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  • #16
    Wise, you've spoken about scar tissue or formation at great lengths and explained it in a manner that makes sense. The question that I have is that so many of the researchers working on therapies claim that scar tissue formation is a porblem. Geron's trial, I believe , to be applied within 14vdays, is to negate scar formation. You've mentioned ways of dissolving or breakdown of CSPG. My question would be ; is there a timelimit for this to occurr. In other words does this have to occurr in the first few weeks after injury or can this be done at any time? Thanks for your explanations Wise.

    keeping on

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    • #17
      Bumped as it got buried.....

      Originally posted by Fly_Pelican_Fly View Post
      Wise, I have to say after the symposium in Brescia I am even more confused by the varying opinions on whether it is common for a traumatic injury to have a scar containing fibrotic tissue.

      In Brescia, Harry Goldsmith, Carlos Lima and even Alok Sharma all claimed that every traumatic chronic lesion they have seen on the operating table has an element of fibrosis. Harry and Carlos, as we know, believe "cleaning" the lesion to remove the fibrosis is important for chronic treatments whereas Alok stressed that this is not something we should do as there is a risk to remaining healthy tissue in the cord.

      I think this is a topic that needs to be discussed at length in a workshop type of setting by a range of experts in the field.

      Comment


      • #18
        I realize that I may be a loner amongst scientists when it comes to the use of the word "scar" referring to the aftermath of spinal cord injury. Over the years, I have spoken up at multiple meetings, questioning speakers who use the word "scar" or "glial scar" with respect to spinal cord injury. I didn't use to be militant on this subject until I saw a talk given by Carlos Lima in 2003. He was presenting his work that transplanted olfactory mucosal into the spinal cord of patients and he said that the surgical team removed a "block" of scar tissue from the spinal cord so that they could stuff nasal mucosa into the hole. He showed pictures of the removed tissues and there were axons in the tissue.

        There is no rational or evidential basis for removing scar tissue from the spinal cord. It is not rational to remove "scar" because the act of removing scar will simply create more scar. There is no evidence that a majority of people with spinal cord injury have a "scar". This is where the discussion usually breaks down. What people are calling "scar" is simply accumulation of glial cells, i.e. astrocytes that grow at injury sites. This is properly called gliosis. To me, the word scar refers to a collagenous tissue formed by fibroblasts, skin cells, that knit damaged tissues together. Fibroblasts are present in most parts of the body. Fibrous and collagenous scars form when we cut skin, liver, heart, lung, and many other organs because these organs have fibroblasts that invade into the injury scar and form scars.

        It is true that if you cut the spinal cord and do not close the dura, fibroblasts do invade into the spinal cord and a fibrous scar may form, lined on the CNS side by astrocytes. However, the vast majority of spinal cord injuries do not involve any penetration of the spinal cord. Displaced bone or disc compresses or contuses the spinal cord, usually without penetrating the dura, a very tough membrane that surrounds and protects the spinal cord. While some fibroblasts are present in the arachnoid membranes outside the spinal cord, fibroblasts are usually excluded from the spinal cord. A contused spinal cord seldom has any collagen within the injury site.

        The vast majority of spinal cord injuries do not involve a penetrating wound of the spinal cord. Normally, no fibroblast resides in the spinal cord and they are carefully excluded by astrocytes, whose job it is to wall off the central nervous system including the spinal cord from peripheral tissues. Astrocytes are responsible for creating the blood brain barrier and line all boundaries between the central nervous system and peripheral tissues. Gliosis is part of the natural repair of the injured spinal cord. In fact, many studies have shown that if you stop gliosis, it is damaging to the spinal cord and the blood brain barrier does not reform.

        Investigators who injure the spinal cord by using a knife, scissors, vibrating probes, or laser beams to cut the spinal cord may of course see a scar at the injury site. At least one study [1] has shown that if the investigator carefully sewed the dura close and prevented invasion of fibroblasts into the injury site, there is no scar formation. I don't question the presence of scar tissues in such injury models. However, if the spinal cord is injured by compression, contusion, or ischemia, there is seldom any collagenous scar tissue in the spinal cord. Stephen Davies uses hemisection or transection model of spinal cord ijnjury, where he cuts the spinal cord. Of course he thinks that scar is important because his model has scar.

        There is also an open question whether "scar" tissues prevent axonal regeneration. For example, in recent studies by Kai Liu, et al. [2] showing rivers of corticospinal tract axons growing across a cut injury site after reducing PTEN expression, he made no attempt to remove the scar tissues and yet many axons regenerated across the injury site. Scientists such as Martin Schwab did not remove scar when he used Nogo blockers to stimulate regeneration [3]. Likewise, scientists who used chondroitinase to enhance regeneration the spinal cord did not remove "scar". For example, Yick, et al. [4] was able to regenerate 40% of the rubrospinal tract in rat spinal cord with chondroitinase and lithium.

