First advanced towards the recovery of walk in mice whose spinal cord was divided -- - - - - The lesions of the spinal cord responsible for the loss of the driving function are irreversible. That is allotted to the fact that the neurons do not manage to regenerate their termination axonale. The team of Alain Privat (unit Inserm 583, Montpellier) identified the cause of this not-regeneration of the spinal cord after section: the surexpression of two proteins in the astrocytes * resulting in the formation from an impenetrable scar. Thanks to models of transgenic mice, deprived of genes ensuring the synthesis of these two proteins, the regeneration of the axons and thus the recovery of the driving function were made possible. This work is published in the edition on line of July 8 of "Proceedings of National Academy of Science of the the USA". In France, one counts today more than 40 000 paraplegic and tetraplegic and each year, the road accidents, diving or other professional falls are responsible for 1 500 new cases of driving handicaps. At the time of these accidents, the traumatic lesions of the spinal cord cause the loss of the permanent voluntary motor activity. This is due to the fact that the terminations axonales of the damaged neurons which lead the nerve impulse coming from the brain and order walk, are not regenerated. There is about thirty years, neuronal regeneration was regarded as impossible in the central, but probable nervous system in the peripheral nervous system. Ten years later, of the researchers showed that the astrocytes or cells gliales * constituted a nonpermissive medium with pushes back axons. Since, many work seeks to restore the locomotion by reconnectant the two ends of the injured spinal cord, up to now without success. Researchers of the unit Inserm 583 in Montpellier, suggested that the regeneration of the axons is prevented by the formation of a scar. This one is due to a gliose astrocytaire. There are increase and accumulation of cells gliales which surexpriment two proteins (the GFAP - Glial Fribillary Acidic Protein - and Vimentin), constituting a kind of impenetrable netting, a hostile environment with regeneration axonale. To check this assumption, the montpelliéraine team sought to block the formation of this scar. The researchers worked out three models of transgenic mice whose genes ensuring the synthesis of these proteins were inactivated: the first group having only gene of the inactivated GFAP, the second that of Vimentin and a last group having two inactivated genes. The researchers then observed, after a lumbar hémisection involving a paralysis of the rear limb corresponding, the behaviors of these mice by comparing them with pilot mice, without change. Whereas these witnesses present a very significant scar, there does not exist pushes back axonale and the test of walk on a grid is negative (the leg falls), the transgenic mice having only one inactivated gene do not present pushes back axonale and do not recover either a locomotor function. On the other hand, the transgenic mice carrying the two changes do not develop a scar and recover a locomotor function. These animals presented a reduction of the reactivity of the astrocytes, associated an increase in the budding of the supraspinaux axons, going until the reconstitution of the circuits leading to functional recovery. These results constitute a "proof of principle" on which can develop an original therapeutic strategy, not only in the traumatic lesions of the central nervous system at the man but in all the pathological processes which involve an obstructive gliose reactional, which is the case of the neurodégénératives diseases like the Parkinson's disease.
The Journal of Neuroscience, August 15, 2001, 21(16):6147-6158
Inactivation of the Glial Fibrillary Acidic Protein Gene, But Not That of Vimentin, Improves Neuronal Survival and Neurite Growth by Modifying Adhesion Molecule Expression
nagyon hosszu cikk, kepekkel.
link:
posted Jul 10, 2003 03:28 AM
http://www.jneurosci.org/cgi/content/full/21/16/6147?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&author1=Alain+Privat&searchid=1057821854186_99&stored_search=&FIRSTINDEX=0&sortspec=relevance&tdate=7/31/2003&resourcetype=1
Source: European Society for Human Reproduction and Embryology
Research by Austrian geneticists has raised the possibility that stem cells[1] could be isolated from amniotic fluid – the protective 'bath water' that surrounds the unborn baby.
Geneticist Professor Markus Hengstschläger and his team at the University of Vienna have isolated a subgroup of cells from amniotic fluid that express a protein called Oct-4 – known to be a key marker for human pluripotent stem cells.
Reporting the findings today (Monday 30 June) in Europe's leading reproductive medicine journal Human Reproduction[2], Professor Hengstschläger stressed that the investigation was at an early stage. A lot more work had to be done to verify the finding, and tests were now under way to establish in which direction the cells could be differentiated. However, preliminary experiments have already provided evidence that they can be differentiated into nerve cells.
If, after extensive research these stem cells do prove to have similar potential to embryonic stem cells, ultimately it could reduce the need to use human embryos as a source, thus easing the tensions in this ethically controversial area.
Professor Hengstschläger believes that his team will know within two years what the amniotic cells are capable of becoming. "We have already presented good evidence in this paper for the existence of stem cells in amniotic fluid and we have evidence for neuronal differentiation. The question for the future will be – what can these cells do, in which directions can they be differentiated? Whether these cells have the same potential as embryonic stem cells is a question that can only be answered by a variety of experiments. However, our gene marker analyses demonstrate that they at least appear to resemble embryonic stem cells."
Professor Hengstschläger's group is the first to identify amniotic fluid as a potential source of pluripotent stem cells although others have previously suggested that amniotic fluid cells might be able to make skin.
To find the cells the researchers examined amniotic fluid taken from routine diagnostic amniocentesis on pregnant women. Genetic tests on 11 independent samples revealed Oct-4 mRNA (messenger RNA) in five of the samples. They went on to test for further indications of their potential and identified stem cell factor (a growth factor), vimentin and the enzyme alkaline phosphatase mRNA expression. All three of these molecules are markers for pluripotent stem cells.
"There is no doubt as to the importance of Oct-4 for the maintenance of stem cells," said Professor Hengstschläger. "Each mammalian pluripotent stem cell line expresses Oct-4, which rapidly disappears when the cells differentiate."
Further tests on the nucleus confirmed that the correct molecule had been analysed and suggested that the Oct-4 protein expression in the amniotic fluid cells was indeed functional.
Professor Hengstschläger said that the fact that only half the amniotic fluid samples were Oct-4 positive and that only 0.1 to 0.5% of cells within these positive samples expressed the Oct-4 transcription factor indicated that there was a distinct sub-population within the amniotic fluid cell sample with the potential to differentiate, rather than indicating that they had simply found a low general background Oct-4 expression. The cells were also shown to have dividing ability because cyclin A – a crucial protein that drives cell division – was present.
"Even if, in due course, we find that this new source of stem cells only have the ability to differentiate into a specific subset of cell lines, this is still an extremely interesting finding," he said. "We believe that our findings, together with the recent demonstration that amniotic fluid can be used for tissue engineering, encourages the further investigation of human amniotic fluid as a putative new source of stem cells with high potency."
Stem cells may be present in the amniotic fluid that cushions a baby in its mother's womb, suggests a new study.
If these cells prove to have the power to differentiate into different tissue types, they may provide a solution to the ethical dilemma associated with using human embryonic stem cells (ESCs), say reproductive scientists.
Markus Henstschläger and colleagues at the University of Vienna, Austria, found that some cells in the amniotic fluid taken from pregnant women during routine amniocentesis expressed a key protein called Oct-4. This is needed to keep ESCs in their state of perpetual youth. Further investigation showed that other important proteins were also expressed.
ESCs are "pluripotent'", i.e. they are primitive cells capable of differentiating into all the different cell types in the body. Many scientists believe they hold great potential for the treatment of degenerative diseases, such as Parkinson's disease. But ESCs are most easily obtained by destroying embryos, a practice some find ethically unacceptable.
Henstschläger's team say their work shows human amniotic fluid "may represent a new source for stem cells without raising the ethical concerns associated with human embryonic research".
Arne Sunde, new chairman of the European Society of Human Reproduction and Embryology, highlighted the findings at the society's annual conference in Madrid on Monday, amid concerns that proposed legislation by the European Union might halt stem cell research.
Stormy ride
"In countries where the use of ESCs could be banned, maybe the use of amniotic fluid stem cells will be acceptable." Sunde told New Scientist. But he cautioned that more research was needed to show the idea was practical.
The controversy over ESC research has meant a stormy ride for an EU-wide directive setting standards for tissue donation, testing and distribution. The proposed directive was amended to include a ban on research designed to create human embryos solely for research purposes or to supply stem cells.
This was overturned on 2 June, leaving the choice over such a ban to individual EU member countries. "However, there will almost certainly be moves to reinstate the ban at the second reading in parliament," stresses a statement from ESHRE.
Sunde opposes the ban and says research on stem cells from embryos remains crucial, but adds that Henstschläger's study highlights that non-embryo based stem cell research is progressing.
Rare but detectable
The Austrian team tested samples of amniotic fluid from 11 women in week 14 of pregnancy and found genetic material coding for Oct-4 in five samples. Cells expressing factors associated with Oct-4 were rare, but detectable, being found in no more than one in 200 cells.
Hengstschlager says it will take two years to find out what the cells are capable of turning into, although preliminary experiments suggest they can become nerve cells.
Sunde says that the clinical implications of stem cells from amniotic fluid are difficult to draw without knowing their potential and speed at which they might differentiate. "Would they have a high enough growth potential?" he asks. "They must be able to multiply fast enough."
He adds they may also be useful as a resource for the newborn baby itself. In some countries, parents are already freezing blood from the umbilical cord of newborns, because this preserves stem cells as a "back-up" for the future.
Journal reference: Human Reproduction (vol 18, p 1489)
Wise Young, MD, PhD, director of the Neuroscience Center and the Spinal Cord Injury Project at Rutgers University, is an internationally-renowned SCI research scientist. Among his accomplishments, Young participated in pioneering research that led to the development of high-dose methylprednisolone as a treatment for acute SCI. This drug improves neurologic recovery by an average of about 20% when given to people within several hours after injury, and its use is now standard practice in SCI trauma care.
