Cataract is a leading cause of blindness and visual impairment in human diabetics. Its incidence is on a rise all over the world. Therapy development to delay the cataract progression is hence becoming crucial, now more than ever. Its surgical therapy has not been fool-proof because of several post-operative complications including posterior capsular opacification, tractional retinal detachment and cystoid macular edema etc. in many patients, especially following YAG capsulotomy. Many older people are not even medically fit for surgery. Hence, delaying cataracts is an important goal of NIH and other agencies. We are therefore intimately engaged with studies on delaying cataract formation. Along with several mechanistic studies on its formation, we have discovered that systemic pyruvate delays the formation of cataracts significantly in diabetic mice wherein the pathogenesis simulates that in humans. Highly encouraged with these findings, we propose to investigate the possible delay of such cataract formation by topical Ethyl Pyruvate (EP). We found that it penetrates the cornea adequately. Preliminary studies are also strongly suggestive of the high likelihood of delaying cataract formation by such-application, not merely with the onset of diabetes but also when belated till early cataractous changes. Hence we are very optimistic and excited with this finding in view of its high clinical potential. We recently established that the beneficial effect of pyruvate is attributable not only to the deactivation of the oxygen centered free radicals, inhibition of glycation and providing metabolic support, but could be also ascribed to its property of scavenging peroxynitrite via its nitrosative decarboxylation and consequent protection against nitrite induced oxidative stress. Being of endogenous origin, the probability of any toxicity due to its topical application is highly remote. With majority of investigations with mouse, pharmacokinetic study of EP penetration will also be done with macaque (Rhesus monkey) such that the findings could provide additional background for potential use in humans. Along with monitoring inhibition of lens opacification, mechanism of action of EP will be ascertained at the levels of morphology, histology, tissue metabolism and apoptotic changes. ? ? ? ?

National Institute of Health (NIH)
National Eye Institute (NEI)
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Anterior Eye Disease Study Section (AED)
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Araj, Houmam H
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University of Maryland Baltimore
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Kronschläger, Martin; Löfgren, Stefan; Yu, Zhaohua et al. (2013) Caffeine eye drops protect against UV-B cataract. Exp Eye Res 113:26-31
Varma, Shambhu D; Kovtun, Svitlana; Hegde, Kavita R (2011) Role of ultraviolet irradiation and oxidative stress in cataract formation-medical prevention by nutritional antioxidants and metabolic agonists. Eye Contact Lens 37:233-45
Varma, Shambhu D; Hegde, Kavita R (2010) Kynurenine-induced photo oxidative damage to lens in vitro: protective effect of caffeine. Mol Cell Biochem 340:49-54
Varma, Shambhu D; Hegde, Kavita R (2010) Prevention of oxidative damage to lens by caffeine. J Ocul Pharmacol Ther 26:73-7
Hegde, K R; Varma, S D (2009) Electron impact mass spectroscopic studies on mouse retinal fatty acids: effect of diabetes. Ophthalmic Res 42:9-14
Hegde, Kavita R; Kovtun, Svitlana; Varma, Shambhu D (2007) Induction of ultraviolet cataracts in vitro: prevention by pyruvate. J Ocul Pharmacol Ther 23:492-502
Varma, S D; Hegde, K R; Kovtun, S (2006) Oxidative damage to lens in culture: reversibility by pyruvate and ethyl pyruvate. Ophthalmologica 220:52-7
Hegde, K R; Varma, S D (2005) Combination of glycemic and oxidative stress in lens: implications in augmentation of cataract formation in diabetes. Free Radic Res 39:513-7
Hegde, K R; Varma, S D (2005) Prevention of cataract by pyruvate in experimentally diabetic mice. Mol Cell Biochem 269:115-20
Hegde, K R; Varma, S D (2005) Cataracts in experimentally diabetic mouse: morphological and apoptotic changes. Diabetes Obes Metab 7:200-4

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