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J Investig Med. 2004 Jan;52(1):33-44.

Nitrosative injury and antioxidant therapy in the management of diabetic neuropathy.

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  • 1Department of Neurology, University of Michigan, 200 Zina Pitcher Place, 4410 Kresge III, Ann Arbor, MI 48109-0585, USA.


Strong evidence implicates oxidative stress as a mediator of diabetes-induced microvascular complications, including distal symmetric polyneuropathy. Dorsal root ganglia neurons are particularly susceptible to glucose-mediated oxidative stress and die by apoptotic mechanisms in animal and cell culture models of diabetes. Key mediators of glucose-induced oxidative injury are superoxide anions and nitric oxide (NO). Superoxides are believed to underlie many of the oxidative changes in hyperglycemic conditions, including increases in aldose reductase and protein kinase C activity. Superoxides can also react with NO, forming peroxynitrite (ONOO-), which rapidly causes protein nitration or nitrosylation, lipid peroxidation, deoxyribonucleic acid (DNA) damage, and cell death. ONOO- formation is dependent on both superoxide and NO concentrations; therefore, cells that constitutively express NO synthase, such as endothelial cells and neurons, may be more vulnerable to ONOO(-)-induced cell death in conditions favoring the production of superoxides. Although NO and ONOO can cause endothelial and neuronal cell death in vitro, in animal models of diabetes, reductions in endothelial NO production can inhibit vasodilatation and cause nerve ischemia. Therefore, ideal therapeutic approaches should limit the formation of superoxides and ONOO while preventing reductions in vascular NO. Despite strong evidence that oxidative stress is associated with complications of diabetes, including neuropathy, the results of clinical trials of antioxidants have shown some promise but not established therapeutic efficacy. Clinical studies of several antioxidants, including alpha-lipoic acid, vitamins C and E, aldose reductase inhibitors, and growth factors, in diabetic neuropathy are discussed.

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