Oxidative Stress And Antioxidant Treatment Effects On Neurovascular Function In Experimental Diabetes

Antioxidant protection mechanisms are compromised in nerves of diabetic rats; lipid peroxidation is increased, and the levels of superoxide dismutase and reduced glutathione (GSH) are decreased, although glutathione peroxidase and reductase remain unchanged (34-37). Long-term exposure to elevated ROS, coupled with diminished endogenous antioxidant protection, could lead to cumulative neurodegenerative changes involving axonopathy and demye-lination, and damage to dorsal root ganglion cell bodies and their mitochondria has been observed (37,38). However, in the short term, ROS effects on vasa nervorum are more important, being responsible for the earliest defects in nerve function in diabetic rats.

A. Antioxidant Treatment, Vascular Endothelium, and Nerve Function

Defective endothelium-dependent relaxation has been found in diabetic animals and in type 1 and type 2 patients (39-47) and is an important target for antioxidant treatment. An example is shown in Figure 2, where the lipophilic ROS scavenger, a-tocopherol, protected rat aorta against a diabetic deficit in NO-mediated endothelium-dependent relaxation to acetylcholine (39). A similar protective effect of ROS scavengers has been noted for vasa nervorum blood flow and NCV. The magnitude of effects possible by this approach is illustrated in Figure 3, where a high dose of the probucol analogue, BM 150639, completely corrected motor NCV and blood flow deficits in diabetic rats. These effects were attenuated by cotreatment with a NO synthase inhibitor, emphasizing the importance of the vasa nervorum NO system (19). The effectiveness of a variety of scavengers has been assessed over the last 5 years, including lipophilic drugs like butylated hydroxytoluene, a-tocopherol (vitamin E), (3-carotene, and probucol, and the hydrophilic scavengers, /V-acetyl-l-cysteine and ascorbic acid (vitamin C) (48-54).

a-Lipoic acid is the subject of considerable current interest and is both lipid and water soluble (55). In experiments on diabetic rats, a-lipoic acid has been shown to improve nerve antioxidant protection by increasing GSH con-

Figure 2 Effects of diabetes and antioxidant treatment with a-tocopherol on endo-thelium-dependent relaxation of phenylephrine-precontracted aortas to acetylcholine in vitro. Groups (» = 14-17); nondiabetic control (O); 8-week streptozotocin-diabetic (•); a-tocopherol (1 g / kg/day) treated from diabetes induction (■). (From Ref. 39.)

Figure 2 Effects of diabetes and antioxidant treatment with a-tocopherol on endo-thelium-dependent relaxation of phenylephrine-precontracted aortas to acetylcholine in vitro. Groups (» = 14-17); nondiabetic control (O); 8-week streptozotocin-diabetic (•); a-tocopherol (1 g / kg/day) treated from diabetes induction (■). (From Ref. 39.)

tent and to correct blood flow and motor and sensory NCV deficits (36,56,57). R and S enantiomers of a-lipoic acid had similar efficacy on impaired nerve function and perfusion (57) and for the inhibition of lipid peroxidation of neural tissues in vitro (56). a-Lipoic acid was found to be approximately 10 times more potent than a-tocopherol in correcting motor NCV deficits in diabetic rats (50,57). Clinical trials of symptomatic and cardiac autonomic neuropathy revealed beneficial effects of a-lipoic acid treatment (58,59).

In rats, the diabetes-induced decrease in sciatic nutritive blood flow was accompanied by a reduction in mean endoneurial oxygen tension, which was prevented by probucol treatment (49). In nondiabetic rats, prooxidant treatment with the antimalarial drug primaquine mimicked the reductions in blood flow, endoneurial oxygen tension, and NCV found in experimental diabetes while having no effect on plasma glucose levels. These effects were blocked by probucol, which stresses the importance of ROS to neurovascular dysfunction. Furthermore, both diabetes and primaquine treatment caused an increase in plasma angiotensin-converting enzyme activity, a marker of endothelial damage, which was attenuated by probucol treatment (49). Effects on plasma

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