Diabetic peripheral neuropathy may be indicated by sensory disorders including spontaneous pain, hyperalgesia or allodynia, by slowed sensory and motor nerve conduction velocities or by structural pathology. Diabetic rats also develop sensory, electrophysiologic and subtle structural disorders. This supports their use as a model of the early stages of hyperglycemia-induced peripheral nerve disorders in the absence of overt structural pathology and allows study of both the etiologic mechanisms linking hyperglycemia to nerve dysfunction and also development of potential therapeutic agents. Recent evidence suggest that peripheral nerve requires ongoing neurotrophic support and that hyperalglycemia disrupts this. Providing exogenous neurotrophic support that either replaces or supercedes diminished endogenous support mechanisms has been proposed as a therapeutic strategy for treating diabetic neuropathy. Prosaposin is the precursor for intracellular saposins but is also secreted in an unprocessed form which has neurotrophic properties. These neurotrophic properties are shared by prosaposin mimetics, small peptides derived from the prosaposin molecule that lack the other properties of saposins. Our preliminary data suggest that prosaposin mimetics called prosaptides prevent or attenuate electrophysiologic, biochemical and structural disorders in the peripheral nerve of diabetic rats, encompassing indices of both sensory and motor function in both large and small fibers. This broad spectrum of efficacy is beneficial for a potential therapeutic because diabetes affects all divisions of the peripheral nervous system. Prosaptides also rapidly ameliorate hyperalgesia in diabetic rats, suggesting a second action distinct from the neurotrophic properties and which may have additional therapeutic benefits to those diabetic patients who develop painful diabetic neuropathy. We propose to establish the therapeutic profiles of prosaptides for treating electrophysiologic and structural disorders of peripheral nerve in diabetic rats that are associated with developing neuropathy and also for treating disorders that reflect pain states. We will also correlate the therapeutic actions of prosaptides with effects on neurochemical abnormalities present in diabetic rats, including investigation of the effect of diabetes on endogenous prosaposin production. The goal is to establish prosaptides as novel therapeutic agents for treating diabetic neuropathy and to provide mechanistic explanations for why hyperglycemia causes nerve disorders.
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