Cyclooxygenase Pathway and Diabetic Neuropathy

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DESCRIPTION (provided by applicant): Present in up to 50 % of diabetic patients, diabetic peripheral neuropathy (DPN), is one of the most threatening complications of diabetes mellitus (D), constituting the leading cause of non-traumatic amputations. To date, a viable treatment for human DPN is not available. Although the pathophysiology of DPN is still quite poorly understood, increased oxidative stress and alterations in cyclooxygenase (COX) pathway activity, with subsequent perturbations in prostanoid metabolism, have been involved as critical factors. The overall hypothesis of this application is that in experimental D activation of the COX-2 pathway by oxidative stress, contributes to the biochemical, functional, neurotrophic and structural deficits of DPN. The objective of this proposal is to delineate the relationships between glucose-mediated oxidative stress, components of the COX pathway, and impaired neurotrophic support in the pathogenesis of DPN. Understanding these mechanisms and their relationship, may provide a rationale for the use of COX-2 selective inhibitors as a new and efficient therapeutic approach in patients with DPN. Streptozotocin-diabetic (STZ-D) rats, mice deficient in the expression of the COX-2 gene, and intervention with COX inhibition will be employed. Experimental DPN will be assessed with functional measurements of motor and sensory nerve conduction velocity (NCV) and nerve blood flow (NBF); light and electron microscopic nerve morphometry; biochemical parameters of nerve energy metabolism, oxidative stress, and antioxidative defense; measures of Schwann cell and sensory neuron apoptosis (AP). The Specific Aims are: Aim 1. To characterize the relationships of glucose-mediated oxidative stress to COX-2 pathway activation on the development of selected biochemical, functional, morphometric and neurotrophic defects in STZ-D rats. Aim 2. Determine the time course for the development of selected biochemical, functional, morphometric, apoptotic and neurotrophic defects in STZ-D mice deficient in the human COX-2 gene. These studies will help to elucidate the mechanism by which oxidative stress and COX pathway influence the development of DPN and, facilitate the design of human studies, in which the aim will be the prevention or reversal of DPN.