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IE Khalil, AB El-Remessy, G Abou-Mohamed, RW Caldwell, RB Caldwell, K Green, GI Liou; Superoxide, Nitric Oxide and Peroxynitrite Are Involved in The NMDA-Induced Retinal Cell Death . Invest. Ophthalmol. Vis. Sci. 2002;43(13):4091.
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Purpose: In glucoma, death of retinal neurons is caused by increased release of excitatory neurotransmitters. The excitotoxin N-methyl-D-aspartate (NMDA) is known to cause apoptosis in rat and rabbit retina. However, the cellular mechanisms that lead to cell death are not clear. It is known that peroxynitrite, an anion and potent oxidant generated by the interaction of nitric oxide and superoxide, can induce apoptosis in several disease models. Based on these facts, we test the hypothesis that NMDA-induced apoptosis occurs via the formation of superoxide anion, nitric oxide and peroxynitrite. Methods: Excitotoxic retinal cell death was induced by intravitreal injection of neutralized NMDA (40 mM) in adult rabbits and rats. The in situ TdT-mediated-dUTP nick end labeling (TUNEL) method was used to analyze apoptosis in retinal cryosections. Retinal levels of superoxide anion, nitric oxide and peroxynitrite were determined by the measurements of lipid peroxides, nitrites and nitrotyrosine (peroxynitrite end-product). Retinal samples were collected 4, 8, 18 and 24 hours after NMDA injection. Results: Intravitreal injection of NMDA induced significant levels of apoptosis within the ganglion cell layer as demonstrated by the presence of numerous TUNEL-positive nuclei. This was positively correlated with positive immunolabeling of nitrotyrosine in retinal cryosections. There was also a time-related accumulation of superoxide anion, nitric oxide and peroxynitrite in the NMDA-injected rat and rabbit retinas. Conclusion: Superoxide, nitric oxide and peroxynitrite may play an important role in the retinal NMDA-induced apoptosis . Foot Note: Dr. Keith Green was deceased on November 22, 2001.
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