We recently interviewed Young about the progress of SCI research today. His responses will be published in two installments; Part 2 will appear in the next issue.
Part 1
Q: Over the last year or two there have been promising breakthroughs in nerve cell regeneration research. Which avenues of research do you think are most likely to lead to a cure for SCI?
A: Much research indicates that spinal axons can regrow but the spinal cord contains substances that prevent growth. Several therapeutic approaches have shown promise in animal studies.
Blocking growth inhibitors in the spinal cord. Martin Schwab and his colleagues at the University of Zurich discovered an antibody called IN-1, which appears to block the growth-inhibiting substances in the spinal cord. These inhibitors appear to be concentrated in myelin, a material that wraps around spinal axons and improves conduction. Myelin is white and consequently areas of the spinal cord that contain myelin are called white matter (WM). Implantation of cells that produce IN-1 in rats promoted spinal cord regeneration. Much effort has gone be used in humans and IN-1 may well be one of the first therapies to go into clinical trial, perhaps in the next two years.
Diverting regenerating axons into gray matter. Heinreich Cheng, Lars Olson, and colleagues in Sweden showed that it is possible to get some regeneration to occur in rats by using peripheral nerve bridges to direct the growth of spinal axons into gray matter (GM), a part of the spinal cord that is more conducive to regeneration. Cheng and Olson's work lends credence to Schwab's finding that WM inhibits growth, demonstrates that axons can grow long distances in GM, and provides a potential surgical approach to reconnecting transected spinal cords.
Building cellular bridges. Several studies suggest that it is possible to use other cells and materials to bridge the gap. Doug Anderson and Paul Reier at the University of Florida at Gainesville transplanted fetal spinal cords to the injury site in humans, based on the notion that fetal cells might support growth. These studies showed that fetal cells will survive at the injury site and will support some growth.
Two patients received fetal cell transplants last year in Florida and dozens have received such transplants in Sweden and Russia. Results from this procedure have been inconclusive so far. Mary Bunge and colleagues at the Miami Project have been using artificial bridges and Schwann cells. More recently, two groups (Geoffrey Raisman of the University of London and Mary Bunge) reported that a special kind of cell from the nose, called olfactory ensheathing glial cells, will support the regeneration of axons in the spinal cord.
Enhancing natural repair mechanisms. Last year the Multicenter Animal Spinal Cord Injury Study, a consortium of SCI laboratories that are working together to develop and test therapies, discovered that injured rat spinal cords show limited regeneration without any external therapy. This has led to intense studies of natural factors that may enhance regeneration. Last month Michal Schwartz and her colleagues at the Weitzmann Institute reported that transplantation of activated macrophages into transected rat spinal cords apparently promotes regeneration and some functional recovery in rats. In our laboratory at Rutgers, we have found that injured spinal cords express a cellular adhesion molecule called L1, and administration of additional L1 to the spinal cord can enhance regeneration and functional recovery in the injured cord.
Q: Can you tell us about your current research?
A: We have devoted much of our effort to developing standardized tools for collaborative research in SCI, and we have validated outcome measures that many laboratories have adopted so that everybody knows what is meant when a rat is said to walk, when there is less tissue damage, or when there is regeneration. Using these tools, the field can now systematically develop and test therapies efficiently.
Most of our laboratory work is focused on four treatments: L1, M1, MP, and pregnenolone. L1 is a cellular adhesion molecule associated with increased growth and recovery in rats (see above). M1, an antibody discovered by Moses Rodriguez at the Mayo Clinic, is in the same family of antibodies as IN-1 (see above) and has been shown to promote remyelination in various animal models. MP is a corticosteroid that not only protects spinal cords against progressive tissue damage but may also promote regeneration. Pregnenolone, a steroid molecule produced by the central nervous system, makes spinal cords tolerant of prolonged oxygen deprivation, and others have reported that it improves repair and regeneration.
Two other projects in the laboratory are also quite exciting. First, we are systematically studying injured spinal cords to find out which molecules expressed after injury can signal axonal growth. If we can identify these signals, it will be possible to apply them to the chronic cord to kickstart growth again.
Second, we have been transplanting fetal oligodendroglial cells into the spinal cord. About a third of those with SCI have enough surviving axons but these axons have been demyelinated and cannot efficiently conduct signals. Last year, we showed that transplanted oligodendroglial cells will remyelinate axons in rats with SCI.
The Spinal Cord Injury Project can be reached at Neuroscience Center, Rutgers University, 604 Allison Rd., D413, Piscataway, NJ 08854-8082 (732-445-6573,445-2061; SSCIProj@biology.rutgers.edu).
Next Issue: In Part 2 of this interview, Wise Young proposes a timetable for a cure for SCI and cautions readers about unproved therapies.
Contact: Marissa Emerson
memerson@hsc.usf.edu
813-974-3300
University of South Florida Health Sciences Center
Stem-like cells from peripheral blood restore function in rats with severe stroke
Tampa, FL (July 7, 2003) -- Rats with severe strokes recovered function following intravenous injections of stem-like cells obtained from circulating human blood -- a finding that points to another potential cell therapy for stroke.
The study, by researchers at the University of South Florida Center of Excellence for Aging and Brain Repair, appears in today's issue of the journal Cell Transplantation.
The human blood donors were injected with granulocyte stimulating factor (G-CSF) to stimulate the release of stem-like cells from their bone marrow into the bloodstream before a blood sample was collected. These stem-like cells are known as peripheral blood progenitor cells.
"This is the first demonstration that G-CSF stimulated peripheral blood cells promote functional recovery after a stroke," said Alison Willing, PhD, assistant professor of neurosurgery and first author of the study. "We were putting these cells into animals 24 hours after a stroke and seeing significant behavioral improvement. The animals behaved almost normally on our tests, just as they had before the stroke. That's pretty amazing."
G-CSF stimulated peripheral blood cells have become an alternative treatment to bone marrow transplants for patients with blood cancers. They are easier to obtain, lead to faster recovery from chemotherapy and better survival.
Dr. Willing and her colleagues wanted to explore whether G-CSF treated peripheral blood cells might also be a treatment for central nervous system disorders. For the last few years, the USF Center for Aging and Brain Repair has been investigating alternatives to human embryonic stem cells, such as adult bone marrow stem cells and human umbilical cord blood (HUCB) cells, as treatments for stroke, spinal cord injury and other neurological disorders.
"Our findings suggest that mobilized peripheral blood cells might be a good candidate for early treatment of central nervous system disorders like stroke," said Paul R. Sanberg, PhD, DSc, professor of neurosurgery and director of the USF Center for Aging and Brain Repair. "They appear to be more readily accessible and easier to isolate than bone marrow and, like bone marrow, could be donated by patients for their own use."
In an editorial accompanying the USF study, authors Cesar Borlongan, PhD, and David Hess, MD, both of the Medical College of Georgia, also suggest that a patient's own peripheral blood stem cells might be a source of cell therapy for stroke. "Administration of G-CSF itself (an already FDA- approved drug) may mobilize progenitor cells from the bone marrow compartment into the peripheral blood where they can 'home' to the brain and have a protective or restorative effect. This would avoid the need to isolate cells and reinject them."
For this pilot study, the USF team compared the effect of G-CSF stimulated peripheral blood cells with that of HUCB cells in a rat model for severe stroke. An earlier report by researchers at USF and Henry Ford Hospital in Detroit reported that intravenous injections of HUCB cells helped rats recover from strokes faster.
The USF team looked at three groups of rats induced to have symptoms of stroke. The first group was intravenously injected with G-CSF stimulated peripheral blood cells 24 hours after a stroke. These cells were collected from the circulating blood of human blood donors through a process known as leukapheresis. Because the donors had received G-CSF before their blood was drawn, the resulting blood sample included a larger-than-normal population of immature, undifferentiated cells with the capacity to become any cell in the body, including neurons.
The second group was intravenously injected with HUCB cells 24 hours after the stroke.
The third group, a control, received no cellular treatment.
The researchers found that, following cell therapy, the stroke-induced hyperactive behavior of the rats was reduced to a pre-stroke level of normal activity. The improvement was similar whether the rats had been treated with peripheral blood cells or HUCB cells. Unlike humans, who are often paralyzed following a severe stroke, rats typically become abnormally active.
In addition, both the G-CSF stimulated peripheral blood cells and HUCB cells prevented the rats from developing stroke-associated motor asymmetry -- the favoring of one side over another. The control rats displayed a significant increase in motor bias following stroke.
The researchers are unsure how these peripheral blood cells improve functional recovery, but they suspect the transplanted cells may secrete protective substances that prevent further brain damage rather than replacing already damaged neurons. One month, the length of the USF study, likely was not enough time for a stem-like peripheral blood cell to change into a replacement neuron and sprout functioning fibers in the brain, Dr. Willing said.
Dr. Willing and her colleagues are continuing to try to determine how the peripheral blood cells work, as well as the optimal time, method and number of cells to deliver following a stroke.
Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells.
Teng YD, Lavik EB, Qu X, Park KI, Ourednik J, Zurakowski D, Langer R, Snyder EY.
Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
To better direct repair following spinal cord injury (SCI), we designed an implant modeled after the intact spinal cord consisting of a multicomponent polymer scaffold seeded with neural stem cells. Implantation of the scaffold-neural stem cells unit into an adult rat hemisection model of SCI promoted long-term improvement in function (persistent for 1 year in some animals) relative to a lesion-control group. At 70 days postinjury, animals implanted with scaffold-plus-cells exhibited coordinated, weight-bearing hindlimb stepping. Histology and immunocytochemical analysis suggested that this recovery might be attributable partly to a reduction in tissue loss from secondary injury processes as well as in diminished glial scarring. Tract tracing demonstrated corticospinal tract fibers passing through the injury epicenter to the caudal cord, a phenomenon not present in untreated groups. Together with evidence of enhanced local GAP-43 expression not seen in controls, these findings suggest a possible regeneration component. These results may suggest a new approach to SCI and, more broadly, may serve as a prototype for multidisciplinary strategies against complex neurological problems.
