Nonpeptide Neurotrophic Mechanisms in Spinal Cord Repair

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Project Summary/Abstract Traumatic spinal cord injury (SCI) is associated with deficits in sensory and motor function, including complete paralysis in severe cases. Severe SCI is currently incurable as there are no medications that can reverse the injury-related nerve tissue damage. Indeed, unlike peripheral tissues that can heal and regain function following lacerations and contusive injuries, the spinal cord is notoriously resistant to regrowth or replacement of neural connections with the brain after injury. The overall goal of this research is to increase understanding of neuroregenerative mechanisms and uncover novel pharmacological targets for the treatment of SCI. Experiments in animal models suggest that boosting the biological activity of nerve growth factors in the spinal cord can nudge the tissue toward a program of regeneration. We have developed a strategy that could deliver such boost using synthetic small molecule compounds. Following rational selection and screening of several small-molecule compounds, we found several members to potently promote the regrowth of damaged nerve cells in a tissue culture model. Some of these compounds are being used as approved drugs for other disorders, and all six compounds are capable of crossing into the CNS from the bloodstream. The shared biochemical properties of the compounds allowed to develop a unifying hypothesis that links the actions of these nonpeptide neurotrophic compounds to the pathways of growth factor signaling and regenerative effects. We believe that the logical next step is to clarify the mechanism by which these compounds work. Completion of the experiments proposed in this project will generate results that should advance such understanding. Thereafter, we will use the knowledge gained to begin to work toward repurposing existing medications or designing new compounds that would promote nerve cell regrowth and repair damaged nerve connections to treat SCI patients.