        Some scientist say that astrocytes secrete chondroitin-6-sulfate proteoglycan (CSPG) which stops axonal growth. While it is true that CSPG does stop axonal growth, CSPG is not "scar". It is a glycoprotein that is present in the extracellular space. While CSPG does stop axonal growth, this is its purpose, i.e. it is present at the edges of the nervous system and its "job" is to channel axons so that they grow within the central nervous system and do not sprout like hair from the surface of the brain and spinal cord. One can have astrocytes without CSPG. In fact, Stephen Davies himself showed that certain types of astrocytes are beneficial for axonal regeneration in spinal cord injury.

        Some people may dismiss my argument as just semantics. I would agree with them if I have not seen so many patients with spinal cord injury coming to me and to this web site saying that "scar" has to be removed from the spinal cord before regeneration can occur. I would agree if there were not people like Carlos Lima whose surgical team actually cut out "scar" from the spinal cord. I would agree if the word "scar" were not used so indiscriminately as to refer to any kind of gliosis, including a company that actually set as its therapeutic goal the elimination of gliosis from spinal cord injury. So, it is not just semantics. Based on the false premise that glia cells block regeneration, surgeons are removing "scar" from human spinal cords. Patients are demanding it. Companies are trying to find ways of removing "scar". So, it is wrong and bad for patients for this term to be floating around. It gives the wrong impression.

        There is one other reason why the use of the word "scar" is inappropriate when applied to gliosis in the spinal cord. There are true fibrous scars that develop in spinal cord injury. For example, as pointed out, when the spinal cord is cut and the dura is not repaired, fibroblasts do move into the spinal cord and form collagenous scars that are walled off by glial cells. Likewise, fibrous adhesions do develop between the spinal cord/roots with surrounding tissues. Removal of these adhesions or untethering the spinal cord is an important surgical procedure that can help restore function. The word scar should be reserved for such fibrous attachments and true scars instead of being meaninglessly applied to gliosis in the spinal cord.

        Scientists should not be using the term "scar" so cavalierly. Words have power to mislead and this is one of those words that have actually led to harmful clinical practices and misleading concepts of spinal cord injury. It scares me every time I see somebody ask a question in the Cure forum about having their "scar" cut out from their spinal cord. Until somebody has better evidence that "scar" is preventing regeneration and that cutting scar out from the spinal cord is doing anything to improve function, I feel the necessity to speak out strongly against the use of the word scar to refer to gliosis in the spinal cord.

        Wise.

        1. Seitz A, Aglow E and Heber-Katz E (2002). Recovery from spinal cord injury: a new transection model in the C57Bl/6 mouse. J Neurosci Res 67: 337-45. The Wistar Institute, Philadelphia, Pennsylvania 19104, USA. Spinal cord transections in mammalian animal models lead to loss of motor function. In this study, we show that functional recovery from complete transection of the adult mouse spinal cord can in fact occur without any intervention if dural injury along with displacement of the ends of the cut cord and fibroblastic infiltration is minimized. Underlying this function is the expression of GAP-43 in axonal growth cones, axonal extension and bridging of the injury site indicated by biocytin retrograde tracing and neuronal remodeling of both the white matter and the gray matter. Such studies suggest a new murine model for the study of spinal cord regeneration.

        2. Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, Tedeschi A, Park KK, Jin D, Cai B, Xu B, Connolly L, Steward O, Zheng B and He Z (2010). PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci 13: 1075-81. F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA. Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.

        3. von Meyenburg J, Brosamle C, Metz GA and Schwab ME (1998). Regeneration and sprouting of chronically injured corticospinal tract fibers in adult rats promoted by NT-3 and the mAb IN-1, which neutralizes myelin-associated neurite growth inhibitors. Exp Neurol 154: 583-94. Brain Research Institute, University of Zurich and Swiss Federal Institute of Technology, Zurich, Switzerland. Myelin-associated inhibitors of neurite growth play an important role in the regenerative failure after injury in the adult mammalian CNS. The application of the mAb IN-1, which efficiently neutralizes the NI-250/35 inhibitory proteins, alone or in combination with neurotrophin-3 (NT-3), has been shown to promote axonal regeneration when applied in acute injury models. To test whether IN-1 application can induce axonal growth also in a chronic injury model, we treated rats with IN-1 and NT-3 starting 2 or 8 weeks after injury. Rats underwent bilateral dorsal hemisection of the spinal cord at the age of 5-6 weeks. Regeneration of corticospinal (CST) fibers into the caudal spinal cord was observed in three of eight of those animals with a 2-week delay between lesion and treatment. CST fibers regenerated for 2-11.4 mm. In the control group sprouting occurred rostral to the lesion but no long-distance regeneration occurred. In animals where treatment started at 8 weeks after injury the longest fibers observed grew up to 2 mm into the caudal spinal cord. The results show that transected corticospinal axons retain the ability to regenerate at least for a few weeks after injury. Functional analysis of these animals showed a slight improvement of functional recovery.

