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    Scar Tissue Blocks Spinal Cord Neurons From Linking

    Scar Tissue Blocks Spinal Cord Neurons From Linking

    Might there be ways to promote regeneration of the cells in the spinal cord or otherwise encourage a restoration of function following injury?
    Such injury can lead to devastating loss of function, and subsequent recovery is often minimal. Accordingly, the factors that inhibit recovery have been a major research focus in recent years.

    A new study conducted in mice by researchers at The Wistar Institute suggests that the key to recovery from severe spinal-cord injury may lie in limiting the scarring process that generally follows such an injury, rather than in an enhanced regenerative capacity.

    In mice where the ability of inflammatory cells to reach the injury site was physically limited, the formation of scar tissue at the site was also limited, the scientists found in their experiments.

    Without the physical barrier of scar tissue to impede their progress, neurons on both sides of the injury site were able to grow and reestablish connections with each other over a period of two to three weeks, leading to substantial recovery of function.

    A report on the study appears in the February 1 issue of the Journal of Neuroscience Research.

    "The problem in recovery from spinal-cord injury appears to be the scar tissue that forms in response to injury," says Ellen Heber-Katz, Ph.D., a professor at The Wistar Institute and senior author on the study. "The scar eliminates the ability of neurons to regrow their axons across the injury site. It's an absolute physical block. We found, however, that if you prevent the scar tissue from forming, the mice recover from their injuries."

    The findings show that physically preventing scar tissue from forming can open the way for recovery from spinal-cord injury, according to Heber-Katz.

    More clinically relevant, perhaps, is that the research also suggests that drugs able to biochemically block scar-tissue formation immediately following such an injury might have a similarly beneficial effect.

    Perhaps most tantalizing is the possibility raised by the study that therapies designed to eliminate existing scar tissue at the site of past injuries might also be helpful.

    "In combination with efforts to address the issue of tissue loss that often accompanies injuries to the human spinal cord, this approach might enable us to design an elegant therapy that permits the cord to heal itself," says Alexander Seitz, M.D., a postdoctoral fellow in the Heber-Katz laboratory and lead author on the study.

    To prevent the formation of scar tissue at the site of injury to the spinal cord, the researchers were careful in their experiments to maintain the integrity of the dura, the outer layer of protective membranes that encloses the spinal cord.

    Doing this left both ends of the damaged cord in close proximity to each other and limited their displacement. It also had the effect of blocking inflammatory cells, particularly the fibroblasts that would normally migrate to the injury site, from being able to reach the site and subsequently proliferate in the gap between the cord ends, leading to scar formation.

    Scar tissue, a long-lasting protein matrix, is important in the body's response to injury, but it represents an absolute barrier for the axonal growth cones of neurons that might otherwise bridge the injury site.

    In addition to senior author Heber-Katz and lead author Seitz, the remaining author on the study is Elsa Aglow, also at The Wistar Institute.

    The research has been generously funded from its inception by the G. Harold and Leila Y. Mathers Charitable Foundation, a private foundation based in Mount Kisco, NY. Recently, the work has also received substantial funding from the F.M. Kirby Foundation in Morristown, NJ, and the National Institutes of Health.


    [Contact: Franklin Hoke, Marion Wyce]

    23-Jan-2002

    #2
    I was wondering if there have been any headway in the functional recovery of dealing with scar tissue.


    David

    Comment


      #3
      David,

      The scar that they are talking about results from a penetrating wound of the spinal cord and leaving the dura open. What the authors found was that by closing the dura, they were able to prevent fibroblast invasion into the injury site and prevent the formation of the scar. This is a very important point because most people (and scientists) continue to mistakenly believe that the "scar" is the reason why there is no regeneration. While there is some fibroblast invasion into the injury site after a contusion or compression injury, it is much less than after a penetrating wound of the spinal cord. What forms in a contusion or a compression injury after the destruction of tissue is only one side of the "scar", glial cells multiplying to segregate what is they consider to be peripheral tissues compared to central nervous tissues. This is one of the important function of glial cells. The line the blood vessels and places where the central nervous system forms interfaces with peripheral tissues. These glial cells secrete a substance called chondroitin-6-sulfate proteoglycans or CSPG. CSPG inhibits axonal growth. In other words, the central nervous system does not want axons to grow outside, except under specially controlled circumstances such as nerve roots and cranial nerves. An enzyme called chondroitinase ABC (CABC) dissolves CSPG and prevents its inhibition of axonal growth. CABC has been reported by several groups now to facilitate regeneration in the brain and spinal cord. There is a great deal of interest in taking CABC into clinical trial.