Exp Neurol. 2003 Jun;181(2):115-29. Related Articles, Links
Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury.
Lu P, Jones LL, Snyder EY, Tuszynski MH.
Department of Neurosciences, University of California at San Diego, 92093-0626, La Jolla, CA, USA
Neural stem cells (NSCs) offer the potential to replace lost tissue after nervous system injury. This study investigated whether grafts of NSCs (mouse clone C17.2) could also specifically support host axonal regeneration after spinal cord injury and sought to identify mechanisms underlying such growth. In vitro, prior to grafting, C17.2 NSCs were found for the first time to naturally constitutively secrete significant quantities of several neurotrophic factors by specific ELISA, including nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor. When grafted to cystic dorsal column lesions in the cervical spinal cord of adult rats, C17.2 NSCs supported extensive growth of host axons of known sensitivity to these growth factors when examined 2 weeks later. Quantitative real-time RT-PCR confirmed that grafted stem cells expressed neurotrophic factor genes in vivo. In addition, NSCs were genetically modified to produce neurotrophin-3, which significantly expanded NSC effects on host axons. Notably, overexpression of one growth factor had a reciprocal effect on expression of another factor. Thus, stem cells can promote host neural repair in part by secreting growth factors, and their regeneration-promoting activities can be modified by gene delivery.
J Neurosci Res. 2002 Sep 15;69(6):925-33. Related Articles, Links
Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats.
Ogawa Y, Sawamoto K, Miyata T, Miyao S, Watanabe M, Nakamura M, Bregman BS, Koike M, Uchiyama Y, Toyama Y, Okano H.
Department of Physiology, Keio University School of Medicine, Tokyo, Japan. hidokano@sc.itc.keio.ac.jp
Neural progenitor cells, including neural stem cells, are a potential expandable source of graft material for transplantation aimed at repairing the damaged CNS. Here we present the first evidence that in vitro-expanded fetus-derived neurosphere cells were able to generate neurons in vivo and improve motor function upon transplantation into an adult rat spinal-cord-contusion injury model. As the source of graft material, we used a neural stem cell-enriched population that was derived from rat embryonic spinal cord (E14.5) and expanded in vitro by neurosphere formation. Nine days after contusion injury, these neurosphere cells were transplanted into adult rat spinal cord at the injury site. Histological analysis 5 weeks after the transplantation showed that mitotic neurogenesis occurred from the transplanted donor progenitor cells within the adult rat spinal cord, a nonneurogenic region; that these donor-derived neurons extended their processes into the host tissues; and that the neurites formed synaptic structures. Furthermore, analysis of motor behavior using a skilled reaching task indicated that the treated rats showed functional recovery. These results indicate that in vitro-expanded neurosphere cells derived from the fetal spinal cord are a potential source for transplantable material for treatment of spinal cord injury. Copyright 2002 Wiley-Liss, Inc.
Effects of embryonic neural stem cells and glial cell line-derived neurotrophic factor in the repair of spinal cord injury]
[Article in Chinese]
Sun Y, Shi J, Fu SL, Lu PH, Xu XM.
Department of Neurobiology, Shanghai Second Medical University, Shanghai 200025; E-mail: neuron@shmu.edu.cn
The ability of implanted embryonic neural stem cells (NSCs) to improve survival, migration, and functional recovery following a compression spinal cord injury (SCI) was tested in adult rats. NSCs were isolated from E14-16 rat cerebral cortex and SCI was produced by using an aneurysm clip applicator applied to the 8th thoracic spinal cord according to method of Dolan and Tator. Two weeks after the injury, NSCs (4 &mgr;l of 1 10(4) cells/&mgr;l) were injected into the lesion site., The grafted NSCs were noted to survive and integrate with the host spinal cord 1 month after transplantation, which was demonstrated by the presence of Hoechst 33342 (a nuclear dye) pre-labeled NSCs within and surrounding the lesion site. Some of these cells remained undifferentiated and were stained with nestin, a marker for NSCs. Transplanted NSCs migrated for at least 3 mm from the injury epicenter towards both the rostral and caudal directions. Significant reduction in the lesion area (P<0.05) and improvement in inclined plane (P<0.05) and BBB locomotor rating scale (P<0.05) were found in the cases that received implantation of NSCs, as compared with those that received vehicle injection. More importantly, when glial cell line-derived neurotrophic factor (GDNF; 1.5 &mgr;g/&mgr;l) was added to the transplants, further reduction in lesion area (P<0.01) and improvement in the function were observed in the combined treatment group as compared with the vehicle infused group. Our results suggest that intraspinal treatment with NSCs and GDNF synergistically reduced lesion size and improved functional outcome after a compressive SCI in adult rats.
Role of human amniotic epithelial cell transplantation in spinal cord injury repair research.
Sankar V, Muthusamy R.
Department of Anatomy, Dr. Arcot Lakshmanaswamy Mudaliar Postgraduate Institute of Basic Medical Sciences, Taramani Campus, University of Madras, 600 113, Chennai, India. venkatsankar@yahoo.com
Human amniotic epithelial cells (HAEC) possess certain properties similar to that of neural and glial cells. In the present work, the potential of HAEC as stem cells for spinal cord injury repair was tested. HAEC obtained from human placenta were labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethyllindocarbocyanine perchlorate (Dil) in the culture medium. These labeled cells were transplanted into the transection cavities in the spinal cord of bonnet monkeys. Results were analyzed after 15 and 60 days of post-transplantation. HAEC cells survived in the monkey spinal cord for up to the maximum period of observation in the present study, i.e. 60 days. HAEC graft was penetrated by the host axons. There was no glial scar at the transection lesion site. Some of the host spinal neurons and axons were labeled with Dil (used to label HAEC) whereas in lesion control group, there was no such host-neuron labeling. This may be either due to the prevention of death in the axotomized neuron's ensuing lesion or due to the neurotrophic effect exhibited by the transplanted HAEC. Further studies would be required to verify these speculations. Therefore from this pilot study it appears that HAEC survive in the transplanted environment, support the growth of host axons through them, prevent the formation of glial scar at the cut ends and may prevent death in axotomized cells or attract the growth of new collateral sprouting. The abovementioned properties, i.e. serving as a suitable milieu for the host axons to grow, preventing glial scar at the lesion site and rescuing axotomized neurons from death were previously reported in the case of neural transplantation studies. Thus it is speculated that HAEC may be having certain properties equal to the beneficial effects of neural tissue in repairing spinal cord injury. Apart from this speculation, there are two more reasons for why HAEC transplantation studies are warranted to understand the long-term effects of such transplantations. First, there was no evidence of immunological rejection probably due to the non-antigenic nature of the HAEC. Second, unlike neural tissue, procurement of HAEC does not involve many legal or ethical problems.
I am the third patient out of the USA to recieve his procedure!! It has been 12 days since the day of surgery and I recovered some sensation within the first couple of days. There was no compression of the cord in my case so it is hard to say why any sensation has returned so soon, even Dr. Lima was confused and "must go think" he is truly one of the most majestic people to walk this earth. I am home as of July 2nd and feel very hopeful for the future.
OK, bare with me, still recovering with the help of some pain meds..
My level was T-7/8, 100% complete, my spinal cord was almost severed Dr. Vital has told me... I have a standing wheelchair and do my own PT. Considering my options for the future at this point regarding more intense PT.
Researcher Predicts Cure
As reported by Rosalie Karunas in SCI Access, published by the University of Michigan Model SCI Care System, Dr. Wise Young was recently cited by Time Magazine as one of America’s Best in Science and Medicine for his research on spinal-cord repair. While Dr. Young heads the Center for Collaborative Neuroscience of Rutgers University, he maintains close contacts with staffs of the University of Michigan Model Spinal Cord Injury Care System and other Model SCI Systems around the country.
“I firmly believe we will develop treatment to restore function!” Dr. Young declares. “I do not believe any single center will come up with a cure. Only the best scientists working together can produce this,” he says.
The Neurologists at South Shore Neurologic Associates have been utilizing 4ap therapy for treatment of fatigue and motor performance for those with multiple sclerosis for more than 10 years with variable clinical effectiveness and excellent safety profile.
Dr. Wise Young, M.D., Ph.D.- (SpineWire):
4AP is a chemical that blocks the fast voltage sensitive potassium channel. In addition to 1,4-diaminopyridine (1,4-DAP), it is one of a handful of drugs that block this particular channel, which is responsible to shortening the action potential generated by sodium currents in neurons. The drug has been used by neurophysiologists for decades. It has not yet been approved by the FDA for clinical use although it has been on the compounded formulary of many pharmacies and can be prescribed by physicians. It has been estimated that over 10,000 people in the U.S. with multiple sclerosis or spinal cord injury are taking the drug.
Clinically, the drug increases the duration of action potentials in demyelinated axons and also the presynaptic terminals of axons. Thus, the drug increases the safety factor of conduction in the spinal cord and increases the amount of neurotransmitter released per action potential. In the mid-1980s, the drug was used to treat multiple sclerosis; at least five small clinical trials have been carried out reporting that 4AP can increase sensory and motor function in people with multiple sclerosis. Demyelination also occurs in spinal cord injury and several clinical trials have been reported to improve motor and sensory function in about one third of people with chronic spinal cord injury, particularly in people with "incomplete" spinal cord injury. It also may reduce spasticity and pain.