        4. 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. Department of Anatomy, Faculty of Medicine, The University of Hong Kong, Hong Kong. After spinal cord injury, enzymatic digestion of chondroitin sulfate proteoglycans promotes axonal regeneration of central nervous system neurons across the lesion scar. We examined whether chondroitinase ABC (ChABC) promotes the axonal regeneration of rubrospinal tract (RST) neurons following injury to the spinal cord. The effect of a GSK-3beta inhibitor, lithium chloride (LiCl), on the regeneration of axotomized RST neurons was also assessed. Adult rats received a unilateral hemisection at the seventh cervical spinal cord segment (C7). Four weeks after different treatments, regeneration of RST axons across the lesion scar was examined by injection of Fluoro-Gold at spinal segment T2, and locomotor recovery was studied by a test of forelimb usage. Injured RST axons did not regenerate spontaneously after spinal cord injury, and intraperitoneal injection of LiCl alone did not promote the regeneration of RST axons. Administration of ChABC at the lesion site enhanced the regeneration of RST axons by 20%. Combined treatment of LiCl together with ChABC significantly increased the regeneration of RST axons to 42%. Animals receiving combined treatment used both forelimbs together more often than animals that received sham or single treatment. Immunoblotting and immunohistochemical analysis revealed that LiCl induced the expression of inactive GSK-3beta as well as the upregulation of Bcl-2 in injured RST neurons. These results indicate that in vivo, LiCl inhibits GSK-3beta and reinforces the regeneration-promoting function of ChABC through a Bcl-2-dependent mechanism. Combined use of LiCl together with ChABC could be a novel treatment for spinal cord injury.
        Last edited by Wise Young; 05-17-2011, 10:29 AM.

        Comment


        • #19
          Originally posted by Young
          Over 100 papers have been published showing that chondroitinase will break down CSPG and allow axons to grow in the spinal cord and the central nervous system
          This is no way directed at you Dr. Young . . . . but over 100 papers and still no application to humans.

          Am I the only one?

          Comment


          • #20
            Originally posted by Schmeky View Post
            This is no way directed at you Dr. Young . . . . but over 100 papers and still no application to humans.

            Am I the only one?
            Schmeky,

            There are several reasons why chondroitinase has not yet gone to trial.

            First, chondroitinase is a very old compound. The composition of matter patent is held by a food company in Japan that has had little interest in licensing it. The processing patent is held by a company called Seikagaku in Japan and that company gave up of developing chondroitinase for spinal cord nearly a decade ago after having spent some money trying to develop the enzyme for soften spinal discs. The use patent for the treatment was licensed by Acorda Therapeutics, which is just beginning to make enough money to consider investing in the development of chondroitinase for spinal cord injury. Spinal cord injury is still considered a small market and most companies are not willing to get into this field without stronger patent protection and certainly not while there is still a recession and economic uncertainty.

            Second, funding for U.S. spinal cord injury research and clinical trials is at its lowest ebb in memory. The combination of the anti-terrorism priorities of this country and the recession essentially wiped out any gain of research funds that we may have had since 1995. In 2011, we are getting less funding for spinal cord injury research and clinical trials from the federal government and state government than we did a decade ago. Last year, Governor Chris Christie of New Jersey diverted funds from the $1/traffic ticket fund for spinal cord injury research and our center at Rutgers was left with a million dollar grant gap. At the Keck Center, we are now running on fumes and a skeleton staff. All efforts by the spinal cord injury community to lobby the government for more research funding essentially stopped two years ago.

            Third, the number of U.S. clinicians who are willing and able to do clinical trials for spinal cord injury therapies is likewise at an all-time low in the U.S. The last major clinical trial for spinal cord injury was by Acorda Therapeutics. We have a couple phase I/II trials and no phase III spinal cord injury therapy trial over the past decade. It has been next-to-impossible to move any therapy into phase III. The pressure on doctors and hospitals to make money and to take care of patients is greater than ever before. Few doctors are willing to give their time and resources like they did in the past. Our effort to move the Christopher & Dana Reeve Paralysis Act through Congress was abandoned before we got the funding. More clinical trials are going on overseas than in the United States.

