Orally Active Multi-Functional Antioxidants Are Neuroprotective in a Rat Model of Light-Induced Retinal Damage

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.

Metal chelator combined with permeability enhancer ameliorates oxidative stress-associated neurodegeneration in rat eyes with elevated intraocular pressure

“…Within ophthalmic diseases, recent studies have shown that oral and systemic administration of the metal chelator deferiprone (DFP) is effective in ameliorating signs of retinal degeneration in transgenic mouse models of age-related macular degeneration [35, 36]. Combination free-radical scavenger/metal chelator compounds have been shown to mitigate retinal damage induced by light [37]. We have previously shown that chelation by EDTA-MSM is effective in reducing oxidative stress-induced toxicity in diabetic cataract and in an in vitro model of neurodegenerative disease [16, 38].…”

Topical Nutraceutical Optixcare EH Ameliorates Experimental Ocular Oxidative Stress in Rats

“…This study was conducted as previously described in detail. 35 Briefly, groups containing twelve 4-5-week-old male Wistar rats receiving either normal rat chow (untreated), normal rat chow and topically treated with Optixcare EH b.i.d., or an oral diet containing 0.05% of the multifunctional antioxidant JHX-4 as described above were dark adapted for 2 weeks. Rats from each group were then individually placed into acrylic, flat-bottom rodent restraints (Plas-Labs, Inc., Lansing, MI) in a light-box apparatus and exposed for 3 h to 1,000 lx of cool white fluorescent light (Lights of America, Los Angeles, CA; light-damaged rats, LD).…”

“…10 Kador has synthesized novel multifunctional antioxidants with the ability to scavenge free radicals and chelate iron independently, and demonstrated that by oral administration, they both delay cataract formation and protect the retina against light damage, a model for AMD. [34][35][36] Based on the hypothesis that oral administration of antioxidants generally fail to achieve adequate levels of antioxidants to the lens, a topical nutraceutical suspension called Optixcare Eye Health (Optixcare EH) is being developed.…”

Potential interactions of prescription and over‐the‐counter medications having antioxidant capabilities with radiation and chemotherapy

“…Outside the area of oncology, an increasing number of publications supports the opinion that commonly used pharmaceuticals may provide a therapeutic benefit partially based on their antioxidant properties . Accordingly, oncology patients with co‐morbid conditions frequently incorporate such pharmaceuticals into their treatment.…”