The version of the drug that is available from pharmacies is an oral and immediate release formulation which has a plasma half-life of about 3-4 hours. The recommended treatment dose is 40 mg per day, in four divided doses. In overdoses, the drug has a risk of causing seizures in patients with multiple sclerosis; however, seizures have not been reported in any spinal-injured patient who has gotten the drug in doses of 40 mg per day or less. Other side effects include restlessness, parasthesias, and increased frequency of bowel movements. Most of these side effects can be avoided by ramping up the dose over a period of several weeks.
Acorda Therapeutics is developing a time-release formulation of the drug that can be given b.i.d. and at higher doses (due to reduced peak levels). This formulation is currently in phase 2 clinical trials and phase 3 trials are being planned. Because the compounded immediate release formula varies significantly from pharmacy to pharmacy, the FDA recently requested that Acorda Therapeutic provide its time-release formulation in a open-label clinical trial to all people who are taking compounded 4AP. The company is in the process of complying with this request. However, neither the timing nor the implementation of this open label trial is clear at the moment.
Acorda: Fampridine. ("4-aminopyridine", "4-AP"), a nerve conduction-enhancing compound which is the first ever shown to restore some neurological function to people with SCI. Fampridine has been shown to increase nerve conduction in impaired axons and to result in improved neurological function in numerous in vitro and animal studies. Several initial human trials of fampridine have also been conducted to date, involving a total of over 400 human subjects with chronic SCI or multiple sclerosis (MS). Patients in these trials have shown improvements in a variety of impaired functions, including increased motor, sensory, bladder, bowel and/or sexual functions, as well as reductions in muscle spasticity and/or chronic pain.
Acorda has exclusive, worldwide licenses to patents covering formulations and SCI uses of fampridine. In January 1997, Acorda entered into a collaboration with Elan Corporation of Athlone, Ireland, concerning Elan’s patented, sustained-release oral tablet formulation of fampridine. Acorda obtained an exclusive, worldwide license to Elan’s fampridine patents for SCI markets, and is responsible for all clinical development and marketing. Elan will manufacture and supply the product to Acorda. In April 1998, Acorda established a joint venture with Elan, 80% owned by Acorda, to develop fampridine for worldwide MS markets as well. Fampridine has "orphan product" designations from the U.S. Food and Drug Administration (FDA) for use in both SCI and MS.
Fampridine Background and Mechanism: Researchers have shown that, contrary to popular belief, the majority of patients with SCI do not have severed cords. Most SCI victims have blunt damage to the cord and the majority has some axons that survive the injury. However, the surviving axons often are damaged and lose part of their myelin, the insulating sheath that permits electrical impulses to be conducted down the axon. Nerve impulses "short circuit" in demyelinated axons much like electricity in a wire whose insulation is stripped. Thus, even though a demyelinated axon is alive, it cannot transmit motor or sensory impulses and the patient effectively loses the use of it. In MS the myelin sheath is damaged by the body’s own immune system, rather than by physical trauma as in SCI.Fampridine’s major action is to block specialized potassium channels on axons. These potassium channels normally "reset" the axon after a nerve impulse passes through it to enable the axon to transmit another impulse. When an axon is demyelinated after injury, large numbers of these potassium channels are exposed and "leak" potassium ions, causing the axon to "short circuit." By closing the exposed potassium channels, fampridine permits the axon to transmit impulses again, even in a demyelinated state.
Wise Young, M.D., Ph.D., Professor II & Director
W. M. Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey
Nelson Biological Laboratories, 604 Allison Rd
Piscataway, New Jersey 08854-8082
tel: 732-445-2061, fax: 732-445-2063
Segal JL, Pathak MS, Hernandez JP, Himber PL, Brunnemann SR and Charter RS (1999).
Safety and efficacy of 4-aminopyridine in humans with spinal cord injury: a long-term, controlled trial. Pharmacotherapy. 19 (6): 713-23.
Summary: STUDY OBJECTIVE: To determine the effects of the long-term administration of 4-aminopyridine (4-AP) on sensorimotor function in humans with long-standing spinal cord injury (SCI). DESIGN: Randomized, open-label, active-treatment control, dosage-blinded study. SETTING: University-affiliated, tertiary-level care, Department of Veterans Affairs Medical Center. PATIENTS: Twenty-one healthy men and women outpatients suffering from traumatic SCI (14 tetraplegic, 7 paraplegic) for 2 years or more. INTERVENTIONS: Dosages of an immediate-release formulation of 4-AP were titrated. At 3 months, 16 subjects were receiving 4-AP 30 mg/day (high dose); 5 subjects were receiving 4-AP 6 mg/day (low dose) and served as an active-treatment control group. MEASUREMENTS AND MAIN RESULTS: Composite motor and sensory scores had statistically significant increases at 3 months. Maximal expiratory pressure, maximal inspiratory pressure, forced vital capacity, and forced expiratory volume in 1 second showed clinically meaningful and/or statistically significant increases among patients receiving 4- AP 30 mg/day. These subjects also had significant decreases in spasticity (modified Ashworth Scale). Serial biochemical profiles and electroencephalographs were unchanged from baseline, and no clinically significant drug toxicity was encountered. CONCLUSIONS: Long-term oral administration of immediate-release 4-AP was associated with improvement in and recovery of sensory and motor function, enhanced pulmonary function, and diminished spasticity in patients with long- standing SCI. 4-Aminopyridine appears to be safe and relatively free from toxicity when administered orally over 3 months. Each patient who received immediate-release 4-AP 30 mg/day showed a response in one or more of the outcome measures.
Gruner JA and Yee AK (1999).
4-Aminopyridine enhances motor evoked potentials following graded spinal cord compression injury in rats. Brain Res. 816 (2): 446-56.
Summary: Although several experimental and clinical studies have demonstrated the ability of 4-aminopyridine (4-AP) to restore electrophysiological and/or behavioral function following chronic spinal cord injury, the mechanism by which this occurs remains unclear. Demonstration of efficacy in rat spinal cord injury has not been reported, evidently because even relatively mild spinal cord contusions that produce only minor permanent locomotor disturbances abolish hind limb myoelectric motor evoked potentials (mMEPs). In this study, mMEPs were recorded acutely 25 days following graded thoracic spinal cord compression in rats. mMEP amplitudes were significantly enhanced by a single, 2 mg/kg i.v. dose of 4-AP. mMEPs were increased in all rats showing some evoked responses initially, and also in some animals which had no responses prior to treatment. 4-AP was further found to increase the maximum following frequency of mMEPs in both normal and injured rats from about 0.1 Hz to between 1 and 10 Hz. These data suggest that 4-AP might act by enhancing synaptic efficacy, as well as enhancing conduction in spinal axons whose myelination has been rendered dysfunctional by trauma. Copyright 1999 Elsevier Science B.V.
Segal JL and Brunnemann SR (1998).
4-Aminopyridine alters gait characteristics and enhances locomotion in spinal cord injured humans. J Spinal Cord Med. 21 (3): 200-4.
Summary: Recovery of useful motor function in humans with spinal cord injury (SCI) is a primary and elusive goal. In this preliminary study, we describe efforts to delineate the pharmacological effects of 4- aminopyridine (4-AP) on gait parameters in spinal cord injured humans who have retained some capacity to ambulate bipedally. A sequential entry, open label study was made of the effects of a single oral administration of an immediate-release formulation of 4-AP on the time- course profile of changes in component parameters of bipedal gait in ambulatory volunteers with chronic SCI. Nine healthy, rehabilitated, community-adapted male volunteers (six tetraparetic, three paraparetic), who sustained their injuries more than one year prior to entry into the study, ingested a single 10-mg dose of 4-aminopyridine after an overnight fast. Gait analysis parameters included velocity (meters/min), cadence (steps/min), stride length (meters), gait cycle (seconds), and double limb support (percent of gait cycle). They were measured for 24 hours using a sampling-rich strategy (nine duplicate measurements over 24 hrs). Repeated measures (randomized block) analysis of variance (ANOVA) and paired t-tests were used to test for the significance of differences between means and variances. The apparent pharmacological effect of 4-AP is associated with statistically significant changes in one or more of the component elements used to assess the characteristics and efficiency of bipedal gait. These changes in gait analysis parameters correspond temporally with the improvements in pulmonary function and heart rate variability previously described by us. 4-AP appears to enhance gait in a subset of humans with SCI. In this preliminary study we report, for the first time, an apparent effect of 4-AP on gait in spinal cord injured humans and suggest that the pharmacological effects of 4-AP may have clinically significant application in the restoration of useful motor function.
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 (3): 147-55.
Summary: Preclinical trials of intravenously administered 4-Aminopyridine (4-AP) have demonstrated transient improvements in neurological function in patients with longstanding spinal cord injury (SCI). The present report describes three patients with SCI who responded favourably in preclinical trials and who were subsequently administered oral (capsule) 4-AP (10 mg b.i.d. or t.i.d.) over a 4 month interval. The three patients (two male: 1 female) all had incomplete tetraplegia (ASIA levels C and D) with the neurological level of the lesion between C5-C7. Following the administration of 4-AP the patients demonstrated marked and sustained reductions in upper (n = 1) or lower extremity (n = 2) spasticity. Other clinical benefits of 4-AP were reduced pain (n = 1), restored muscle strength (n = 3), improved sensation (n = 2), voluntary control of bowel function (n = 1), and sustained penile tumescence (n = 2). The patients exhibited improved hand function (n = 1), enhanced mobility in transfers and gait (n = 2), with improved energy and endurance. Only trivial side effects (transient light- headedness) were observed. In one case, the enhanced neurological function allowed the patient to stand with support for the first time post injury (16 years). The time course of therapeutic response to the initial dose matched the pharmacokinetic elimination profile derived from serum and urine analysis. There was no evidence of renal or hepatic toxicity with prolonged use. These results indicate a therapeutic benefit of oral 4-Aminopyridine in the management of various neurological deficits in a select group of SCI patients.
