Abstract
BackgroundProgression of age-related macular degeneration has been linked to iron dysregulation and oxidative stress that induce apoptosis of neural retinal cells. Since both antioxidants and chelating agents have been reported to reduce the progression of retinal lesions associated with AMD in experimental animals, the present study evaluates the ability of multi-functional antioxidants containing functional groups that can independently chelate redox metals and quench free radicals to protect the retina against light-induced retinal degeneration, a rat model of dry atrophic AMD.Methods/ResultsProof of concept studies were conducted to evaluate the ability of 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) to reduce retinal damage in 2-week dark adapted Wistar rats exposed to 1000 lx of light for 3 hours. Assessment of the oxidative stress markers 4- hydroxynonenal and nitrotyrosine modified proteins and Thioredoxin by ELISA and Western blots indicated that these compounds reduced the oxidative insult caused by light exposure. The beneficial antioxidant effects of these compounds in providing significant functional and structural protection were confirmed by electroretinography and quantitative histology of the retina.Conclusions/SignificanceThe present study suggests that multi-functional compounds may be effective candidates for preventive therapy of AMD.
Highlights
Age-related macular degeneration (AMD), the leading cause of blindness in people over the age of 65 in the United States [1,2], occurs in two major forms
Light-induced retinal degeneration in animals has been extensively used to evaluate neuroprotective candidates for the treatment of retinal degenerations such as AMD because lightdamaged photoreceptors undergo oxidation-induced apoptosis similar to that observed in AMD [39,40]
An important mechanism in light-induced retinal injury is hydroxyl radicalmediated lipid peroxidation that is propagated through HaberWeiss and Fenton reactions catalyzed by iron or copper [10,11,41,42]
Summary
Age-related macular degeneration (AMD), the leading cause of blindness in people over the age of 65 in the United States [1,2], occurs in two major forms. Animal models currently used to identify and evaluate new therapies for AMD include transgenic, immunized, and natural murine models; laser photocoagulation and natural primate models; and laser-induced neovascularization and light-induced retinal damage rat models [3,5,6]. Progression of age-related macular degeneration has been linked to iron dysregulation and oxidative stress that induce apoptosis of neural retinal cells. Since both antioxidants and chelating agents have been reported to reduce the progression of retinal lesions associated with AMD in experimental animals, the present study evaluates the ability of multi-functional antioxidants containing functional groups that can independently chelate redox metals and quench free radicals to protect the retina against light-induced retinal degeneration, a rat model of dry atrophic AMD
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