that restore function in chronic spinal cord injury.

3. Will a cure work for chronic spinal cord injury?

I believe there will be effective restorative therapies for chronic spinal cord injury for the following reasons. First, much animal and human data indicate that regeneration of relatively few axons can restore function such as walking, bladder function, and sexual function. This is because the spinal cord contains much of the circuitry necessary to execute and control these functions. Only 10% of the axons in the spinal cord are necessary and sufficient to restore locomotor and other functions.  Second, axons continue to try to regrow for many years after injury. Treatments that provide a path for growth, that negate factors that inhibit growth, and that provide long-term stimulation of axonal growth can restore function.  Third, many people recover function years after injury.  These observations give me hope that there will be therapies that facilitate functional recovery in chronic spinal cord injury.

4. What can I do now to be ready for the cure?

People with spinal cord injury should work hard to take care of their body and to prevent muscle and bone atrophy that may prevent recovery of function. This includes disciplined exercise to maintain their muscle and bone.  They must take care of their skin, bladder, and bowels. People should avoid procedures that cause irreversible loss of peripheral nerve and other functions. On the other hand, it is important to weigh the benefits of procedures such as tendon transfers, which can provide greater functionality and independence for people with weak hands. Likewise, certain procedures such as Mitrofanoff and bladder augmentation to reduce bladder spasticity may provide greater independence but may not be easily reversible.  Finally, many studies have shown that people with the highest levels of education after injury are more likely to have better quality of life and health. It is important that people do not neglect their brain, the most important part of their body.

5. What can I do about spasticity, spasms, and neuropathic pain?

Many people suffer from spasticity (increased tone), spasms (spontaneous movements), and neuropathic pain (in areas below the injury site where there sensory loss). Neurons that have lost their inputs tend to become hyperexcitable. Spasticity is the most common manifestation of spinal motoneurons that have been disconnected from the brain. Several treatments reduce spasticity. The most commonly used anti-spasticity drug is baclofen (a drug that stimulates GABA-B receptors in the spinal cord). Oral doses (80-120 mg/day) of baclofen reduce spasticity.  However, for some people such doses are not enough or have too many side effects.  For these people, it may be useful to combine lower doses of baclofen with clonidine or tizanidine, which activate alpha-adrenergic receptors. While anti-spasticity drugs reduce spasticity, they also weaken muscles and may cause flaccidity and muscle atrophy. So, people should titrate the dose of anti-spasticity drugs so that they retain some muscle tone.  Unless they are taken in doses high enough to cause flaccidity, anti-spasticity drugs usually do not prevent spasms.  However, gabapentin (Neurontin) and other anti-epileptic drugs may reduce both spasms and neuropathic pain.  Neuropathic pain results from increased excitability of sensory neurons that have been disconnected and may manifest in “burning”, “freezing”, or “pressure” pain.  People accommodate to gabapentin and high doses of as much as 4000 mg/day may be necessary for pain relief.  In some people, low doses (20 mg/day) of the tricyclic anti-depressant drug amitriptyline (Elavil) may provide relief from neuropathic pain.  Intrathecal delivery of baclofen or morphine may be necessary.

6. How can I exercise and will it do any good?

Exercise is difficult for paralyzed people and specialized equipment may be necessary.  First, most people should stand for an hour or two every day.  This can be done with standing frames.  A device called a Glider 6000 allows both standing and leg movements.  Second, functional electrical stimulation (FES) can be used to activate muscles.  Arms and legs can be stimulated to pedal exercise devices.  Third, standing, walking, and swimming in a pool allows people to exercise in an environment where the water supports their weight. Fourth, weight-supported treadmill ambulation training improves walking recovery. Finally, people should think about setting aside a month or two every year where they would essentially engage in full-time training. During the rest of the year, they need to maintain the gains that they have achieved by spending an hour or so per day on exercising. Although there have been few formal studies of the subject, many people with spinal cord injury have reported significant increases in the girth of their legs when they use FES regularly.

