A conus medullaris syndrome results from trauma to the sacral portion of the spinal cord and associated lumbosacral roots. Such injuries cause paralysis and sensory impairment of the lower extremities, pain, as well as bladder, bowel, and sexual dysfunctions. No successful treatments are presently available for patients with these injuries. We have developed a clinically relevant model for the study of conus medullaris/ cauda equina injury and repair in the rat. In this model, lumbosacral ventral roots are avulsed from the surface of the spinal cord and subsequently surgically implanted into the conus medullaris. During the initial research period, we demonstrated that this ventral root implantation strategy is neuroprotective, promotes axonal regeneration, and results in functional reinnervation of the lower urinary tract. The renewal of this project has three new aims: 1) to determine cell death mechanisms of autonomic and motor neurons after a lumbosacral ventral root avulsion (VRA) injury; 2) to determine potential neuroprotective effects of minocycline and complement inhibition; 3) determine whether minocycline and/or complement inhibition may augment functional reinnervation of the lower urinary tract after a lumbosacral VRA injury followed by acute and delayed surgical implantations of avulsed roots into the conus medullaris. We will use a combined therapeutic strategy approach to study neuronal death mechanisms, neuroprotection, and functional reinnervation of the lower urinary tract after lumbosacral VRA injury and repair. We will perform surgical root avulsions and implantations, pharmacological treatment, immunohistochemistry, electron microscopy, retrograde tracing techniques, stereology, and functional urodynamic studies of the lower urinary tract. Our proposed studies will provide a better understanding of death mechanisms for autonomic and motor neuron death in the spinal cord after proximal cauda equina injuries. We will also investigate new pharmacological strategies to protect these neurons against motor root injury-induced cell death in combination with root implantation to augment the function of the lower urinary tract. We believe that our proposal has translational research potential for the development of new treatments for patients with conus medullaris/cauda equina injuries. ? ? ?
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