Spinal cord injury is frequently followed by the loss of supraspinal control of sensory, autonomic and motor functions at the sublesional level. In order to enhance recovery in spinal cord-injured patients, we have developed three fundamental strategies in experimental models. These strategies define in turn three chronological levels of postlesional intervention in the spinal cord. Neuroprotection soon after injury using pharmacological tools to reduce the progressive secondary injury processes that follow during the first week after the initial lesion. This strategy was conducted up to clinical trials, showing that a pharmacological therapy can reduce the permanent neurological deficit that usually follows an acute injury of the central nervous system (CNS). A second strategy, which is initiated not long after the lesion, aims at promoting axonal regeneration by acting on the main barrier to regeneration of lesioned axons: the glial scar. Finally a mid-term substitutive strategy is the management of the sublesional spinal cord by sensorimotor stimulation and/or supply of missing key afferents, such as monoaminergic systems. These three strategies are reviewed. Only a combination of these different approaches will be able to provide an optimal basis for potential therapeutic interventions directed to functional recovery after spinal cord injury.
"Spinal cord injury (SCI) is a devastating pathology with currently no effective treatment of any symptom, that often leads to permanent loss of motor, sensory and autonomic functions (for review see , ). In SCI, lack of spontaneous axonal regeneration, and the correlative absence of functional recovery, is not primarily due to an endogenous inability of axon to re-grow  but is impeded by a combination of inhibitory factors, including astrocyte scarring . Many studies have investigated the effects of grafting a variety of cells in several animal models of spinal cord injury (, , for review see , , , , ) and have reported beneficial but also severe detrimental side effects . "
[Show abstract][Hide abstract] ABSTRACT: Spinal cord injury (SCI) is a widely spread pathology with currently no effective treatment for any symptom. Regenerative medicine through cell transplantation is a very attractive strategy and may be used in different non-exclusive ways to promote functional recovery. We investigated functional and structural outcomes after grafting human embryonic neural progenitors (hENPs) in spinal cord-lesioned rats.
With the objective of translation to clinics we have chosen a paradigm of delayed grafting, i.e., one week after lesion, in a severe model of spinal cord compression in adult rats. hENPs were either naïve or engineered to express Neurogenin 2 (Ngn2). Moreover, we have compared integrating and non-integrating lentiviral vectors, since the latter present reduced risks of insertional mutagenesis. We show that transplantation of hENPs transduced to express Ngn2 fully restore weight support and improve functional motor recovery after severe spinal cord compression at thoracic level. This was correlated with partial restoration of serotonin innervations at lumbar level, and translocation of 5HT1A receptors to the plasma membrane of motoneurons. Since hENPs were not detectable 4 weeks after grafting, transitory expression of Ngn2 appears sufficient to achieve motor recovery and to permit axonal regeneration. Importantly, we also demonstrate that transplantation of naïve hENPs is detrimental to functional recovery.
Transplantation and short-term survival of Ngn2-expressing hENPs restore weight support after SCI and partially restore serotonin fibers density and 5HT1A receptor pattern caudal to the lesion. Moreover, grafting of naïve-hENPs was found to worsen the outcome versus injured only animals, thus pointing to the possible detrimental effect of stem cell-based therapy per se in SCI. This is of major importance given the increasing number of clinical trials involving cell grafting developed for SCI patients.
PLoS ONE 12/2010; 5(12):e15914. DOI:10.1371/journal.pone.0015914 · 3.23 Impact Factor
"However, when facing the tremendous number of questions from patients, one must keep in mind that physicians and paramedics may provide practical and functional help and minimize medical complication but can certainly not provide a miracle cure. Before presenting advances in SCI basic research      , it is a prerequisite to remind to the reader that basic research will not only depend on our actual and future knowledge in neuroanatomy and neuro-imagery of both control and pathological tissues but also on neurophysiology and neurobiology data gathered on animal models. Our overview of research axes is dedicated to the presentation of our current knowledge of animal and human spinal cords, both in control and pathological situations. "
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Thanks to the Internet, we can now have access to more information about spinal cord repair. Spinal cord injured (SCI) patients request more information and hospitals offer specific spinal cord repair medical consultations. OBJECTIVE: Provide practical and relevant elements to physicians and other healthcare professionals involved in the care of SCI patients in order to provide adequate answers to their questions. METHOD: Our literature review was based on English and French publications indexed in PubMed and the main Internet websites dedicated to spinal cord repair. RESULTS: A wide array of research possibilities including notions of anatomy, physiology, biology, anatomopathology and spinal cord imaging is available for the global care of the SCI patient. Prevention and repair strategies (regeneration, transplant, stem cells, gene therapy, biomaterials, using sublesional uninjured spinal tissue, electrical stimulation, brain/computer interface, etc.) for the injured spinal cord are under development. It is necessary to detail the studies conducted and define the limits of these new strategies and benchmark them to the realistic medical and rehabilitation care available to these patients. CONCLUSION: Research is quickly progressing and clinical trials will be developed in the near future. They will have to answer to strict methodological and ethical guidelines. They will first be designed for a small number of patients. The results will probably be fragmented and progress will be made through different successive steps.
Annals of physical and rehabilitation medicine 05/2009; 52(4). DOI:10.1016/j.annrmp.2008.10.004
"failed in clinical trials principally because of their side effects (Ikonomidou and Turski 2002; Hoyte et al. 2004). Over the last decade, our laboratory has developed therapeutic strategies for acute degenerative diseases and in particular SCI (Gimenez et al. 1998; Gimenez y Ribotta et al. 2002; Privat 2005). One approach, which consisted in developing neuroprotective molecules based on the structure of the PCP, led us to identify GK11 as a potential new drug candidate (Hirbec et al. 2001a). "
[Show abstract][Hide abstract] ABSTRACT: Over-stimulation of NMDA receptors (NMDARs) is involved in many neurodegenerative disorders. Thus, developing safe NMDAR antagonists is of high therapeutic interest. GK11 is a high affinity uncompetitive NMDAR antagonist with low intrinsic neurotoxicity, shown to be promising for treating CNS trauma. In the present study, we investigated the molecular basis of its interaction with NMDARs and compared this with the reference molecule MK801. We show, on primary cultures of hippocampal neurons, that GK11 exhibits neuroprotection properties similar to those of MK801, but in contrast with MK801, GK11 is not toxic to neurons. Using patch-clamp techniques, we also show that on NR1a/NR2B receptors, GK11 totally blocks the NMDA-mediated currents but has a six-fold lower IC(50) than MK801. On NR1a/NR2A receptors, it displays similar affinity but fails to totally prevent the currents. As NR2A is preferentially localized at synapses and NR2B at extrasynaptic sites, we investigated, using calcium imaging and patch-clamp approaches, the effects of GK11 on either synaptic or extrasynaptic NMDA-mediated responses. Here we demonstrate that in contrast with MK801, GK11 better preserve the synaptic NMDA-mediated currents. Our study supports that the selectivity of GK11 for NR2B containing receptors accounts contributes, at least partially, for its safer pharmacological profile.
Journal of Neurochemistry 12/2007; 103(4):1682-96. DOI:10.1111/j.1471-4159.2007.04925.x · 4.28 Impact Factor
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