Potter PJ, Hayes KC, Segal JL, Hsieh JT, Brunnemann SR, Delaney GA, Tierney DS and Mason D (1998).
Randomized double-blind crossover trial of fampridine-SR (sustained release 4-aminopyridine) in patients with incomplete spinal cord injury. J Neurotrauma. 15 (10): 837-49.
Summary: A randomized double-blind dose-titration crossover trial of the safety and efficacy of oral fampridine-SR (sustained release 4-aminopyridine) was conducted on spinal cord injured (SCI) patients at two centers. Twenty-six patients (n = 26) with incomplete lesions completed the trial. These patients all had chronic (>2 years) and stable neurological deficits. They received fampridine-SR 12.5 and 17.5 mg b.i.d. over a 2-week treatment period, followed by a 1-week washout and 2 weeks of placebo, or vice versa. Patients reported significant benefit of fampridine-SR over placebo on patient satisfaction (McNemar's test, p2 0.05) and quality of life scores (p2 0.01). Sensory scores (p1 0.01), including both pin prick (p1 = 0.059) and light touch (p1 = 0.058), and motor scores (adjusted to reflect only paretic segments) (p1 0.01) all yielded evidence of benefit of fampridine-SR over placebo. The Ashworth scale of spasticity was significantly (p2 0.05) reduced when patients received fampridine-SR. There were no statistically significant benefits of the drug on measures of pain or bowel, bladder and sexual function, or functional independence. Side effects of lightheadedness and nausea were transient and trivial relative to efficacy, and approximately 30 percent of patients reported a wish to continue to use fampridine-SR. The clinical benefits most likely derive from the K+ channel blocking action of the drug. Potassium channel blockade enhances axonal conduction across demyelinated internodes and enhances neuroneuronal and neuromuscular transmission in preserved axons. These results provide the first evidence of therapeutic benefit of fampridine-SR in SCI patients.
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 (3): 135-49.
Summary: The potassium (K+) channel-blocking agent 4-aminopyridine (4-AP) is currently being investigated for its potential therapeutic value in patients with spinal cord injury (SCI). The present study was designed to test the hypothesis that 4-AP ameliorates central motor conduction deficits in individuals with SCI. Oral 4-AP (10 mg) was administered to 19 (n = 19) SCI subjects with stable neurological deficits. Their response to the drug was monitored using motor evoked potentials (MEPs) following transcranial magnetic stimulation of motor cortex and various measures of segmental or peripheral reflex activity (F-waves, H-reflex, and M-response) recorded from lower limb muscles. The mean MEP amplitude in the extensor digitorum brevis muscle (left) was significantly (p .05) increased from x = .25 +/- .42 mV to x = .59 +/- 1.04 mV at 2 h after drug administration, and the cortical stimulation threshold was reduced (p ..05) by 5.8 percent. Similar results were obtained in all subjects exhibiting MEPs (n = 13) and in all muscles (n = 6) studied. These changes were maintained at 4 h postdrug. MEP latencies were reduced in all subjects who initially exhibited abnormally prolonged MEP latencies relative to control group (n = 13) values. F- wave, H-reflex, and M-response values (latency and amplitude) were not systematically altered by 4-AP, leading to the conclusion that it was central motor conduction that was enhanced. This interpretation was supported by observed reductions in central motor conduction time (CMCT) in the majority of SCI subjects from whom CMCT measurements were obtained, two of whom anecdotally reported improved motor control after 4-AP, and by increased MEP:M-wave amplitude ratios. The MEP:M-wave ratios indicated that the magnitude of the effect of 4-AP on motoneuron recruitment was not large, in absolute terms (4 percent motoneuron pool), but was appreciable relative to the initial level of motoneuron recruitment. These results provide the first statistically significant, objective evidence of improved functioning of the neuromuscular system in chronically injured SCI subjects receiving 4-AP and suggest that the improvements are mediated through enhanced central conduction. The results further support the emerging view that pharmaceutical management of central conduction deficits may prove to be a useful therapeutic strategy for some patients with long-standing SCI.
Pinter MJ, Waldeck RF, Cope TC and Cork LC (1997).
Effects of 4-aminopyridine on muscle and motor unit force in canine motor neuron disease. J Neurosci. 17 (11): 4500-7.
Summary: Hereditary Canine Spinal Muscular Atrophy (HCSMA) is an autosomal dominant disorder of motor neurons that shares features with human motor neuron disease. In animals exhibiting the accelerated phenotype (homozygotes), we demonstrated previously that many motor units exhibit functional deficits that likely reflect underlying deficits in neurotrans-mission. The drug 4-aminopyridine (4AP) blocks voltage- dependent potassium conductances and is capable of increasing neurotransmission by overcoming axonal conduction block or by increasing transmitter release. In this study, we determined whether and to what extent 4AP could enhance muscle force production in HCSMA. Systemic 4AP (1-2 mg/kg) increased nerve-evoked whole muscle twitch force and electromyograms (EMG) to a greater extent in older homozygous animals than in similarly aged, symptomless HCSMA animals or in one younger homozygous animal. The possibility that this difference was caused by the presence of failing motor units in the muscles from homozygotes was tested directly by administering 4AP while recording force produced by failing motor units. The results showed that the twitch force and EMG of failing motor units could be significantly increased by 4AP, whereas no effect was observed in a nonfailing motor unit from a symptomless, aged-matched HCSMA animal. The ability of 4AP to increase force in failing units may be related to the extent of failure. Although 4AP increased peak forces during unit tetanic activation, tetanic force failure was not eliminated. These results demonstrate that the force outputs of failing motor units in HCSMA homozygotes can be increased by 4AP. Possible sites of 4AP action are considered.
Segal JL and Brunnemann SR (1997).
4-Aminopyridine improves pulmonary function in quadriplegic humans with longstanding spinal cord injury. Pharmacotherapy. 17 (3): 415-23.
Summary: STUDY OBJECTIVE: To test the hypothesis that 4-aminopyridine (4-AP) might cause clinically evident improvement in pulmonary function in humans with chronic spinal cord injury (chronic SCI). DESIGN: Balanced, open-label study with subjects consecutively enrolled. SETTING: Spinal Cord Injury Service, university-affiliated tertiary level care Department of Veterans Affairs Medical Center. PATIENTS: Seventeen healthy men and women suffering from traumatic SCI (11 quadriplegic, 6 paraplegic patients) for more than 1 year. INTERVENTIONS: Each subject was given a single dose of 4-AP 10 mg orally in an immediate-release formulation. MEASUREMENTS AND MAIN RESULTS: Significant increases in mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) that persisted for at least 12 hours were demonstrated in quadriplegic patients beginning 6 hours after 4-AP administration. Tests of pulmonary function that demonstrated statistically significant increases at any time were also numerically, if not statistically, increased at 24 hours compared with pretreatment values obtained in 4-AP-naive subjects. CONCLUSIONS: The administration of a single dose of an immediate-release formulation of 4-AP to humans with longstanding, traumatic quadriplegia is associated with sustained, clinically meaningful, and statistically significant improvements in pulmonary function. We suggest that the administration of 4-AP may have a salutary effect in patients suffering from SCI and appears to be associated with potentially clinically significant reductions in the pathophysiologic pulmonary sequelae of SCI.
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 (2): 553-62.
Summary: Blockade of potassium channels with the drug 4-aminopyridine has been shown to effect recovery of action potential conduction in myelinated axons under a variety of pathological conditions, but the mechanism and significance of this phenomenon are not completely understood. This study examined the effects of a range of 4-aminopyridine concentrations on conduction in an experimental model of chronic spinal cord injury in guinea-pigs, using sucrose-gap recording from isolated spinal cord strips. The amplitude of the compound action potential increased in response to bath application of 4-aminopyridine, with a threshold between 0.5 and 1 microM and the peak response between 10 and 100 microns. Conduction was suppressed at concentrations of 1 and 10 mM. Uninjured white matter showed no effect on the compound potential of 4- aminopyridine below 1 mM, but there was a similar suppression at concentrations above 1 mM, accompanied by marked membrane depolarization. Peripheral nerve showed only slight action potential suppression and depolarization in the presence of 10 mM 4- aminopyridine. The sensitivity of injured axons to 1 microM 4- aminopyridine is consistent with the hypothesis that some beneficial effects of the drug seen in patients with spinal cord injury are related to improved conduction in myelinated axons, since cerebrospinal fluid levels of 4-aminopyridine should approach this concentration following clinical systemic doses, although it remains likely that synaptic effects also play a role. The blockade of action potential conduction produced by much higher levels of 4-aminopyridine in vitro is possibly a consequence of interference with the resting potential mechanism of the axon membrane, which appears to differ between central and peripheral nerve fibers.
Shi R and Blight AR (1996).
Compression injury of mammalian spinal cord in vitro and the dynamics of action potential conduction failure. J Neurophysiol. 76 (3): 1572-80.