7. What is osteoporosis, its mechanisms and consequences, and ways to reverse it?

Osteoporosis is bone loss.  It occurs after spinal cord injury, particularly in the pelvis and leg bones below the injury site. The mechanism is not well understood but appears to be related to loss of gravitational and other mechanical stresses on the bone. In acute spinal cord injury, bone begins to decalcify within days after spinal cord injury, with significant increases in urine calcium (hypercalciuria) within 10 days. The pattern of bone loss is 2-4 times greater than those associated with prolonged bed rest without spinal cord injury. Increased dietary calcium intake may slow down but does not prevent the bone loss.  Parathyroid hormone level is usually low in the first year but may increase above normal after the first year. Substantial (25-43%) decreases in bone mineral densities occur in the leg bones within a year and may exceed 50% loss by 10 years.  People with spasticity have less bone loss than those who are flaccid. Osteoporosis is associated with greater fracture rates. The Model Spinal Cord Injury System, for example, reported a 14% incidence of fracture by 5 years after injury, 28% and 39% by 10 and 15 years, usually in the most demineralized bone. People with complete spinal cord injury and paraplegia have ten times greater fracture rates than incomplete injury or tetraplegia. Weight bearing and bicycling with functional electrical stimulation may prevent osteoporosis. Bisphosphonates (Pamidronate) and parathyroid hormone (Teriparatide) can reduce osteoporosis and fracture rates in people with chronic spinal cord injury.  Much research is underway to find effective therapies of osteoporosis.

8.  What is autonomic dysreflexia, its mechanisms and consequences, and treatments?

Autonomic dysreflexia (AD) refers to increased activity of the sympathetic nervous system, associated with profuse sweating, rash, elevated blood pressure, and vasodilation above the injury level.  AD usually causes a headache due to vasodilation of brain blood vessels. Heart rate falls and vision may be blurred. Nasal congestion may be present. Between 40-90% of people with spinal cord injury suffer from AD.  It is more severe in people with spinal cord injury above T6. AD can be triggered by many potential causes, including bladder distension, urinary tract infection, and manipulation of the bowel and bladder system, pain or irritation, menstruation, labor and delivery, sexual intercourse, temperature changes, constrictive clothing, sunburns, and insect bites. When AD occurs, doctors usually catheterize the bladder to ensure adequate urinary drainage, check for fecal impaction manually using lidocaine jelly as a lubricant, and eliminate all other potential causes of irritation to the body. Treatment includes use of the calcium channel blocker Nifedipine (Procardia 10 mg capsule) to reduce blood pressure or adrenergic alpha-receptor blocking agent phenoxybenzamine (10 mg twice a day), mecamylamine (Inversine 2.5 mg orally), and Diazoxide (Hyperstat 1-3 mg/kg).  Doctors in emergency room may not know how to handle AD crises in people with spinal cord injury and it may be useful for patients to carry a card that give treatment instructions.

9. What is syringomyelia, its mechanisms and consequences, and treatments?

Syringomyelia refers to the development a spinal cord cyst that results from enlargement of the central canal. The central canal is typically tiny and not visible on magnetic resonance images (MRI) of the spinal cord. As many as 15% of people develop a syringomyelic cyst in their spinal cords and 5% may show symptoms of pain and loss of function associated with cyst enlargement, as early as one month and as late as 45 years after injury. Pain is the most commonly reported symptom associated with syringomyelia. Other symptoms include increased weakness, loss of sensation, greater spasticity, and increased sweating. The symptoms may be aggravated by postural changes and Valsalva maneuver (that increase pressure in the chest).  It may also be associated with changes in bladder reflexes, autonomic dysreflexia, painless joint deformity or swelling, increased spasticity, dissociation of sensation and temperature, respiratory impairment. Syringomyelic cysts can be observed with MRI scans. It is usually associated with scarring of meninges or arachnoid membranes of the spinal cord, observable with CT-scan with myelography. Surgical intervention is recommended when there is progressive neurological loss. Traditionally, syringomyelia has been treated with shunting of the cyst by placement of a catheter between the cyst and the subarachnoid space or pleural cavity. But shunting alone is frequently associated with shunt blockade within a year. More recent studies suggest that meticulous removal of adhesions with duroplasty (repairing the dura by grafting membrane) to re-establish subarachnoid cerebrospinal fluid flow is more effective and may eliminate the cyst in 80% of cases.

10.  How does spinal cord injury affect sexual function and what can be done to improve such function?

Most people with spinal cord injury above the T10 will continue to have reflex erections associated with stimulation. Some people may have prolonged erections called priapism. A majority can have ejaculation although increased stimulation including vibration may be required. In many people, ejaculation may be retrograde, i.e. the ejaculate goes into the bladder rather comes out, because the external sphincter may be open. Retrograde ejaculation should not be harmful or cause urinary tract infections. A serious associated complication of sexual intercourse in both men and women is the occurrence of autonomic dysreflexia (AD) with orgasm, with associated headaches and other symptoms of AD. These can be treated with drugs to lower blood pressure (see answer to AD above). In addition, sexual intercourse may be associated with increased spasticity and spasms. People with injuries below T10 may have damage to the spinal cord centers responsible for erection and ejaculation. Many techniques are available to increase erection, including drugs such as Sildenafil (Viagra), vacuum pumps, cock rings, and penile prostheses. Several studies have reported that women with “complete” spinal cord injury can achieve orgasms, possibly through neural pathways outside of the spinal cord.