            So, what can be done? I have been pushing as hard as I can within Acorda to urge them to invest into chondroitinase and more into spinal cord injury research. Hopefully, the fruits of that pushing will show up soon. In the meantime, we need to do other things to move things forward rather than sit around and complain. So, what else can we do?

            • The community must raise the money for its own clinical trials. As I have pointed out earlier, if 10% of the community (say 100,000 people) paid a dollar a day to support the trials in the United States, this would add up to $36.5 million per year. We are just getting this program going.
            • People must lobby Congress and state governments to fund more spinal cord injury clinical trials. For much of the last two years, such lobbying would have and did fell on deaf ears. Since the demise of bin Laden and the easing of the recession, now is the time to restart lobbying.
            • We must get a few trials going and hope that the success of these trials will attract more companies and money to get into the field. Once we have the first therapy that improves function in chronic spinal cord, many companies will want to jump on the bandwagon.

            Finally, let's work together to make all of this happen.

            Wise.
            Last edited by Wise Young; 05-17-2011, 09:23 PM.

            Comment


            • #21
              "• The community must raise the money for its own clinical trials. As I have pointed out earlier, if 10% of the community (say 100,000 people) paid a dollar a day to support the trials in the United States, this would add up to $36.5 million per year. We are just getting this program going."

              Dr.Wise, concerning this point ,it was a good suggestion made by Antiquity("Perhaps a mandatory, one time membership fee could be considered")(/forum/showthread.php?p=1207372#post1207372 post#193) .Implementation of it would considerably enhance the membership status and at the same time probably will bring closer the "club" dissolution what is a desire of this club unintentional members.

              Comment


              • #22
                Originally posted by Wise Young View Post
                There is no rational or evidential basis for removing scar tissue from the spinal cord. It is not rational to remove "scar" because the act of removing scar will simply create more scar. There is no evidence that a majority of people with spinal cord injury have a "scar". This is where the discussion usually breaks down. What people are calling "scar" is simply accumulation of glial cells, i.e. astrocytes that grow at injury sites. This is properly called gliosis.
                .
                Wise,

                I have watched lectures of yours where you mention necrotic material being removed during intradural decompression. Is this necrotic matter gliosis related, and why would you suggest that removal of it seemed to provide such benefit to the patients?

                Thanks

                Comment


                • #23
                  Originally posted by Wise Young View Post

                  • The community must raise the money for its own clinical trials. As I have pointed out earlier, if 10% of the community (say 100,000 people) paid a dollar a day to support the trials in the United States, this would add up to $36.5 million per year. We are just getting this program going.

                  Finally, let's work together to make all of this happen.

                  Wise.
                  Thank you for the reminder. You prompted me to make my 2011 $365 donation to JustADollar.

                  Comment


                  • #24
                    Originally posted by kivi66 View Post
                    "• The community must raise the money for its own clinical trials. As I have pointed out earlier, if 10% of the community (say 100,000 people) paid a dollar a day to support the trials in the United States, this would add up to $36.5 million per year. We are just getting this program going."

                    Dr.Wise, concerning this point ,it was a good suggestion made by Antiquity("Perhaps a mandatory, one time membership fee could be considered")(/forum/showthread.php?p=1207372#post1207372 post#193) .Implementation of it would considerably enhance the membership status and at the same time probably will bring closer the "club" dissolution what is a desire of this club unintentional members.
                    kivi66, as I have pointed out many times, CareCure is not for fundraising. It is a free information service for the community.

                    Even if we were to decide to impose a membership fee of some kind, I suspect that less than 10% of the members of this site would be interested in contributing. It will only end up harming CareCure and will not help the cause.

                    wise.

                    Comment


                    • #25
                      Originally posted by KofQ View Post
                      Wise,

                      I have watched lectures of yours where you mention necrotic material being removed during intradural decompression. Is this necrotic matter gliosis related, and why would you suggest that removal of it seemed to provide such benefit to the patients?

                      Thanks
                      Necrotic tissue eventually is removed by macrophages. The macrophages are slowly replaced by glial cells. It is likely that all the dead and dying tissues are releasing toxins that are killing cells in the surrounding cord.

                      Wise.