Summary: 1. White matter strips from the ventral spinal cord of adult guinea pigs were isolated in vitro, and their electrophysiological characteristics and response to controlled focal compression injury were examined. A double sucrose gap technique was used for stimulation and recording at opposite ends of a 12.5 mm-diam central well superfused with oxygenated Krebs solution. 2. The compound action potential recorded with the sucrose gap was similar in form to single fiber potentials recorded with intra-axonal electrodes, including the presence of a prolonged depolarizing afterpotential. 3. Three types of conduction block resulting from compression were identified: an immediate, spontaneously reversible component, which may result from a transient increase in membrane permeability and consequent disturbance of ionic distribution; a second component that was irreversible within 1-2 h of recording, perhaps resulting from complete axolemmal disruption; and a third component, which may have been due to disruption of the myelin sheath, that appeared to be reversible with application of 10-100 microM of the potassium channel blocker 4- aminopyridine. 4. Conduction deficits-decreased amplitude and increased latency of the compound potential-were stable between 5 and 60 min postinjury, and their intensity corellated with the extent of initial compression over a full range of severity. 5. Stimulus-response data indicate that mechanical damage to axons in compression was evenly distributed across the caliber spectrum, suggesting that the susceptibility of large caliber axons seen histopathologically after injury in vivo may be based on delayed, secondary processes. 6. The model provides the ability to monitor changes in the properties of central myelinated axons after compression injury in the absence of pathological variables related to vascular damage. This initial investigation found no evidence of secondary deterioration of axons in the 1st h after injury, although there was evidence of both transient and lasting mechanical damage to axons and their myelin sheaths.
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 (4): 433-46.
Summary: 4-Aminopyridine (4-AP) is a potassium channel blocking agent with the ability to restore conduction in demyelinated internodes of axons of the spinal cord. The present investigation sought to obtain electrophysiologic evidence of the effect of 4-AP in ameliorating central conduction deficits in a group of patients (n = 6) with spinal cord injury (SCI). The group was selected on the basis of having temperature-dependent central conduction deficits. 4-AP (24-25 mg total dose) was delivered intravenously at 6 mgh-1 or 15 mgh-1 while somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) were recorded as indices of central conduction. Two patients exhibited marked increases in the amplitude of cortical SEPs, and in one of these, 4-AP brought about a reduced central conduction time from L1 to cortex. Four patients revealed increased amplitude MEPs with concomitant reduction in latency indicative of enhanced conduction in corticospinal or corticobulbospinal pathways. Two of these patients demonstrated increased voluntary motor unit recruitment following 4-AP. Clinical examination revealed reduced spasticity (n = 2), reduced pain (n = 1), increased sensation (n = 1), improved leg movement (n = 3), and restored voluntary control of bowel (n = 1). These results support the hypothesis that 4-AP induces neurologic benefits in some patients with SCI. They are also consistent with the emerging concept that pharmaceutical amelioration of central conduction deficits caused by focal demyelination may contribute to the management of a select group of patients with compressive or contusive SCI.
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 [see comments]. J Neurotrauma. 10 (1): 1-18.
Summary: The potassium channel blocking drug 4-aminopyridine (4-AP) was administered to eight patients with chronic spinal cord injury, in a therapeutic trial based on the ability of the drug to restore conduction of impulses in demyelinated nerve fibers. The study was performed using a randomized, double-blind, crossover design, so that each patient received the drug and a vehicle placebo on different occasions, separated by 2 weeks. Drug and placebo were delivered by infusion over 2 h. An escalating total dose from 18.0 to 33.5 mg was used over the course of the study. Subjects were evaluated neurologically before and after the infusion. Two subjects returned for a second trial after 4 months and were examined daily for 3 to 4 days following drug infusion. Side effects were consistent with previous reports. Administration of the drug was associated with significant temporary neurologic improvement in five of six patients with incomplete spinal cord injury. No effect was detected in two cases of complete paraplegia and one of two severe incomplete cases (Frankel class B). Improvements in neurologic status following drug administration included increased motor control and sensory ability below the injury, and reduction in chronic pain and spasticity. The effects persisted up to 48 h after infusion of the drug, and patients largely returned to preinfusion status by 3 days. Compared with the more rapid elimination of the drug, these prolonged neurologic effects appear to involve a secondary response and are probably not a direct expression of potassium channel blockade.
Noseworthy JH (1993).
Clinical trials in multiple sclerosis. Curr Opin Neurol Neurosurg. 6 (2): 209-15.
Summary: In this past year, there has only been modest progress in the search for an effective treatment for multiple sclerosis and its complications, although a number of carefully designed trials are in progress. No treatment predictably slows the course of active disease. The marginal benefits previously claimed for azathioprine have been strengthened by a meta-analysis of previously published work. Methylprednisolone may have a minor role in the treatment of very severe, acute optic neuritis but prednisone use may predispose patients to recurrent optic neuritis. 4-Aminopyridine and 3,4-diaminopyridine may prove useful for the symptomatic treatment of some multiple sclerosis patients; pemoline may be an alternative to amantadine for the control of fatigue; and acetazolamide may be an alternative to carbamazepine and phenytoin for the treatment of painful tonic spasms.
van Diemen HA, Polman CH, van Dongen MM, Nauta JJ, Strijers RL, van Loenen AC, Bertelsmann FW and Koetsier JC (1993).
4-Aminopyridine induces functional improvement in multiple sclerosis patients: a neurophysiological study. J Neurol Sci. 116 (2): 220-6.
Summary: This study reports on the neurophysiological measurements that were performed in the context of a randomized, double-blind, placebo- controlled, cross-over study with intravenously administered 4- aminopyridine (4-AP) in 70 patients with definite multiple sclerosis (MS). A beneficial effect of 4-AP was found for both visual evoked response and eye movement registration parameters. This study extends the experimental data obtained on animal nerve fibers, showing that 4- AP can improve impulse conduction in demyelinated nerve, to clinical data which indicate that 4-AP induces an objective improvement in the central nervous system function in MS-patients. It thereby also provides a theoretical basis for clinical efficacy of 4-AP in MS.
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 (4): 216-24.
Summary: 4-Aminopyridine (4-AP) is a K+ channel blocking agent that enhances nerve conduction through areas of demyelination by prolonging the duration of the action potential and increasing the safety factor for conduction. We have investigated the effects of 4-AP (24 mg total dose- intravenous) in 6 patients with spinal cord injury (3 complete, 3 incomplete) with the intent of overcoming central conduction block, or slowing, due to demyelination. Vital signs remained stable and only mild side effects were noted. The 3 patients with incomplete injuries all demonstrated enhanced volitional EMG interference patterns and one patient exhibited restored toe movements. The changes were reversed on drug washout. There were no changes in segmental reflex activities. These results are consistent with those obtained from 4-AP trials with animal models of spinal cord injury, showing modest therapeutic benefit attributable to enhanced central conduction.
van Diemen HA, Polman CH, van Dongen TM, van Loenen AC, Nauta JJ, Taphoorn MJ, van Walbeek HK and Koetsier JC (1992).
The effect of 4-aminopyridine on clinical signs in multiple sclerosis: a randomized, placebo-controlled, double-blind, cross-over study. Ann Neurol. 32 (2): 123-30.
Summary: To find out whether treatment with 4-aminopyridine is beneficial in multiple sclerosis (MS), 70 patients with definite MS entered into a randomized, double-blind, placebo-controlled, cross-over trial in which they were treated with 4-aminopyridine and placebo for 12 weeks each (maximum dose, 0.5 mg/kg of body weight). The estimated effect of the treatment as measured with the Kurtzke expanded disability status scale, which was the main evaluation parameter, was 0.28 point (p = 0.001). A significant decrease in the scale score (1.0 point or more) was encountered in 10 patients (16.4 percent) during oral treatment with 4-aminopyridine whereas it was not seen during placebo treatment (p less than 0.05). A significant subjective improvement (defined as an improvement that significantly affected the activities of normal daily life) was indicated by 18 patients (29.5 percent) during 4-aminopyridine treatment and by 1 patient (1.6 percent) during placebo treatment (p less than 0.05). Significant improvements related to 4-aminopyridine occurred in a number of neurophysiological parameters. No serious side effects were encountered. However, subjective side effects such as paresthesias, dizziness, and light-headedness were frequently reported during 4-aminopyridine treatment. Analysis of subgroups revealed that there was no difference in efficacy between those patients randomized to receive 4-aminopyridine and then placebo and those randomized to receive placebo and then 4-aminopyridine or between patients with and those without subjective side effects. Especially patients with temperature- sensitive symptoms and patients characterized by having a longer duration of the disease and being in a progressive phase of the disease were likely to show clear clinical benefit.
Stefoski D, Davis FA, Fitzsimmons WE, Luskin SS, Rush J and Parkhurst GW (1991).
4-Aminopyridine in multiple sclerosis: prolonged administration. Neurology. 41 (9): 1344-8.
Summary: In an earlier study, we demonstrated efficacy of single oral doses of 4-aminopyridine (4-AP) in improving motor and visual signs in multiple sclerosis (MS) patients for a mean of 4.97 hours. We attempted to determine whether efficacy could safely be prolonged using multiple daily doses over several days by administering 7.5 to 52.5 mg 4-AP to 17 temperature-sensitive MS patients in one to three daily doses at 3- to 4-hour intervals over 1 to 5 days in a double-blind study. Nine of these patients were also tested with identically appearing placebo. Thirteen of the 17 patients (76 percent) given 4-AP showed clinically important motor and visual improvements compared with three of nine in the placebo group. Average peak improvement scores were 0.40 for 4-AP and 0.12 for placebo. Seventy percent of the daily 4-AP improvements lasted 7 to 10 hours. The improvements for two consecutive doses of 4- AP lasted a mean of 7.07 hours (83 percent of the average 8.53-hour treatment- observation period) compared with 2.36 hours for placebo (26 percent of the average 9.06-hour treatment-observation period). No serious side effects occurred. 4-AP is a promising drug for the symptomatic treatment of MS.
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 (2): 103-19.
