Previous studies from this and other laboratories suggest that an intraocular generation of certain reactive oxygen species (ROS) constitutes a major risk factor in the pathogenesis of cataracts. The PI has also demonstrated that the ROS can be effectively scavenged by pyruvate preventing cataracts in selenite and galactose models. In addition, he has recently observed that it inhibits lens protein glycation and polyol synthesis as well. Hence, he hypothesizes that such ketoacids and their esters can perform a useful role in cataract prevention. It is commonly known that the bio-effectiveness of the esters is greater than that of the parent compound because of their enhance translocation into the cell. Therefore, further studies will be conducted with the following specific aims. 1. Study the antioxidant effect of ethyl pyruvate in vitro by assessing its ability to prevent against oxidative damage to the lens active transport, loss GSH, ATP, and of soluble proteins due to their oxidative in solubilization. The hydrolysis of the ester will also be studied. 2. Extend these studies with alpha- ketoglutarate and its ester in view of its slower metabolism and consequently a more sustained bio- availability. 3. Study the in vivo effectiveness of the esters against oxidative stress and cataract formation induced by sodium selenite and galactose. 4. Determination of the anti-glycating effect of the keto compounds using purified bovine lens crystallins. The preventive process supposedly involves their ROS scavenging properties and/or competitive inhibition of the Schiff base formation between the keto group of the sugars and the lens protein -NH2. 5. Study the prevention of such glycation by these compounds in vivo in diabetic and galactosemic animals.
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