Holiday Hopes for Spinal Cord Injury

December 17, 2008

Holiday Hopes for Spinal Cord Injury
by Wise Young PhD MD
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, Piscataway, NJ 08854-8082
17 December 2008

I write to wish everybody Happy Holidays and to explain why I have so much hope for 2009:

  1. A Renaissance of Stem Cell Research. For nearly 8 years, the Bush Administration has suppressed not only embryonic stem cell (ESC) research but all stem cell research.  Last year, for example, NIH funded only $600 million of stem cell research, i.e. $300 million for animal stem cells, $260 million for human adult stem cells, and $40 million for human ESC.  The total NIH budget was about $30 billion i 2007.  So, even though stem cells are widely acknowledged by scientists to be the most important biomedical advance of the decade, the NIH spent only 2% of its budget on all of stem cell research, only 1% on human stem cells, and less than 0.2% on human ESC research.  The Obama Administration will lift these restrictions and strongly encourage stem cell research.  I hope for a renaissance of stem cell research in 2009.
  2. The Christopher and Dana Reeve Paralysis Act.  In 2003, Christopher Reeve proposed legislation to encourage research to reverse paralysis.  Now called the Christopher and Dana Reeve Paralysis Act (CDRPA), this bill will fund NIH and other governmental agencies to accelerate development of therapies to reverse paralysis.  In 2005 and each year after Christopher Reeve’s untimely death, members of the spinal cord injury community lobbied in Washington DC for the bill.  In 2006, the House and Senate resurrected the bill.  In October 2007, the House of Representatives passed the bill by a large majority and sent the bill to the Senate.  However, Senator Tom Coburn of Oklahoma singlehandedly stopped the bill and prevented it from coming to a vote.  With a larger Democratic majority in the Senate, CRDPA should pass in 2009.  I sincerely hope that it will bring much needed funding for paralysis research and clinical trials for spinal cord injury.
  3. Promising SCI Therapies.  Many therapies improve neurological recovery in animal SCI models.
    • Nogo receptor protein. Biogen recently made a soluble Nogo receptor protein that will bind to all molecules that activate the Nogo receptor.  Animal eperiments suggest that this protein stimulates regeneration after spinal cordinjury. They are thinking of starting clinical trials in China.  I hope so.
    • Chondroitinase. The extracellular matrix of injured spinal cords accumulate a substance called chondroitin-6-sulfate proteoglycan (CSPG) and blocks regeneration.  Chondroitinase is a bacterial enzyme that breaks down CSPG and allows regeneration of axons.  Many laboratories since 2001 have confirmed that chondrotinase facilitates regeneration in the spinal cord of rats.  Acorda Therapeutics licensed this treatment and is developing it.  I hope that it goes into clinical trial.
    • Decorin. This is an extracellular protein that Stephen Davies found to enhance regeneration in the spinal cord.  He is now doing experiments in chronic spinal cord injury.  Decorin is a natural substance that normally “decorates” collagen but is not usually found in the injured spinal cord.  Thus is an interesting and important therapeutic approach to regenerating the spinal cord.  I hope that the experiments in chronic spinal cord injury show positive results.
    • Mesenchymal Stem Cells. These are stem cells present in many tissues, including bone marrow, fat, skin, blood, and gut.  Many laboratories have reported that these mesenchymal stem cells are beneficial in animal models of spinal cord injury, including stimulation of remyelination.  Because these cells would be isolated from the same individuals, they should be immune-compatible.  Many groups are beginning to study such cells for stroke in clinical trial.
    • Induced Pluripotent Stem Cells. Until recently, there were only two source of immune-compatible stem cells for transplantation: umbilical cord blood and bone marrow mesenchymal stem cells.  Now, for the first time, by expressing four genes, scientists can convert skin and other cells to pluripotent stem cells.  Many groups are working feverishly on safe methods to convert these cells without using viruses and with less risk of producing tumors.  I am looking forward to reports of beneficial effects of IPS cell transplants in spinal cord injury.
  4. Clinical trials.  Several therapies are already in or should soon be in clinical trial.
    • Nogo antibody.* Nogo is a myelin protein that blocks regeneration. Novartis is now testing Nogo antibodies in patients with chronic spinal cord injury in Europe.  This antibody has shown promise in animal studies. I hope that this trial shows positive results.
