Protective effects of glucosamine-kynurenic acid after compression-induced spinal cord injury in the rat

Kynurenic acid (KYNA), a metabolite of the essential amino acid L-tryptophan, is a broad spectrum antagonist of excitatory amino acid receptors, which have also anticonvulsant and neuroprotective properties. After spinal cord injury (SCI), excitotoxicity is considered to play a significant role in the processes of secondary tissue destruction in both grey and white matter of the spinal cord. In this study, we have tested the potential therapeutic effect of glucosamine-kynurenic acid, administered after experimental compression-induced SCI in the rat. Spinal application of glucosamine-kynurenic acid continually for 24 hr after experimental SCI resulted in improved motor function recovery, beginning from the first week of evaluation and continuing until the end of the study (4 weeks). After 4 weeks' survival, quantitative morphometric analysis of the spinal cord showed that glucosamine-kynurenic acid treatment was associated with improved tissue preservation at the lesion site. These findings indicate that spinal application of glucosaminekynurenic acid is neuroprotective and improves the outcome even when administered after spinal trauma. Our results suggest that the treatments initiated in early posttraumatic period can alleviate secondary injury and improve the final outcome after SCI

Erratum: Establishment of a canine spinal cord injury model induced by epidural balloon compression

A model that provides reproducible, submaximal yet sufficient spinal cord injury is needed to allow experiments leading to development of therapeutic techniques and prediction of clinical outcome to be conducted. This study describes an experimental model for spinal cord injury that uses three different volumes of balloon inflation and durations of compression to create a controlled gradation outcome in adult dogs. Twenty-seven mongrel dogs were used for this study. A 3-french embolectomy catheter was inserted into the epidural space through a left hemilaminectomy hole at the L4 vertebral arch. Balloons were then inflated with 50, 100, or 150 µl of a contrast agent at the L1 level for 6, 12, or 24 h and spinal canal occlusion (SCO) measured using computed tomography. Olby score was used to evaluate the extent of spinal cord injury and a histopathologic examination was conducted 1 week after surgery. The SCO of the 50, 100, and 150 µl inflations was 22-46%, 51-70%, and 75-89%, respectively (p < 0.05). Olby scores were diminished significantly by a combination of the level of SCO and duration of inflation in all groups. Olby scores in the groups of 150 µl-12 h, 150 µl-24 h, and 100 µl-24 h were 0.5, 0, and 1.7, respectively. Based on these results, a SCO > 50% for 24 h, and > 75% for 12 h induces paraplegia up to a week after spinal cord injury

Grafted Human Embryonic Progenitors Expressing Neurogenin-2 Stimulate Axonal Sprouting and Improve Motor Recovery after Severe Spinal Cord Injury

7 p.Background: 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.Methods and Principal Findings: 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 naive 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 naive hENPs is detrimental to functional recovery.Conclusions and Significance: 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 naive-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.This study was supported by the European Union FP6 "RESCUE" STREP; the "Institut pour la Recherche sur la Moelle Epiniere"; the "Academie de Medecine"; the "Societe Francaise de Neurochirurgie"; "Verticale" and the "Association Demain Debout Aquitaine". The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Mesenchymal Stem Cell Graft Improves Recovery after Spinal Cord Injury in Adult Rats through Neurotrophic and Pro-Angiogenic Actions

Numerous strategies have been managed to improve functional recovery after spinal cord injury (SCI) but an optimal strategy doesn't exist yet. Actually, it is the complexity of the injured spinal cord pathophysiology that begets the multifactorial approaches assessed to favour tissue protection, axonal regrowth and functional recovery. In this context, it appears that mesenchymal stem cells (MSCs) could take an interesting part. The aim of this study is to graft MSCs after a spinal cord compression injury in adult rat to assess their effect on functional recovery and to highlight their mechanisms of action. We found that in intravenously grafted animals, MSCs induce, as early as 1 week after the graft, an improvement of their open field and grid navigation scores compared to control animals. At the histological analysis of their dissected spinal cord, no MSCs were found within the host despite their BrdU labelling performed before the graft, whatever the delay observed: 7, 14 or 21 days. However, a cytokine array performed on spinal cord extracts 3 days after MSC graft reveals a significant increase of NGF expression in the injured tissue. Also, a significant tissue sparing effect of MSC graft was observed. Finally, we also show that MSCs promote vascularisation, as the density of blood vessels within the lesioned area was higher in grafted rats. In conclusion, we bring here some new evidences that MSCs most likely act throughout their secretions and not via their own integration/differentiation within the host tissue