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C.B. Cingolani, B. Rogers, J. Shen, L. Lu, P.A. Campochiaro; Intraocular Injection of Paraquat; A New Model of Oxidative Damage–induced Retinal Degeneration . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1599.
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Purpose: Paraquat is a bipyridyl herbicide that is capable of generating reactive oxygen species (ROS) by uncoupling oxidative phosphorylation in mitochondria. Since the excess ROS are produced in mitochondria, it provides a tool to probe the components of the oxidative defense system that protect that cellular compartment. Systemic injection of paraquat has been used as oxidative stress to test antioxidant therapies in several tissues. In this study, we evaluated the effects of intraocular injection of paraquat. Methods:C57BL/6 or Balb/C mice were given an intravitreous injection of 1 µl of 0.5, 0.75, or 1 mM paraquat in one eye and 1 µl of PBS in the fellow eye. At 3 or 7 days after injection, mice had electroretinograms (ERGs) or were euthanized and ocular frozen sections were cut. Sections were used for TUNEL staining, staining for biomarkers of oxidative damage, or to measure outer nuclear layer thickness. Results: At both 3 and 7 days after injection of 0.75 or 1 mM paraquat, there was significant reduction in a– and b–wave ERG amplitudes. Eyes injected with 0.5 mM paraquat showed a significant reduction in b–wave, but not a–wave amplitude compared to PBS–injected eyes. Paraquat–injected eyes also showed increased staining for acrolein, a biomarker for lipid peroxidation, nitrotyrosine, a marker for oxidative damage to proteins, and 8–hydroxy–deoxyguanosine, a marker for oxidative damage to DNA. There were many TUNEL–positive cells in paraquat–injected eyes, which were rare or not present in PBS–injected eyes. Seven days after injection of 0.5 mM paraquat, outer nuclear layer thickness was significantly thinned by 17% in C57BL/6 mice and 33% in Balb/C mice compared to controls. Conclusions: Intravitreous paraquat induces apoptosis of retinal neurons and reduced retinal function from oxidative damage. It provides a model to test treatments designed to bolster the oxidative defense system of retinal cells, and will help to determine how well they target the mitochondrial compartment of the cells.
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