      Wise.

      Comment


        #4
        Originally posted by Wise Young:


        There is a great deal of interest in taking CABC into clinical trial.

        Wise.
        Wise does this interest in a clinical trial involve acute or chronic patients? And do you you know who it is that is interested from both a research view point as well as a clinician viewpoint? This is something I want to support.

        Thanks in advance.
        What we do in life echoes in eternity. Maximus - Gladiator

        Comment


          #5
          Larwatson,

          Most of the animal studies to date still involve acute spinal cord injury models. For example, Bradbury, et al. applied the chondroitinase shortly after injury and injected it every other day or so for 2 weeks. There is also very exciting data indicating the chondroitinase increases "plasticity" of the visual cortex (this is work done in collaboration with Jim Fawcett who is a leader in the field of chondroitinase) so that it opens the "critical window" for visual recovery after lesions of the brain or loss of vision due to amblyopia during development (i.e. when a child has a wandering eye, visual function in that eye is suppressed and the child can become effectively blind in that eye because of lack of use). I know of several other laboratories that will be reporting positive results in chondroitinase treatments of spinal cord injury and will post about these as soon as the information becomes public.

          To my knowledge, several companies are committing seriously to developing chondroitinase as a regenerative therapy. These include Acorda Therapeutics and Seikagaku. There are other startup companies as well that have been rumored to be starting chondroitinase studies in England and around the world. I have heard that several companies are looking seriously into finding a "human chondroitinase" but so far I haven't yet heard of a positive result.

          By the way, as you may have heard, the market conditions were not strong enough for Acorda to succeed in going public last week and the company will probably wait until its Fampridine trials are over with before attempting an IPO again. This will probably be in 6 months time.

          Finally, we will be starting chondroitinase studies in the chronic spinal cord contusion model at the Rutgers Keck Center.

          Wise.

          Comment


            #6
            I've for a long time been curious as to what clinicians mean, exactly, by "scar tissue," and I've wondered that people were mistaking it as a cause rather than as a clinical manifestation of sci.. I'm wondering if current-day diagnostic tools are sensitive enough to be used soon after a patient's acute phase to pinpoint the (perhaps different) ways in which scar tissue can form and the differential outcomes of different mechanisms of scar formation. Or is a scar a scar, regardless of how it forms?

            After a spinal ependymoma and subsequent laminectomy and radiation treatment (in 1965), I walked out of the hospital, only to have a complete and permanent relapse about 8 mos. after the original hospitalization. Another laminectomy showed the cord to be "necrotic," and in the years since drs. have referred to "scar tissue." I've had some cat scans over the years, but they lacked the resolution to be useful. My own inexpert opinion is that ultimately my particular sci arose from radiation necrosis of the blood vessels at the focus of the original tumor, though I've never gotten professional reaction to this idea.

            Though Dr. Wise implies that scar formation is germane only with penetrating wounds, it might be that in a case such as mine the fibroblasts are transported to the wound site lots slower than in the case of acute wounds. If so, given adequate tools, the mechanisms of scar formation and the results of various interventions might be better studied in patients with spinal tumors. (Of course, therapies are much better now, so perhaps tumor patients no longer undergo relapse.) - fw

            Comment


              #7
              i have a question about scare in spinal cord,........ can´t use a laser to eliminate it?
              if the scare is eliminated the way to recovery get more easy, no?
              excuse my poor english.
              -Ramps in buildings are necessary, but it would be usefull to have another ones for people (mind/heart).....

              -Hoc non pereo habebo fortior me

              Comment


                #8
                Isildur, I feel almost as like a little hobbit standing amongst a horde of scarmongers.
                For a majority of people with spinal cord injury that does not involve a penetrating wound of the spinal cord, I don't think the "scar" is an obstacle to regeneration. Even if there is a scar, chondroitinase is likely to solve the problem because this treatment has been shown to regenerate spinal cords that have been cut and therefore do have scars. Wise.

