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Rubrospinal neurons after chronic cervical spinal cord injury Kwon, Brian K.


Many experimental therapies have been developed that appear to have encouraging therapeutic potential in animal models of acute spinal cord injury. It has become increasingly evident however, that their effectiveness is reduced when applied chronically after the injury. This loss of effectiveness over time is an issue of obvious and critical relevance for the many individuals with chronic spinal cord injury. Thus, the overall objective of this thesis was to evaluate some of the challenges that impede axonal regeneration in a chronic spinal cord injury setting, and develop therapeutic strategies for this condition. My hypothesis was that that axonal regeneration can be achieved by chronically injured CNS neurons with the appropriate administration of neurotrophic factors The findings can be summarized as follows: Two months after cervical axotomy, rubrospinal neurons undergo significant atrophy and exhibit limited expression of GAP-43 and Tα1 tubulin, genes thought to be important for axonal regeneration. They appear to maintain full length TrkB receptors on their cell bodies, and while their uninjured axons within the cervical spinal cord also contain TrkB receptors, the injured axons at the level of the spinal cord axotomy do not. Consistent with this, BDNF applied to the spinal cord injury site at three exponentially increasing concentrations did not reverse rubrospinal cell atrophy, did not stimulate GAP-43 and Tα1 tubulin expression, and did not promote axonal regeneration of rubrospinal axons into the permissive environment of a peripheral nerve transplant. At 12 months after cervical axotomy, a stereologic evaluation of rubrospinal neurons demonstrates that rubrospinal neurons are in fact alive, but very atrophic. Similar to the findings at 2 months post-injury, the rubrospinal neurons 12 months post-injury display limited expression of GAP-43 and Tα1 tubulin but do maintain full length TrkB receptors on their cell bodies. At this chronic time point, the administration of BDNF to the injured cell bodies reversed neuronal atrophy, stimulated GAP-43 and Tα1 tubuin expression, and promoted axonal regeneration into peripheral nerve transplants. These findings suggest that axonal regeneration is possible in the chronic spinal cord injury setting, but that the administration of neurotrophic factors to promote this growth response must be targetted appropriately. It is hoped that further study in the obstacles that impede axonal regeneration after chronic spinal cord injury will give rise to therapies for this devastating condition.

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