    • Cethrin.*  Bioaxone completed a phase 2 clinical trial showing that Cethrin improves neurologic recovery in patients with spinal cord injury.  Cethrin is a modified bacterial toxin that blocks rho, the intracellular messenger for the Nogo receptor.  Alceres recently bought Bioaxone and will start more trials with Cethrin.  I hope that they are successful in raising funds for the trial.
    • Lithium.  In 2004, Yick, et al. at Hong Kong University reported that lithium and chondroitinase stimulate regeneration and improve neurological recovery after spinal cord injury.  Recent studies indicate that lithium stimulates stem cells to proliferate and produce neurotrophins, including nerve growth factor (NGF), neurotrophin-3 (NT-3), and glia-derived neurotrophic factor (GDNF).  A recent clinical trials suggests that lithium may be beneficial for amyotrophic lateral sclerosis.  ChinaSCINet completed a phase 1 trial showing that lithium can be safely given to people with chronic spinal cord injury and is now doing a phase 2 study comparing a 6-week course of lithium with placebo.  I hope that this trial shows positive results.
    • Umbilical cord blood mononuclear cells (UCBMC). Several independent laboratories have reported beneficial effects of UCBMC on animal SCI models.  Several clinics have been using the cells.  The China Spinal Cord Injury Network is applying for permission to carry out the first clinical trial of this treatment in chronic spinal cord injury.
    • Embryonic stem cells (ESC). Hans Keirstead at UC Irvine has reported that human ESC-derived oligodendroglial precursor cells improve regeneration and locomotor recovery in rats.  Regeneron has applied for permission to test these cells in patients with subacute spinal cord injury.  The trial is likely to be approved in 2009 and will be the first clinical trial of human ESC.
    • Schwann cell transplants. Much animal data suggest beneficial effects of Schwann cell transplants in spinal cord injury, particularly in combination with drugs that increase cAMP levels in the spinal cord.  After being discussed for many years, the first clinical trials of Schwann cell transplants for spinal cord injury may start in the United States.  Several groups in China have transplanted fetal and adult Schwann cells to people with subacute and chronic spinal cord injury.  The Miami Project is planning clinical trials to assess autografts of Schwann cells.  I hope that these trials start in 2009.
  5. Clinical Trial Networks.  Clinical trial networks are being established for spinal cord injury around the world.
    • The China Spinal Cord Injury Network (ChinaSCINet).  This is a network of 24 major spinal cord injury centers in mainland China, Hong Kong, and Taiwan.  This is the network that I have spent four years building in China.  We completed an observation trial of over 500 subjects, a phase 1 study to assess safety and feasibility of giving a 6-week course of lithium to people with chronic SCI, and started a phase 2 trial to compare lithium versus placebo treatment of chronic SCI.  We have applied for a phase 2 to assess increasing doses of umbilical cord blood mononuclear cell (UCBM) transplants and a phase 3 trial to assess UCBM cells with and without lithium.
    • A U.S. Spinal Cord Injury Network. We are planning and raising money for this network to do parallel clinical trials of cord blood mononuclear cell transplants and lithium transplants in chronic spinal cord injury.  Several centers have signed up for this study in New Jersey, Philadelophia, New York, and Austin (TX).  During 2009, we will be training and fundraising.  We hope to start trials in 2010.
    • North American Spinal Cord Injury Network. Funded in part by Reeve Foundation, this network has already started an observational trial.  It is planning trials of acute spinal cord injury therapies in conjunction with other networks.
    • Rehabilitation Networks. In France, a network of 148 rehabilitation units that treat SCI have begun to work together.  In the United States, the Spinal Cord Injury Locomotor Trial (SCILT) evaluated walking outcomes.

In summary, there is much reason for hope for spinal cord injury research.  The year 2009 should be a renaissance of stem cell research. Hopefully, Congress will pass the Christopher and Dana Reeve Paralysis Act, which many of us have lobbied for, to provide much needed funding for paralysis research and clinical trials.  Many promising therapies have been shown to improve recovery in animals and are ready for clinical trials.  Several clinical trial networks have been or are being formed to test these therapies.  I believe that much of this hard work will come to fruition in 2009.  Merry Christmas and Happy New Year!

Wise.

Please post responses:  Holiday Hopes for Spinal Cord Injury on CareCure.