Bavetta, Sebastiano; (1999) New methodologies for the treatment of experimental spinal cord injury. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Spinal cord injury afflicts approximately 45,000 patients in the UK, many of whom are condemned to years of disability. However, new therapeutic approaches are being developed to reduce secondary injury and to stimulate regeneration. Immunophilin molecules are highly concentrated within the CNS, and their ligands FK506, Cyclosporin A and GPI 1046 have significant effects on neurons. There is also evidence that intestinal muscularis externa, containing myenteric plexus, can stimulate axonal regeneration following implantation into the CNS. This thesis has investigated these approaches to experimental spinal cord injury. FK506 (n=66) and GPI 1046 (n=11) were administered to adult rats following partial transection of the thoracic dorsal columns. FK506 stimulated regeneration of severed sensory axons for short distances rostral to the lesion and also reduced the likelihood of axonal destruction compared to controls (n=45). This effect on axons was independent of protective effects on the parent cell bodies, which remain viable even without treatment. GPI 1046 did not influence axonal survival. Muscularis externa grafts were implanted into the spinal cords of Fischer rats and outcome was assessed functionally and histologically. These grafts had less effect on axonal regeneration in the spinal cord than in the striatum, and no clear effect on lesion size. The presence, within the intestine, of both BDNF and NT-3 mRNA was investigated using in situ hybridization, while the properties of dissociated intestinal muscularis externa smooth muscle cells were assessed with electron microscopy following implantation into the striatum. This thesis has demonstrated that the effects of muscularis externa on injured axons are less in the spinal cord than in the striatum, but that its cells may be suitable for genetic modification prior to implantation. In addition the findings suggest that immunophilin ligands may have important therapeutic applications for spinal cord injury.

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