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K. R. Hegde, S. D. Varma; Retinal Damage by Oxidative Stress. Protection by Pyruvate and Other -ketoacid Metabolites. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4550.
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Oxidative stress due to in situ generation of reactive oxygen species (ROS) is considered to be a significant risk factor in the pathogenesis of many eye diseases including the retinopathies. The purpose of this study was to further investigate the susceptibility of the retina to ROS stress, and examine its prevention by α-ketoacids such as pyruvate, acting as a potent ROS scavenger in addition to its role as a metabolic agonist. The phenomenon was further assessed by determining the fatty acid composition of the normal and diabetic retina.Methods: Retinal explants from CD-1 mice were incubated for 2.5 hrs. in medium 199 generating ROS by the action of xanthine oxidase and uricase on xanthine (0.5mM), in the absence and presence of 10mM pyruvate. Oxidative damage to the tissue was assessed by determining GSH depletion and malonaldehyde (MDA) generation, the latter being a lipid peroxidation index. Diabetes was induced by intraperitoneal streptozotocin administration. Fatty acid analysis was done after trans-esterification of the tissue lipids and resolution of the esters and their identification by mass spectroscopy coupled to gas chromatography.Results: ROS exposure of the explants decreased their GSH accompanied with an increase of MDA. These deleterious effects were substantially attenuated by pyruvate addition to the medium. It was further noted that the fatty acid content of the diabetic retina was ~thrice of that in the normals, suggesting lipidosis. The fatty acid composition of the normal mouse retina included palmitic (31.5%), oleic (17.5%), stearic (25.3%), arachidonic (9.7%) and docosahexaenoic (DHA) (12.5%) acids. The most significant change in diabetes, in addition to a generalized increase of fatty acid amounts, was the DHA decrease (~50% of the normal).
: Theresults demonstrate that the retina is highly susceptible to damage by oxyradical production, proven by the significant loss of GSH and increase in MDA. That ROS generation constitutes a significant risk factor in the development of retinopathy was further apparent by changes in the fatty acid profile of the diabetic retina represented particularly by a highly significant decrease of DHA, a prominent polyunsaturated fatty acid highly susceptible to oxidative breakdown causing membrane disruption and generation of toxic aldehydes. These changes in the retina may precede appearance of vasculopathy. The results also suggest that compounds such as pyruvate and other α-ketoacids may prove therapeutically beneficial against oxidation induced retinopathies.
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