                      Comment


                      • #26
                        Wise, thanks for making a very complicated issue better understood. While I am hopeful for the future "cure" for spinal cord trauma, I wanted to know if any of these interventions (CABC) would have applications in chronic spinal cord central pain. Would these same glial cells be responsible for severe neuralgia, or paresthesia w/pain?
                        My apologies if this is not the correct forum, but I am fairly new to this site and trying to research as much information on chronic neuropathic pain.
                        Thanks again.

                        Comment


                        • #27
                          Originally posted by BobG603 View Post
                          Wise, thanks for making a very complicated issue better understood. While I am hopeful for the future "cure" for spinal cord trauma, I wanted to know if any of these interventions (CABC) would have applications in chronic spinal cord central pain. Would these same glial cells be responsible for severe neuralgia, or paresthesia w/pain?
                          My apologies if this is not the correct forum, but I am fairly new to this site and trying to research as much information on chronic neuropathic pain.
                          Thanks again.
                          Bob,

                          Until recently, there was no credible rationale for stem cell therapies or regenerative therapies to have any beneficial effects on neuropathic pain. In fact, the worry that may scientists and clinicians had was that the therapies may make neuropathic pain worse [1]. Of course, some people thought that transplantation of neural stem cells that can make inhibitory GABAergic neurons may inhibit neuropathic pain [2]. Davies, et al. [3] reported that certain types of transplanted astrocyte can make pain worse. Karimi-Abdolrezaee, et al. [4] reported that the combination of transplanted neural progenitor cells, growth factors, and CABC did not increase neuropathic pain in animals.

                          Stem cells are now recognized to be anti-inflammatory and even anti-immune. While the mechanisms of these anti-immune/inflammatory effects are not well understood, the FDA recently approved the use of mesenchymal stem cells to treat graft-versus-host disease (GVHD) which occurs when transplanted bone marrow cells attack the body of the person receiving the cells. Umbilical cord blood has also been recognized to have these effects, possibly explaining why umbilical cord blood does not have to have perfect 6:6 HLA matching in order to engraft. One possibility is that stem cells, when transplanted to the spinal cord or even given intravenously or intrathecally, may release cytokines and other factors that inhibit inflammation in the spinal cord. Inflammation is believed to be one of the mechanisms by which neuropathic pain develops. Of course, inflammation is associated with neurotrophin production and these, in turn, stimulate sprouting that may aggravate neuropathic pain. However, all these theories don't amount to a pile of beans without evidence that stem cells reduce neuropathic pain. The proof is in the pudding.

                          Clinical trial experience suggest that increased pain may be a consequence of stem cell transplants. For example, in 2007, Yoon, et al. [5] reported that patients treated with bone marrow cell transplants during the subacute phase after injury may have increased neuropathic pain. Kishk, et al. [6] recently reported that 24 or 43 subjects that received intrathecal administration of autologous bone marrow cells developed neuropathic pain. Note that these are in chronic patients that are an average of 3.6 years after injury. Recently, we incidentally observed that lithium reduced neuropathic pain in patients with chronic spinal cord injury [in preparation].

                          So, evidence that stem cells or other regenerative therapies will reduce neuropathic pain is not yet available. There is some evidence suggesting that stem cell therapies may increase neuropathic pain but more evidence is required to document this.

                          Wise.

                          Cited References

                          1. Macias MY, Syring MB, Pizzi MA, Crowe MJ, Alexanian AR and Kurpad SN (2006). Pain with no gain: allodynia following neural stem cell transplantation in spinal cord injury. Exp Neurol 201: 335-48. Department of Neurosurgery, Neuroscience Research Laboratories, Medical College of Wisconsin and Clement J Zablocki VA Medical Center, Milwaukee, WI 53226, USA. Transplantation of neural stem cells (NSCs) in the injured spinal cord has been shown to improve functional outcome; however, recent evidence has demonstrated forelimb allodynia following transplantation of embryonic NSCs. The aim of this study was to investigate whether transplantation of murine C17.2 NSCs alone or transfected with glial-derived neurotrophic factor (C17.2/GDNF) would induce allodynia in transplanted spinal cord-injured animals. One week after a T8-level spinal cord injury (SCI), C17.2, C17.2/GDNF or normal saline was injected at the injury site. Locomotor function and sensory recovery to thermal and mechanical stimuli were then measured. Spinal cords were processed immunohistochemically at the injury/transplantation site for characterization of NSC survival and differentiation; and at the cervicothoracic level for calcitonin gene-related peptide (CGRP), a neuropeptide expressed in dorsal horn nocioceptive neurons, and growth-associated protein-43 (GAP43), a marker of neuronal sprouting. Locomotor function was not significantly improved following NSC transplantation at any time (P >0.05). Significant forelimb thermal and mechanical allodynia were observed following transplantation with both NSC populations (P <0.05). The C17.2 and C17.2/GDNF NSCs survived and differentiated into a predominately astrocytic population. Calcitonin gene-related peptide and GAP43 immunoreactivity significantly increased and co-localized in cervicothoracic dorsal horn laminae I-III following C17.2 and C17.2/GDNF transplantation. This study demonstrated that murine C17.2 NSCs differentiated primarily into astrocytes when transplanted into the injured spinal cord, and resulted in thermal and mechanical forelimb allodynia. Sprouting of nocioceptive afferents occurred rostral to the injury/transplantation site only in allodynic animals, suggesting a principal role in this aberrant pain state. Further, a difference in the degree of allodynia was noted between C17.2- and C17.2/GDNF transplant-treated groups; this difference correlated with the level of CGRP/GAP43 immunoreactivity and sprouting observed in the cervicothoracic dorsal horns. Both allodynia- and CGRP/GAP43-positive afferent sprouting were less in the C17.2/GDNF group compared to the C17.2 group, suggesting a possible protective or analgesic effect of GDNF on post-injury neuropathic pain.