Summary: A Phase I trial of 4-aminopyridine (4-AP) was carried out in 39 dogs referred to the veterinary teaching hospital with naturally occurring traumatic paraplegia or paraparesis. The rationale for the study was provided by the observation that 4-AP restores conduction in demyelinated nerve fibers in experimental spinal cord injury. Most injuries (77 percent) resulted from degenerative disk disease, occurring at or near the thoracolumbar junction, and producing chronic, complete paraplegia. Neurological examination of each dog was recorded on videotape before and at intervals after administration of 4-AP. The drug was administered systemically in total doses between 0.5 and 1 mg/kg body weight. Three areas of neurological status changed significantly at 15-45 minutes following administration of 4-AP: (a) striking improvements in hindlimb placing occurred in 18 animals; (b) increased awareness of painful stimuli to the hindlimb in 10 animals; (c) partial recovery of the cutaneus trunci muscle reflex of the back skin in 9 animals. These effects reversed within a few hours of administration. Other animals (36 percent) showed no change in neurological signs except a slight enhancement of hindlimb reflex tone. Significant side effects were seen in 6 dogs receiving higher intravenous doses, with elevation of body temperature and apparent anxiety, leading to mild seizures in 3 of the animals. These seizures were controlled with diazepam. The results indicate that conduction block may contribute significantly to functional deficits in closed-cord injuries and that potassium channel blockade may prove to be a valid, if limited approach to therapeutic intervention in chronic paraplegia and paraparesis.
Hayes KC, Blight AR, Potter PJ, Brown WF, Wolfe DL, Hsieh JTC and Lam S (1991).
Effects of intravenous 4-aminopyridine on neurological function in chronic spinal cord injured patients: preliminary observations. Third IBRO World Conf. of Neuroscience.
Bever CT, Jr., Leslie J, Camenga DL, Panitch HS and Johnson KP (1990).
Preliminary trial of 3,4-diaminopyridine in patients with multiple sclerosis. Ann Neurol. 27 (4): 421-7.
Summary: Ten patients with multiple sclerosis (MS) were enrolled in a preliminary trial of the potassium channel blocker, 3,4-diaminopyridine, to evaluate drug toxicity and pharmacokinetics. The patients were treated with oral 3,4-diaminopyridine, first with increasing single doses up to 100 mg and then with divided dosage for up to 3 weeks. Paresthesias were reported by all patients and abdominal pain was dose limiting in 6 patients. 3,4-Diaminopyridine levels and half-life varied widely from patient to patient. Cerebrospinal fluid levels of 3,4-diaminopyridine were about 10 percent of those in serum. Neither seizures nor epileptiform changes on electroencephalographic examination occurred. Small reversible improvements in specific neurological deficits were seen on examination in all patients and reversible improvement in visual evoked response latencies were found in 2 patients. These results suggest that further study of 3,4-diaminopyridine in patients with MS is warranted.
Davis FA, Stefoski D and Rush J (1990).
Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis [see comments]. Ann Neurol. 27 (2): 186-92.
Summary: 4-Aminopyridine (4-AP), a potassium channel blocker, restores conduction in blocked, demyelinated animal nerve. Its administration to multiple sclerosis (MS) patients produces transient neurological improvements. Vision improves after either oral or intravenous administration, whereas motor function improvement has been reported only with the latter. To assess further its potential as a practical symptomatic treatment, we studied the efficacy of single, oral doses of 4-AP on both visual and motor signs in MS. Twenty temperature-sensitive male MS patients were given either 10 to 25 mg of 4-AP or identically appearing lactose placebo capsules. Static quantitative perimetry, critical flicker-fusion, visual acuity, visual evoked potentials, and videotaped neurological examinations were monitored. All of 15 MS patients given 4-AP mildly to markedly improved. Motor functions (power, coordination, gait) improved in 9 of 13 involved, vision in 11 of 13, and oculomotor functions in 1 of 2. Improvements developed gradually at doses as low as 10 mg, usually beginning within 60 minutes after drug administration, and reversed gradually over 4 to 7 hours. No serious adverse effects occurred. No significant changes were observed in 5 MS patients given placebo. We conclude that orally administered 4- AP produces clinically important improvements in multiple, chronic deficits in MS. Further studies are warranted to assess efficacy and safety of prolonged administration.
Information on this page was obtained from Web pages from Spinewire and Acorda
Human olfactory mucosa grafts in traumatic spinal cord injuries: a way to cure paralysis?
By carlos lima, Hospital Egas Moniz- Lisbon- Portugal
Recent published articles showed that transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats. A medical team at the Hospital Egas Moniz, in Lisbon- Portugal has performed for the first time in humans, an autologous graft of olfactory mucosa at the injured spinal cord in 3 patients. The first procedure was performed at 2001, July with the transplant with olfactory mucosa to a six month cervical (C7, T1) cyst contusion type lesion (complete transverse section) from a female patient with 21 years old. The surgery time was about four hours. There were no complications ( no fever, no infections or other side effects) and four days after the patient was discharged. She started to have some sensory recovery about 1 month later and 2 months later she started to have voluntary control on abdominal muscles. Two month ago she started to have voluntary control at the gluteos and left leg adutor muscles and stands up by both legs without any devices on it. The NMR 3 months after the operation showed a filling and continuity of the graft within the cavity. Three months after the operation olfaction was completely recovered. The two others patients wait for results since they were operated within the last month. In theory the graft furnished stem cells (olfactory basal cells), neurons, schwann cells and olfactory ensheathing cells with putative potential for regeneration and may prove to become a reliable method to cure paralysis.
HAMILTON (CP) — Scientists at McMaster University say they have achieved a major advance in spinal cord research, giving renewed hope for an eventual cure to Canada's 36,000 paraplegics and quadriplegics.
Researchers have found that spinal nerves can successfully regenerate when intestinal cells are transplanted into a severed spinal cord.
"This means there is a method here for regenerating fibres through the central nervous system with a relatively innocuous technique," said lead researcher Dr. Michel Rathbone.
So far, they have had a 100 per cent success rate in experiments with animals.
In experiments with rats, Rathbone's laboratory extracted cells called "enteric glia cells" from the gut, purified it, and injected it into sensory nerves going into the spinal cord, which had been surgically cut.
"We were able to regenerate the fibres in the spinal cord," said Rathbone, a professor of medicine in the faculty of health sciences.
"This is quite different from putting something around (the fibres) or just helping the few that remain."
"These are regenerating fibres growing into the spinal cord."
Rathbone said there are many advantages to harvesting enteric glia cells from the nervous system of a person's own intestines or gut.
There is no fear of rejection because transplanted cells come from the same person. As well, these are mature cells, which gets around the thorny moral issue surrounding stem cells, which are harvested from embryos.
Glia cells do a number of things, from controlling interconnections between nerve cells to covering axons, the nerve cell process that carries an impulse away from the cell to a muscle.
Rathbone and his research team will publish their results in November at meetings for the Society for Neuroscience in San Diego, Cali.
The Canadian Spinal Research Organization, a group made up of paraplegics and quadriplegics whose sole goal is to find a cure for spinal injuries, has provided more than $1 million in funding support to Rathbone's laboratory at McMaster over the past eight years.
Rathbone anticipates the lab will be working with larger animals, such as dogs, in a couple of years.
"Then, we can move fairly quickly to human studies. That could be another two or three years."
OLFACTORY ENSHEATHING CELLS IN REPAIR OF THE DAMAGED SPINAL CORD
Professor Phil Waite and her team at the Neural Injury Research Unit, University of New South Wales
There has been much excitement recently about the possibility of repairing the spinal cord following injury. Several groups
are reporting that some regeneration is possible after complete transection of the spinal cord in adult animals, and this has raised
the hopes that treatment for paraplegia may eventually be possible. Our group is collaborating with Prof. Alan Mackay-Sim
and his team at Griffith University, Brisbane, to use a special type of glial cell found in the olfactory system, the olfactory
ensheathing cell (OEC), to promote recovery of movement in rats. These cells normally support and guide the growing
axons of olfactory neurons from the periphery into the olfactory bulb. Unlike other brain regions, reconnection normally takes
place in this olfactory pathway even in adult life.
Previous studies have used OECs isolated from the brain. Our laboratory is using OECs from peripheral nasal tissue
because of its clinical potential. In humans, such tissue can be obtained relatively easily, by a simple nasal biopsy. For spinal
cord injury this biopsy could be taken from someone with paraplegia or quadriplegia and the cells cultured and transplanted
into the patient's own cord. This is a major advance as it solves the difficulties of obtaining tissue as well as reducing the
chances of rejection.
Our lab has performed complete transections of the spinal cord in adult rats and has shown that peripheral OECs
are as effective in promoting functional recovery as previous studies using OECs from the brain. After OEC treatment, we
have evidence of partial recovery of hindlimb movement and changes in reflex excitability below the injury. In addition we can
show partial structural reconnection of nerve processes across the injury site. Some of these reconnections, from
serotonergic pathways, are involved in descending control of the spinal cord and are therefore likely to contribute to the
improved reflex function.
Our overall aim now is to advance towards the use of OECs in human spinal cord injury - this is now one step closer
with the commencement of clinical trials at the Princess Alexandra Hospital in Brisbane. An important part of treating spinal
cord injured patients with OECs is being able to target the therapy to the right location within the cord, at an appropriate
time for regeneration to be encouraged. We are currently investigating the survival, migration and repair potential of human
OECs at different times after transplantation. We use impaction as well as transection injuries, to provide realistic models of
human cord damage. Hence these results in rats will be relevant to the use of OECs in human paraplegia.
