Studies on antioxidant treatment have shown that ROS makes a marked contribution to the etiology of nerve dysfunction in experimental diabetes. Effects on vasa nervorum predominate in the short term; ROS cause dysfunction of vascular endothelium which at the very least reduces NO-mediated vasodilation and increases local vasoconstrictor production and reactivity. The effects of oxidative stress are crucial, complex, and far reaching, causing basic changes in cell signaling such as PKC and NF-kB that affect a plethora of systems involved in the maintenance of vascular control and integrity. ROS effects also impinge on prostanoid and EDHF systems, further exacerbating a diabetic deficit of substrate availability in the former. The result is reduced nerve perfusion, causing endoneurial hypoxia, which in turn is responsible for NCV and other functional deficits. Autooxidation of glucose and its metabolites and other transition metal-catalyzed reactions such as advanced glycation are important sources of ROS. Polyol pathway activity contributes to oxidative stress by compromising the glutathione redox cycle. Antioxidant treatment strategies, in combination with good metabolic control, offer a potential way forward in the prevention or control of diabetic neuropathy and other vascular complications. The powerful synergistic interactions between ROS-NO and n-6 essential fatty acid-prostanoid mechanisms on nerve perfusion offer a potential therapeutic advantage for the use of antioxidant-GLA mixtures and novel compounds.
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