Spinal cord injury (SCI) is devastating. Not only does it reduce the ability to move but also the ability to control bladder/bowel movements and sexual functions. It affects mostly young men since 60% of SCI victims are 30 year old or younger. Current treatment of SCI is unsuccessful and relies only on use of methylprednisolone, which is controversial since its outcome on functional recovery is poor. Hence the need for a better and safer treatment of SCI. To identify molecules that may be active in the re-establishment of connectivity in the injured spinal cord we have developed a strategy of identifying molecular cues involved in the organization of the developing spinal cord during embryogenesis. We have identified endogenously synthesized steroid compounds, neurosteroids, that are involved in the organization of the developing nervous system. We have demonstrated that the neurosteroid, DHEA, promotes motor neuron induction and enhances the axonal growth of neuronal populations participating in sensory-motor circuits during embryogenesis. This suggested that DHEA may be effective in regenerating the disrupted connections affected by SCI. To test this hypothesis we have developed a mouse model of moderate contusive SCI that mimics traumatism occurring in humans. Our preliminary results have established that DHEA promotes neurological recovery after moderate SCI. We are proposing to confirm these results and to establish the efficiency of DHEA in promoting regain of function by using both behavioral testing and histopathology, (aim 1). We will particularly determine if DHEA has neuroprotective properties toward motor neurons.
In aim 2 we will determine the concentration of DHEA delivered to the injured spinal cord and if this level can be optimized by different therapeutic regimen. We will also determine if SCI modulates the neurosteroidogenesis and if treatment with DHEA further modifies neurosteroidogenesis along the time course of neurologic recovery. We will then determine the mechanisms by which DHEA affects locomotor recovery by studying axonal regeneration and sprouting within circuits that control movements (aim 3) and circuits that control non-voluntary contractile muscles such as the bladder (aim 4). Finally, since locomotor recovery does not only occur through axonal regrowth but rather derives from reducing the growth inhibition in the microenvironment proximal to the site of injury and since DHEA has been reported to control reactive microglia, we will study the effect of our treatment in the development of microglial inflammation and scar formation in both experimental groups (aim 5).
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| Fiore, Christelle; Inman, Denise M; Hirose, Shijiro et al. (2004) Treatment with the neurosteroid dehydroepiandrosterone promotes recovery of motor behavior after moderate contusive spinal cord injury in the mouse. J Neurosci Res 75:391-400 |
