Preliminary experiments in rats with the diphenylpiperazines, flunarizine and cinnarizine, have shown their capability to protect dorsal root ganglion (DRG) neurons in vivo from cell death after sciatic nerve injury and to prevent neuronal death in vitro in embryonic DRG neurons after neurotrophic deprivation. the definitive goals of this proposal are to characterize the neuronal protective effects of these diphenylpiperazines in both the peripheral and central nervous systems; to examine drugs that share pharmacological properties with the diphenylpiperazines, flunarizine and cinnarizine, and thereby, define the mechanisms responsible for its neuronal protective capability; to evaluate the efficacy of combinations of neuronal protective agents with diphenylpiperazines; and to determine long-term consequences on neuronal survival and regeneration. the outlined studies will characterize the pharmacological efficacy of the diphenylpiperazines and related agents to decrease the deleterious effects of neuronal injury and provide insight into the mechanisms of neuronal death that occur after injury and during development. The ability to alter the neuronal response to injury and to trophic factor deprivation has potential major therapeutic utility in the clinical treatment of numerous pathological conditions that afflict the nervous system (e.g., head injury, peripheral nerve injury, cerebral ischemia, or subarachnoid hemorrhage). By further understanding the mechanism of neuronal death related to trophic factor deprivation, one may be able to develop strategies to treat neurodegenerative disorders characterized by neuronal death. Specifically, the studies will examine the ability of flunarizine and cinnarizine to protect neurons in the DRG, ventral horn of the spinal cord, retina, and the facial nucleus in the brain stem after axotomy. Neuronal survival will be quantitated by using light and electron microscopy to obtain neuronal and axonal counts. The protective effects of agents that share pharmacologic properties with these diphenylpiperazines will be systematically examined in cell culture to characterize specific properties that promote survival and define the mechanisms involved. Neuronal survival will be examined in a bioassay with dissociated embryonic DRG neurons by phase-contrast microscopy and by fluorescent microscopy with propydium iodide. Long-term modulation of the regenerative capability after injury with diphenylpiperazines will be evaluated in the distal tributaries of the sciatic nerve with counts of myelinated and unmyelinated axons and with horseradish peroxidase retrograde labeling experiments.
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