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M. Zhang, T. Xiao, G. Campbell, N.H. Ansari; A Novel Approach Towards Prevention of Oxidation–Induced Cataractogenesis . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4123.
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It has been clearly established that oxidative stress plays a critical role in the pathogenesis of cataracts of various etiologies and that transition metals mediate the formation of reactive oxygen species. We have demonstrated earlier that under conditions of oxidative stress, generation of the lipid peroxidation product, 4–hydroxynonenal (HNE), induces toxicity in cultured human lens epithelial cells and rat lens. Toxicity, as determined by the levels of protein–HNE adducts and extent of apoptosis, was further enhanced when detoxification of HNE was decreased by silencing Aldehyde Dehydrogenase 1A1 (ALDH1A1). The aim of this study was to investigate if a metal chelator could prevent the oxidation–associated toxic parameters and thereby prevent lens opacification.
Formulations of disodium ethylenediamine tetraacetic acid (EDTA) as the metal chelator and methylsulfonylmethane (MSM) as the "carrier" for EDTA were prepared according to the proprietary methodology of Chakshu Research Inc., California. Human lens epithelial cells and rat lens were exposed to H2O2, Fenton reaction or high glucose in the absence or presence of various concentrations of EDTA or MSM or both. Various parameters such as cell viability protein–HNE adducts, ALDH1A1 induction and apoptosis were measured at different time intervals in the HLEC and rat lens epithelium. Lens opacification was quantified using digital image analysis.
Oxidative stress, due to H2O2, Fenton reaction or glucose, down–regulated the levels of ALDH1A1, increased protein–HNE adducts and apoptosis and decreased the cell viability and increased the lens opacification. EDTA alone did not impart any significant protection against oxidation–induced toxicity in HLEC and rat lens. MSM alone demonstrated some protection while EDTA + MSM imparted impressive protection.
Oxidative stress generated in the HLEC and rat lens appears predominantly to be metal–mediated. MSM probably, facilitates the entry of EDTA in the cells enabling EDTA to chelate the metal ions and thus inhibiting the downstream toxic events which lead to cataract formation.
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