At present, neurosurgeons are unwilling to intervene during the acute phase in human spinal cord trauma, because of the
risk of aggravating the damage. We have shown that delaying transplantation of OECs until the acute injury period is over, and
glial scar tissue is formed, is still followed by significant locomotor recovery. Results from our current migration studies will allow
neurosurgeons to target cells to the most effective sites in the cord.
Further information: http://anatomy.med.unsw.edu.au/waite/waite.htm
Neuro Therapeutics Inc. (NTI) is engaged in an active pre-clinical program for the development of effective immunological protocols to stimulate improved regeneration of injured neurons after traumatic injury of the spinal cord or brain.
The leading technology is based on discoveries made by members of CORD (Collaboration On Repair Discoveries) at The University of British Columbia (UBC). NTI, a spin-off company of UBC, holds worldwide rights to intellectual property invented at UBC by NTI’s co-founders. We have provided a graphic animation explaining how the technology improves neuronal regeneration.
The patented and patent-pending immunological composition and protocol employs the administration of components of the serum complement protein cascade, along with a myelin-specific antibody that has a high affinity for serum complement. Based on animal experiments, benefit is incurred by the direct infusion of the immunological composition into the damaged region of the injured central nervous system (CNS). The myelin-specific antibody serves to direct and limit the attack by serum complement to CNS myelin.
This experimental therapy temporarily eliminates or disrupts myelin surrounding the injury site. Previous studies have demonstrated that the presence of CNS myelin (made by oligodendroglial cells of the CNS) inhibits the effective regeneration of neurons after injury. After the immunological therapy is discontinued and the neurons have functionally regenerated, subsequent maturing oligodendroglial cells will replace the CNS myelin.
Target Discovery
NTI has developed two new proprietary technologies that target G-protein Coupled Receptors (GPCRs). GPCRs are the largest family of cell surface receptors in the human body and thus are among the major control points for coordinating physiological processes in the body. They span the surface membrane of all cells and receive signals both from other cells in the body and from the environment. The activated GPCR transduces this signal, through a biochemical cascade pathway, to the nucleus where it triggers the appropriate physiological response by modifying gene expression patterns.
GPCRs have long proven to be clinically relevant drug targets. Over 300 of the GPCR genes have been identified to date; however, all estimates suggest there are about 1,000 additional GPCRs in the human genome. While only about 15% of the GPCRs in the human body have been studied, they account for nearly half of all the pharmaceutical drugs on the market and drugs targeting GPCRs are associated with a very wide range of therapeutic categories including, central nervous system (CNS) disorders. Conservative estimates suggest that pharmacogenomic and proteomic functional analyses of GPCRs will double the size of the current drug market drug.
NTI has developed a proprietary, insect cell-based functional assay system for the expression of human GPCRs, which is our Core Assay Technology. This novel assay system will speed the analysis of known (e.g. serotonin and dopamine) and newly discovered GPCRs, as well as reduce the costs of drug discovery. The current suites of available drugs often have limited efficacy and/or adverse side effects for a significant proportion of the population. NTI's Core Assay Technology, in combination with patient-based pharmacogenomics approaches, will allow us to develop second-generation drugs with significantly enhanced efficacy and reduced side effects. In addition, it will allow NTI to develop new drugs targeting specific sub-groups of individuals with a CNS disorder (e.g. chronic pain after spinal cord injury) that are poorly served by the current "one drug fits all" model.
NTI is refining a proprietary Self-selecting Autocrine Loop Technology, which allows us to identify new ligands, both agonists and antagonists, for GPCRs. This technology has several applications but is developed specifically to mine through known classes GPCRs, as well as undefined GPCRs known as 'orphan' receptors, that is, receptors whose modality of action and disease targets have yet to be identified. NTI's Core Assay and Self-selecting Autocrine Loop Technologies, when used in concert, will greatly reduce the time required for target validation among 'orphan' GPCR receptors, and the development of leading drug compounds to identified GPCR targets.
Des neurochirurgiens français ont restauré une contraction musculaire chez des paraplégiques
LE MONDE | 17.05.02 | 12h57
La greffe de nerfs au niveau de la moelle épiničre sectionnée provoque une repousse de neurones qui reconstitue une liaison avec les muscles des jambes.
Un groupe de neurochirurgiens français révčle dans le prochain numéro, daté de juin, de la revue spécialisée Journal of Neurotrauma avoir obtenu les premiers résultats positifs, chez l'homme, aprčs une greffe de neurones pratiquée au niveau de la moelle épiničre chez des personnes paraplégiques.
Si elle ne constitue pas stricto sensu une réponse concrčte aux handicaps majeurs dont souffrent les victimes de lésions de la moelle épiničre, cette premičre marque ŕ l'évidence une étape importante.
Elle ouvre aussi de réelles perspectives dans un domaine oů, en dépit des avancées dans le champ de la neurologie, les progrčs thérapeutiques sont inexistants ou presque.
La premičre française concerne un patient victime d'un accident de la circulation automobile et qui avait perdu l'usage de ses deux membres inférieurs. L'intervention a été pratiquée, un an aprčs l'accident, par un groupe de neurochirurgiens dirigés par les professeurs Marc Tadié (hôpital Bicętre, Le Kremlin-Bicętre) et Roger Robert (CHU de Nantes). L'opération réunissait, notamment, les professeurs Jean-François Mathé, Pierre Guiheneuc et Brigitte Perrain-Verbe. Elle avait au préalable été autorisée par un comité de protection des personnes, le patient ayant été dűment informé du fait qu'il s'agissait d'une expérimentation chirurgicale dont il ne tirerait, selon toute vraisemblance, aucun bénéfice.
Neuf mois aprčs cette greffe, le premier patient montrait qu'il était redevenu capable de contracter, de maničre volontaire, certains faisceaux des fibres de ses muscles des jambes, ceux dits " adducteurs de la cuisse" et " psoas". Ce phénomčne a été vérifié et confirmé par des enregistrements électrophysiologiques. Plus spectaculaire encore, cette restitution partielle des fonctions musculaires continue, deux ans aprčs l'intervention chirurgicale, ŕ s'améliorer. "Aprčs de nombreux travaux menés chez l'animal, ceci montre que la technique visant ŕ faire repousser des neurones par l'intermédiaire d'un greffon de nerf périphérique, de les faire sortir vers la moelle épiničre et d'atteindre une cible musculaire est également possible chez l'ętre humain", résume-t-on auprčs de l'Institut pour la recherche sur la moelle épiničre qui a financé ces travaux.
"En pratique, nous avons, dans un premier temps, prélevé une fraction du nerf sural [un nerf innervant certains des muscles du mollet], fraction que nous avons sectionnée et placée sous forme de pontage entre l'extrémité des axones sectionnés au-dessus de la lésion de la colonne vertébrale et les racines motrices situées en dessous de cette męme lésion au niveau des deuxičme, troisičme et quatričme vertčbres lombaires, explique le professeur Tadié. Une deuxičme greffe, identique, de neurones périphériques a été pratiquée, de la męme maničre, en controlatéral. Nous n'avons pas eu de complication chirurgicale. Avec deux ans de recul, la contraction musculaire volontaire semble se renforcer et une ébauche de sensibilité est apparue chez notre patient."
Le professeur Tadié explique que, lui et ses collaborateurs, n'ont pas souhaité rendre publics plus tôt ces résultats spectaculaires pour des raisons ŕ la fois médicales et scientifiques. "Nous souhaitions nous assurer que les résultats obtenus n'étaient pas éphémčres", résume-t-il.
L'un des éléments les plus prometteurs de ce travail tient ŕ la physiologie induite par cette greffe. "Ce ne sont pas les fragments du nerf sural que nous introduisons dans une forme de "pontage" qui permettent de rétablir le lien entre les extrémités sectionnées des neurones, précise-t-il. En fait ces fragments neuronaux, les éléments cellulaires et moléculaires qui les composent servent ŕ la fois de guide et d'attracteurs. Ces sont eux qui provoquent la repousse neuronale, les cellules reprenant leur croissance sur une distance de 25 ŕ 30 centimčtres pour rejoindre les muscles dont elles assuraient l'innervation avant l'accident du patient." Alors męme qu'ils visaient précisément un tel objectif, les auteurs de cette premičre confient ętre profondément impressionnés par ce résultat qui, aprčs d'autres récemment obtenus, vient démontrer l'extraordinaire plasticité du systčme nerveux central et les possibles applications thérapeutiques qui, en toute logique, pourraient en résulter.
"L'intervention a duré plus de dix heures et a nécessité la collaboration de deux équipes de neurochirurgiens spécialisés, explique le professeur Tadié. De nombreux travaux de recherche et d'expérimentation sont encore nécessaires avant d'envisager la possible restauration de la motricité et de la sensibilité dans des régions étendues des zones paralysées des personnes paraplégiques ou tétraplégiques. Et nous ne souhaitons, en aucune maničre, que ces personnes nourrissent, ŕ court terme, de vains espoirs. Pour autant comment ne pas dire notre enthousiasme devant ces premiers acquis ?" Deux autres patients, paraplégiques depuis plus d'un an, ont d'ores et déjŕ été greffés de maničre similaire, et une série d'autres interventions sont programmées ŕ court terme. "Cette premičre intervention chez l'homme paraplégique, visant ŕ reconnecter un muscle de topographie sous lésionnelle ŕ la moelle épiničre dorsale sus lésionnelle, confirme les possibilités de régénération axonale de la moelle épiničre humaine", estime, pour sa part, le professeur Alain Privat (unité Inserm Développement, plasticité, vieillissement du systčme nerveux, université de Montpellier). Le résultat, męme s'il reste encore modeste pour le patient, implique la nécessité de poursuivre les recherches dans cette voie."
