This study addresses the effects of the thiol protease inhibitor, leupeptin, on muscle and peripheral nerve before and after epineural neurorrhaphy (nerve repair) in a primate model. Our histological and ultrastructural studies focus on leupeptin's potential inhibitory in vivo effects on neural and muscle calcium activated neutral protease (CANP). This enzyme has been implicated in partially mediating both Wallerian degeneration and secondary denervation muscle atrophy. We propose to investigate leupeptin's potential for inhibition of these degenerative events by use of standard techniques in light and electron microscopy, as well as, immunohistochemical ultrastructural methods. Using this latter technique, the tissue loci of calcium activated neutral protease in normal muscle and nerve will be determined. Next, the distribution of this protease after nerve repair and leupeptin treatment will be investigated. Additionally, acetylcholine receptor distribution will be examined in innervated and denervated muscle in response to leupeptin treatment. Serial toxicological and absorption studies after intramuscular leupeptin administration are planned. The information gained may give us a better insight into neuromuscular degeneration following nerve repair. The long-term goal of the investigation is to examine leupeptin as an adjunctive therapy for facilitating neuromuscular recovery after the microsurgical repair of severed peripheral nerves.
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