Effects of antioxidants on nerve and vascular dysfunction in experimental diabetes.
Reactive oxygen species (ROS) are elevated by metabolic changes in diabetes, including autoxidation and increased advanced glycation. Endogenous protection by the glutathione redox cycle is also compromised by the competing NADPH requirement of elevated polyol pathway flux. Antioxidant treatment strategies prevent or reverse nerve conduction velocity (NCV) deficits in diabetic rats. These include lipophilic scavengers such as butylated hydroxytoluene, probucol and vitamin E, more hydrophilic agents like alpha-lipoic acid and acetyl cysteine, and transition metal chelators that inhibit autoxidation. In the long-term, elevated ROS cause cumulative damage to neurons and Schwann cells, however, they also have a deleterious effect on nerve blood flow in the short term. This causes endoneurial hypoxia, which is responsible for early NCV deficits. Antioxidant treatment corrects the blood flow deficit and promotes normal endoneurial oxygenation. ROS cause antioxidant-preventable vascular endothelium abnormalities, neutralizing nitric oxide mediated vasodilation and increasing reactivity to vasoconstrictors. Unsaturated fatty acids are a major target for ROS and essential fatty acid metabolism is impaired by diabetes. Gamma-linolenic acid stimulates vasodilator prostanoid production, and there are marked synergistic interactions between gamma-linolenic acid and antioxidants. This has encouraged the development of novel drugs such as ascorbyl-gamma-linolenic acid and gamma-linolenic acid-lipoic acid with enhanced therapeutic potential.
Cameron
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Department of Biomedical Sciences, University of Aberdeen, Scotland, UK. n.e.cameron@abdn.ac.uk
Cotter
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MA
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D005228:Fatty Acids, Essential / Q000378:metabolism; D006801:Humans; D009431:Neural Conduction / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000502:physiology
D000975:Antioxidants; D005228:Fatty Acids, Essential; D017382:Reactive Oxygen Species