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Grant Abstract

Grant Number: 3R29EY008547-05S1
PI Name: Naseem Ansari
Project Title: Oxidative Damage in Sugar Induced Cataractogenesis

Abstract: DESCRIPTION (adapted from applicant's abstract): Increased polyol accumulation in diabetic and galactosemic rat lens has been implicated in the pathophysiology of sugar-induced cataractogenesis. However, the applicant's recent studies alone cannot explain the formation of such cataracts. The applicant has shown that antioxidants such as butylated hydroxytoluene (BHT) can delay or prevent galactosemic and diabetic cataractogenesis formation in rats even though the lens polyol levels in the antioxidant-treated group were twice as much as in the corresponding galactosemic and diabetic groups with mature cataract. However, aldose reductase appears to be involved in sugar-induced cataractogenesis because inhibition of this enzyme by aldose reductase inhibitors prevents or significantly delays cataractogenesis. An alternative hypothesis could involve oxidative damage due to increased formation of oxidizing species in hyperglycemia because of autoxidation of monosaccharides or a decreased defense capacity of the lens against oxidants. This is supported by the applicant's preliminary studies in which he has found that sugar-induced cataractogenesis is significantly advanced by allopurinol (antiuricemic drug) which forms free radicals. The objective of the proposal is to understand the mechanism of oxidative damage in hyperglycemia (galactosemia and diabetes) and hyperglycemia-allopurinol-induced cataractogenesis and to study the mechanism of prevention or significant delay of cataractogenesis in these models by BHT. The biochemical mechanisms of sugar-induced cataractogenesis, advancement by allopurinol and prevention by BHT would be studied by following the metabolic alterations which precede or follow protein modifications leading to light scattering. At various stages of cataractogenesis in the above mentioned rat models and in rat lens cultures free radicals would be identified and quantitated by ESR, MDA-protein adducts would be determined by using specific antibodies and MDA and high molecular weight protein aggregates would be determined by thiobarbituric acid and gel filtration methods respectively. The proposed studies should help in understanding the formation and role of oxidants in sugar-induced and hyperglycemia-allopurinol cataract models. Understanding of the mechanisms of advancement of sugar-induced cataractogenesis by allopurinol in diabetes would have significant clinical implications, because diabetic subjects with gout treated with allopurinol are likely to be at higher risk of developing cataracts as compared to normal subjects given allopurinol.

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