                          2. Mukhida K, Mendez I, McLeod M, Kobayashi N, Haughn C, Milne B, Baghbaderani B, Sen A, Behie LA and Hong M (2007). Spinal GABAergic transplants attenuate mechanical allodynia in a rat model of neuropathic pain. Stem Cells 25: 2874-85. Cell Restoration Laboratory, Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada. Injury to the spinal cord or peripheral nerves can lead to the development of allodynia due to the loss of inhibitory tone involved in spinal sensory function. The potential of intraspinal transplants of GABAergic cells to restore inhibitory tone and thus decrease pain behaviors in a rat model of neuropathic pain was investigated. Allodynia of the left hind paw was induced in rats by unilateral L5- 6 spinal nerve root ligation. Mechanical sensitivity was assessed using von Frey filaments. Postinjury, transgenic fetal green fluorescent protein mouse GABAergic cells or human neural precursor cells (HNPCs) expanded in suspension bioreactors and differentiated into a GABAergic phenotype were transplanted into the spinal cord. Control rats received undifferentiated HNPCs or cell suspension medium only. Animals that received either fetal mouse GABAergic cell or differentiated GABAergic HNPC intraspinal transplants demonstrated a significant increase in paw withdrawal thresholds at 1 week post-transplantation that was sustained for 6 weeks. Transplanted fetal mouse GABAergic cells demonstrated immunoreactivity for glutamic acid decarboxylase and GABA that colocalized with green fluorescent protein. Intraspinally transplanted differentiated GABAergic HNPCs demonstrated immunoreactivity for GABA and beta-III tubulin. In contrast, intraspinal transplantation of undifferentiated HNPCs, which predominantly differentiated into astrocytes, or cell suspension medium did not affect any behavioral recovery. Intraspinally transplanted GABAergic cells can reduce allodynia in a rat model of neuropathic pain. In addition, HNPCs expanded in a standardized fashion in suspension bioreactors and differentiated into a GABAergic phenotype may be an alternative to fetal cells for cell-based therapies to treat chronic pain syndromes.

                          3. 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. Department of Neurosurgery, Anschutz Medical Campus, University of Colorado Denver, 12800 East 19th Ave, Aurora, CO 80045, USA. Stephen.Davies@UCHSC.edu. ABSTRACT: BACKGROUND: Two critical challenges in developing cell-transplantation therapies for injured or diseased tissues are to identify optimal cells and harmful side effects. This is of particular concern in the case of spinal cord injury, where recent studies have shown that transplanted neuroepithelial stem cells can generate pain syndromes. RESULTS: We have previously shown that astrocytes derived from glial-restricted precursor cells (GRPs) treated with bone morphogenetic protein-4 (BMP-4) can promote robust axon regeneration and functional recovery when transplanted into rat spinal cord injuries. In contrast, we now show that transplantation of GRP-derived astrocytes (GDAs) generated by exposure to the gp130 agonist ciliary neurotrophic factor (GDAsCNTF), the other major signaling pathway involved in astrogenesis, results in failure of axon regeneration and functional recovery. Moreover, transplantation of GDACNTF cells promoted the onset of mechanical allodynia and thermal hyperalgesia at 2 weeks after injury, an effect that persisted through 5 weeks post-injury. Delayed onset of similar neuropathic pain was also caused by transplantation of undifferentiated GRPs. In contrast, rats transplanted with GDAsBMP did not exhibit pain syndromes. CONCLUSION: Our results show that not all astrocytes derived from embryonic precursors are equally beneficial for spinal cord repair and they provide the first identification of a differentiated neural cell type that can cause pain syndromes on transplantation into the damaged spinal cord, emphasizing the importance of evaluating the capacity of candidate cells to cause allodynia before initiating clinical trials. They also confirm the particular promise of GDAs treated with bone morphogenetic protein for spinal cord injury repair.