                Comment


                  #9
                  Greetings

                  Dr. Young - you stated some companies re seriously looking into "finding a human chondroitinase"
                  Please don't tell me that after reading so many reports over several years about chondroitinase, that we aren't at the human level yet ?
                  And I suppose once this is found (in whatever time frame) it will be used on rats for years before even getting to a clinical human trial ?
                  Please explain.

                  Paul

                  Comment


                    #10
                    Dr. Young,

                    There are some prominent researhers that believe axons survive after a contusion and substantial function could be restored if the axons could be re-mylienated.

                    Is there any evidence to support this theory?

                    Comment


                      #11
                      Originally posted by paulsask:

                      Greetings

                      Dr. Young - you stated some companies re seriously looking into "finding a human chondroitinase"
                      Please don't tell me that after reading so many reports over several years about chondroitinase, that we aren't at the human level yet ?
                      And I suppose once this is found (in whatever time frame) it will be used on rats for years before even getting to a clinical human trial ?
                      Please explain.

                      Paul
                      Paul, the first work showing that chondroitinase was effective in spinal cord injury came with Elizabeth Bradbury and her team in London approximately a year ago (2002). Several laboratories had tried prior to her, including Jerry Silver who had proposed that it would work, without success. The reason for her success was that she found a way of measuring the activity of chondroitinase and showed that it loses activity within two days and has to be injected fresh into the spinal cord every day or every other day. This was quite a feat and she did it, showing that it worked. Several laboratories have studied it in the brain and showed that it stimulates regeneration in the brain. But the key to her success was the successful deployment of an assay that definitively showed that the chondroitinase was breaking down CSPG. This allowed her to determine the appropriate dose and timing of the drug that would break down CSPG and hence produce regeneration.

                      Chondroitinase ABC is made by a common bacterium (Proteus vulgaris) that most humans have been exposed to. Thus, it tends to be strongly inflammatory and immunogenic. It also loses activity very easily. One of the worries is that the enzyme is rapiadly inactivated by the immune response. Therefore, a number of companies have been looking for the human chondroitinase, without a great deal of success. As it turns out, there is no such thing as a human chondroitinase although there are some human enzymes that appear to break down CSPG. Among these is an enzyme called hyaluronidase. There is an effort underway to assess human hyalurodinase and see if it is as good as bacterial chondroitinase. In addition, much effort is going into finding more stable forms of chondrotinase that would be more for human use.

                      Things are actually moving ahead much faster than I would have expected considering that first convincing data that chondroitinase is beneficial in spinal cord injury came out about a year ago. Chondroitinase was the hottest regenerative treatment at the Society for Neuroscience this year and the excitement is spurring the field on. So, we should be expecting big things in the field in the coming year.

                      Wise.

                      Comment


                        #12
                        I was wondering if any more progress has been made with the hyaluronidase enzyme or any other scar inhibitor?



                        David

                        Comment


                          #13
                          Dr. Young,

                          Thanks for the clarification on all the scar parameters involved with injury. So if I have this right, where there is a tear to the Dura from injury, the body automatically sends a certain enzyme to prevent the axons from growing outside of the torn dura. This forms the scar. Unless it is a site where peripheral nerves are branching out then the body is ok with things exiting the dura.
                          That being said in doing a surgical procedure to remove the scar tissue and opening up the dura would send the message to the immune system that in fact it needed to respond the same way, trying to for another scar. In any event there has to be a way to dissolve the existing scar w/o invasive surgery and clear the path so that work begins inside the Dura to regenerate the damaged cord.
                          The body gets no red flags sent to the immune system saying the integrity of the Dura has been compromised and regeneration begins. The SCI patient then takes lots of vitamins, eats right, heals, which leads to no more cathings, suppositories, nerve pain, spasms, depression, anger , anxiety or sending used latex to a landfill.

                          Life is wonderful again!

                          Chris

                          Comment


                            #14
                            COLLAGENASE


                            - i found this word that is an enzyme that may eat away scar tissues. Does any body know if this has any potential.



                            David

                            Comment


                              #15
                              This may be old news, it is dated 2001. The British Researchers have coaxed regeneration in rats with an enzyme to block scar tissue. The researches seem to think they have two of the three main obsticles in SCI repair figured out. They also said that trials were about 4 years away but this was said 3 years ago. Does anyone one know what has became of this study so far?

                              SOURCE


                              David

                              Comment

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