Abstract
BackgroundAge-related cataract is a worldwide health care problem whose progression has been linked to oxidative stress and the accumulation of redox-active metals. Since there is no specific animal model for human age-related cataract, multiple animal models must be used to evaluate potential therapies that may delay and/or prevent cataract formation.Methods/Principal FindingsProof of concept studies were conducted to evaluate 4-(5-hydroxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 4) and 4-(5-hydroxy-4,6-dimethoxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 8), multi-functional antioxidants that can independently chelate redox metals and quench free radicals, on their ability to delay the progression of diabetic “sugar” cataracts and gamma radiation-induced cataracts. Prior to 15 Gy of whole head irradiation, select groups of Long Evans rats received either diet containing compound 4 or 8, or a single i.p. injection of panthethine, a radioprotective agent. Compared to untreated, irradiated rats, treatment with pantethine, 4 and 8 delayed initial lens changes by 4, 47, and 38 days, respectively, and the average formation of posterior subcapsular opacities by 23, 53 and 58 days, respectively. In the second study, select groups of diabetic Sprague Dawley rats were administered chow containing compounds 4, 8 or the aldose reductase inhibitor AL1576. As anticipated, treatment with AL1576 prevented cataract by inhibiting sorbitol formation in the lens. However, compared to untreated rats, compounds 4 and 8 delayed vacuole formation by 20 days and 12 days, respectively, and cortical cataract formation by 8 and 3 days, respectively, without reducing lenticular sorbitol. Using in vitro lens culture in 30 mM xylose to model diabetic “sugar” cataract formation, western blots confirmed that multi-functional antioxidants reduced endoplasmic reticulum stress.Conclusions/SignificanceMulti-functional antioxidants delayed cataract formation in two diverse rat models. These studies provide a proof of concept that a general cataract treatment focused on reducing oxidative stress instead of a specific mechanism of cataractogenesis can be developed.
Highlights
Cataract is a major worldwide health care problem that especially affects the elderly
To determine if the multi-functional antioxidants can protect against radiation-induced cataracts, pigmented Long Evans rats received 15 Gy of gamma radiation (Cobalt 60 source) to the whole head, an amount established to result in 100% incidence of cataract development in albino animals [27,33]
Groups 3 and 4 were administered standard rodent diet supplemented with either 0.025 wt% of compound 4 or 8 for two weeks prior to whole head irradiation and continued for the duration of the study
Summary
Cataract is a major worldwide health care problem that especially affects the elderly. It is the leading cause of preventable blindness in the world, especially in developing countries in Africa and Asia [1,2]. The development of a nonsurgical treatment for cataracts would have a profound beneficial impact on human health and healthcare costs [1,4,5]. The development of an efficacious anti-cataract drug would have a beneficial impact on both human health and healthcare costs. Since there is no specific animal model for human age-related cataract, multiple animal models must be used to evaluate potential therapies that may delay and/or prevent cataract formation
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