                          4. Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Schut D and Fehlings MG (2010). Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. J Neurosci 30: 1657-76. Division of Genetics and Development, Toronto Western Research Institute and Krembil Neuroscience Center, University Health Network, Toronto, Ontario M5T 2S8, Canada. karimis@cc.umanitoba.ca. The transplantation of neural stem/progenitor cells (NPCs) is a promising therapeutic strategy for spinal cord injury (SCI). However, to date NPC transplantation has exhibited only limited success in the treatment of chronic SCI. Here, we show that chondroitin sulfate proteoglycans (CSPGs) in the glial scar around the site of chronic SCI negatively influence the long-term survival and integration of transplanted NPCs and their therapeutic potential for promoting functional repair and plasticity. We targeted CSPGs in the chronically injured spinal cord by sustained infusion of chondroitinase ABC (ChABC). One week later, the same rats were treated with transplants of NPCs and transient infusion of growth factors, EGF, bFGF, and PDGF-AA. We demonstrate that perturbing CSPGs dramatically optimizes NPC transplantation in chronic SCI. Engrafted NPCs successfully integrate and extensively migrate within the host spinal cord and principally differentiate into oligodendrocytes. Furthermore, this combined strategy promoted the axonal integrity and plasticity of the corticospinal tract and enhanced the plasticity of descending serotonergic pathways. These neuroanatomical changes were also associated with significantly improved neurobehavioral recovery after chronic SCI. Importantly, this strategy did not enhance the aberrant synaptic connectivity of pain afferents, nor did it exacerbate posttraumatic neuropathic pain. For the first time, we demonstrate key biological and functional benefits for the combined use of ChABC, growth factors, and NPCs to repair the chronically injured spinal cord. These findings could potentially bring us closer to the application of NPCs for patients suffering from chronic SCI or other conditions characterized by the formation of a glial scar.

                          5. Yoon SH, Shim YS, Park YH, Chung JK, Nam JH, Kim MO, Park HC, Park SR, Min BH, Kim EY, Choi BH, Park H and Ha Y (2007). Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-colony stimulating factor: Phase I/II clinical trial. Stem Cells 25: 2066-73. Inha Neural Repair Center, Department of Neurosurgery, Inha University College of Medicine, 7-206, Sinheung-dong 3-ga, Jung-Gu, Incheon, Korea. To assess the safety and therapeutic efficacy of autologous human bone marrow cell (BMC) transplantation and the administration of granulocyte macrophage-colony stimulating factor (GM-CSF), a phase I/II open-label and nonrandomized study was conducted on 35 complete spinal cord injury patients. The BMCs were transplanted by injection into the surrounding area of the spinal cord injury site within 14 injury days (n = 17), between 14 days and 8 weeks (n = 6), and at more than 8 weeks (n = 12) after injury. In the control group, all patients (n = 13) were treated only with conventional decompression and fusion surgery without BMC transplantation. The patients underwent preoperative and follow-up neurological assessment using the American Spinal Injury Association Impairment Scale (AIS), electrophysiological monitoring, and magnetic resonance imaging (MRI). The mean follow-up period was 10.4 months after injury. At 4 months, the MRI analysis showed the enlargement of spinal cords and the small enhancement of the cell implantation sites, which were not any adverse lesions such as malignant transformation, hemorrhage, new cysts, or infections. Furthermore, the BMC transplantation and GM-CSF administration were not associated with any serious adverse clinical events increasing morbidities. The AIS grade increased in 30.4% of the acute and subacute treated patients (AIS A to B or C), whereas no significant improvement was observed in the chronic treatment group. Increasing neuropathic pain during the treatment and tumor formation at the site of transplantation are still remaining to be investigated. Long-term and large scale multicenter clinical study is required to determine its precise therapeutic effect. Disclosure of potential conflicts of interest is found at the end of this article.

