Neuropathy is a devastating complication of diabetes mellitus. While conventional medical treatment attenuates the development of diabetic neuropathy, perfect glycemic control is difficult to achieve in many patients and points to the need for additional therapeutic options. Although hyperglycemia has been identified as the primary metabolic disturbance underlying neurological complications, the link between early metabolic events and subsequent structural changes, such as segmental demyelination and axonal degeneration, remains unknown. Oxidative stress has been implicated in the pathogenesis of diabetic neuropathy and overproduction of superoxide by mitochondrial electron-transport chains has recently been proposed to be the common element linking polyol pathway flux, AGE formation, PKC activation and hexosamine pathway flux as mechanisms of hyperglycemia-induced damage. Because there is little direct evidence supporting oxidative stress as the link between early metabolic events and subsequent structural injury, the underlying hypothesis of this proposal presumes that structural injury of unmyelinated and myelinated fibers in diabetic neuropathy is the culmination of hyperglycemia-induced oxidative stress and mitochondrial dysfunction in Schwann cells and neurons. A corollary to this hypothesis is that treatment with appropriate anti-oxidants and/or agents that restore mitochondrial function will ameliorate pathological injury to these nerve fibers. The hypothesis will be tested using carefully selected animal models that replicate injury to unmyelinated and myelinated fibers present in human diabetic neuropathy. Degeneration of the intra-epidermal innervation in streptozotocin-diabetic rats and mice, Schwann cell injury in the sciatic nerve and roots of streptozotocin-diabetic rats, and demyelination and axonal degeneration in peroneal nerve biopsies from cats with spontaneously occurring diabetes will be investigated using behavioral, electrophysiological, biochemical and histological assessments in combination with appropriate treatments to alleviate oxidative stress and mitochondrial dysfunction. Using these experimental and clinical animal models of diabetic nerve injury, three specific aims will determine whether 1) loss of intra-epidermal innervation 2) Schwann injury, and 3) demyelination and axonal degeneration are consequences of oxidative stress and mitochondrial dysfunction. ? ? ?
