Peripheral neuropathy is the most common complication associated with diabetes mellitus. Yet, in spite of its prevalence and debilitating consequences, the pathogenesis of diabetic neuropathy remains an enigma. While hyperglycemia has been identified as the fundamental metabolic disturbance, the relationship between early metabolic events characterized by electrophysiologic abnormalities and subsequent structural changes of nerve remains unclear. Previous work has shown that hyperglycemia-induced, exaggerated polyol-pathway flux underlies a number of the biochemical and functional disorders in experimental diabetes. More recently, in nerve and muscle, polyol-pathway flux has been shown to be associated with degenerative Schwann cell changes, axonal dwindling, contractile changes and myofiber degeneration that are prevented when the key enzyme of the pathway, aldose reductase, is inhibited. How inhibition of aldose reductase, an enzyme present in Schwann cells and myofibers, can restore axonal caliber is puzzling unless exaggerated polyol pathway activity disrupts other aspects of Schwann cell and/or skeletal muscle metabolism that influence the maintenance of axonal structure and function. Ciliary neurotrophic factor (CNTF), a Schwann cell-derived neurotrophic factor implicated in neurofilament synthesis, is decreased in experimental diabetes and may represent a facto capable of influencing the maintenance of axonal structure and function. The synthesis and release of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), two neurotrophins normally localized to skeletal muscle but after nerve injury also found in proliferating Schwann cells, may also be disrupted by polyol accumulation and thus have an adverse impact on the maintenance of axonal structure and function, as well as regeneration in experimental diabetes. The overall goal of the research outlined in this proposal is to examine the possibility that hyperglycemia-induced, exaggerated polyol-pathway activity hinders the production of neurotrophic factors, thereby disrupting the maintenance of axonal function and structure and impairing the ability to respond to injury. These experiments will be conducted with two well characterized rodent models of experimental diabetes: galactose intoxication and streptozotocin diabetes. The specific objectives are organized into three broad categories: 1) the impact of hyperglycemia on the bioactivity, protein, mRNA and retrograde transport of neurotrophic factors; 2) the impact of exogenous neurotrophic factor treatment on electrophysiologic, slow axonal transport and structural abnormalities likely to result from polyol accumulation; and 3) the impact of experimental diabetes on the expression of Schwann cell-derived neurotrophic factors after crush injury and the effect of exogenous treatment on the incidence and quality of regeneration. Thus, this research proposal will integrate physiologic, biochemical, morphologic and molecular biologic techniques to determine and study the functional and structural abnormalities resulting from deficits of neurotrophic factors in experimental diabetes.
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