                          6. Kishk NA, Gabr H, Hamdy S, Afifi L, Abokresha N, Mahmoud H, Wafaie A and Bilal D (2010). Case Control Series of Intrathecal Autologous Bone Marrow Mesenchymal Stem Cell Therapy for Chronic Spinal Cord Injury. Neurorehabil Neural Repair BACKGROUND: Autologous bone marrow mesenchymal cells that include stem cells (MSCs) are a clinically attractive cellular therapy option to try to treat severe spinal cord injury (SCI). OBJECTIVE: To study the possible value of MSCs injected intrathecally to enhance rehabilitation. METHODS: This case control, convenience sample included 64 patients, at a mean of 3.6 years after SCI. Forty-four subjects received monthly intrathecal autologous MSCs for 6 months and 20 subjects, who would not agree to the procedures, served as controls. All subjects received rehabilitation therapies 3 times weekly. Subjects were evaluated at entry and at 12 months after completing the 6-months intervention. By the ASIA Impairment Scale, ASIA grading of completeness of injury, Ashworth Spasticity Scale, Functional Ambulation Classification, and bladder and bowel control questionnaire. RESULTS: No differences were found in baseline measures and descriptors between the MSC group and control group. Although a higher percentage of the MSC group increased motor scores by 1-2 points and changed from ASIA A to B, no significant between-group improvements were found in clinical measures. Adverse effects of cells included spasticity and, in 24 out of the 43 patients developed neuropathic pain. One subject with a history of post-infectious myelitis developed encephalomyelitis after her third injection. CONCLUSION: Autologus MSCs may have side effects and may be contraindicated in patients with a history of myelitis. Their utility in treating chronic traumatic SCI needs further study in pre-clinical models and in randomized controlled trials before they should be offered to patients.

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                          • #28
                            I remember from my spinal cord stimulator days (1986) that the doctor said he was unable to push the stimulator above my C-5 injury level because the area was blocked by scar tissue. He could barely get to C-6.

                            Would a doctor today encountering the same problem in someone else still call the problem "scar tissue?"
                            Alan

                            Proofread carefully to see if you any words out.

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                            • #29
                              I'm trying to understand what happens to the nerves after a spinal cord ischemia...is it possible that nerve cells might never rengenerate. I have a friend who has regained motor skills, but no sensory ( he can't feel anything). Could the myelin be destroyed? His SC stroke was C2-C8 but he was also given heavy dose of steroids within 12 hours. I'm just not really understanding how he can have motor without sensory? Are they different parts of the nerve ending? Could it be possible that sensory would never come back? I found the below info, but can't really tell if this is relevant more for spinal cord injuries from an accident or trauma. Also, he had an MRA and blood vessels looked normal and according to one doc his spinal cord actually showed shrinkage after the two doses of steroids ( the 2nd MRI he had about 5 days after stroke).

                              This is what I pulled from NINDS site, but not sure if this happens during spinal cord stroke too. That's my main ? I guess. "When nerve cells die, they release excessive amounts of a neurotransmitter called glutamate. Since surviving nerve cells also release glutamate as part of their normal communication process, excess glutamate floods the cellular environment, which pushes cells into overdrive and self-destruction. Researchers are investigating compounds that could keep nerve cells from responding to glutamate, potentially minimizing the extent of secondary damage."

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                              • #30
                                Originally posted by Sarahale View Post
                                I'm trying to understand what happens to the nerves after a spinal cord ischemia...is it possible that nerve cells might never rengenerate. I have a friend who has regained motor skills, but no sensory ( he can't feel anything). Could the myelin be destroyed? His SC stroke was C2-C8 but he was also given heavy dose of steroids within 12 hours. I'm just not really understanding how he can have motor without sensory? Are they different parts of the nerve ending? Could it be possible that sensory would never come back? I found the below info, but can't really tell if this is relevant more for spinal cord injuries from an accident or trauma. Also, he had an MRA and blood vessels looked normal and according to one doc his spinal cord actually showed shrinkage after the two doses of steroids ( the 2nd MRI he had about 5 days after stroke).

                                This is what I pulled from NINDS site, but not sure if this happens during spinal cord stroke too. That's my main ? I guess. "When nerve cells die, they release excessive amounts of a neurotransmitter called glutamate. Since surviving nerve cells also release glutamate as part of their normal communication process, excess glutamate floods the cellular environment, which pushes cells into overdrive and self-destruction. Researchers are investigating compounds that could keep nerve cells from responding to glutamate, potentially minimizing the extent of secondary damage."
                                Sarahale,

                                Thank you very much for your post and questions. The answer to your questions will take some time to formulate because the reasons for your confusion are legitimate and are based on long-established misunderstandings of the spinal cord both by the public and scientists. Give me a few days to answer your question. I will do so in another thread since the discussion will include much more than whether there is "scar" in the spinal cord. It would require an explanation of what a "stroke" does to the spinal cord, what structures are responsible for motor and sensory function, the difference between neuronal and axonal regeneration, and what recovery of motor function entails.

                                Wise.

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