The primary objective of the proposal is to study biochemical and pharmacological strategies for preventing cataractogenesis using diabetic and oxidative stress animal models and lens culture. We anticipate that certain physiological alpha keto acids could play such a preventive role, especially pyruvate. This is based on our observation that it inhibits polyol synthesis, glycation, AGE formation, and oxidative stress in lens culture and most importantly, its effectiveness against the actual cataract formation in galactosemic animals. We will now test the hypotheses (I) that exogenously administered pyruvate will inhibit cataractogenesis in diabetic rats with high lens aldose reductase (AR) activity, (2) that it will be effective also in diabetic mice with low lens AR, but being subject to ROS and glycation stress, causing structural and functional protein and lipid changes, (3) that the chaperone activity of the alpha-crystallin is decreased by the high levels of fructose, as in the diabetic lens, and (4) that pyruvate will also protect against the combined stress of diabetes and oxidation. The pyruvate effects are attributable to the reactivity of its keto group, situated adjacent to the carboxyl group. Therefore, we hypothesize (5) that other keto acids with greater cell permeability and lower metabolism should be physiologically more effective. Hypotheses #1 to #4 will be verified by the delay in cataract formation in diabetic animals given pyruvate in the diet and drinking water with reference to the controls with comparable hyperglycemia. Basal controls with and without pyruvate will also be run. GSH-peroxidase knockout mice will be used for specific aim #3. The levels of sorbitol, fructose, glycated proteins, AGE, ATP, GSH, malonaldehyde (MDA) and the chaperone activity of alpha-crystallin will be determined in all the groups. Hypothesis #5 will be verified by the relative activity of the keto acids in scavenging ROS, and their effectiveness in preventing lens damage in culture, as indexed by the cation pump activity, and the above biochemical parameters.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY001292-28
Application #
6819727
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Liberman, Ellen S
Project Start
1978-09-01
Project End
2006-09-29
Budget Start
2004-12-01
Budget End
2006-09-29
Support Year
28
Fiscal Year
2005
Total Cost
$297,000
Indirect Cost
Name
University of Maryland Baltimore
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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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