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MM Cruz, S Ornelas Walker, KP Kolostyak, FN Ross-Cisneros, J Sebag, CJ C Hsia, AA Sadun; Influence of Brimonidine (alpha-2 agonist) and Nitroxide Ester (ETOPS) on Retinal Cell Survival Following Apoptotic Stimulus . Invest. Ophthalmol. Vis. Sci. 2002;43(13):766.
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Purpose: To compare purported neuroprotective agents in their ability to rescue human retinoblastoma cells undergoing apoptosis induced by TNF-alpha in vitro. Pentoxifylline, dizocilipine (MK-801), 3-aminobenzamide (3-ABA), Brimonidine, and TOPS-ester (ethyl-2,2',6,6'-tetramethylpiperidylidene-1-oxyl-succinate, or "ETOPS") were evaluated. Brimonidine is a selective alpha-2 agonist which has been reported to increase growth factor expression and apoptosis cascade inhibition, while ETOPS has been reported to decrease reactive oxygen species toxicity in several challenge systems. Methods: Degrees of apoptosis detected via annexin V fluorescent apoptosis cytometry were compared over a 24 hour period to assess the relative neuroprotective efficacy between the representative agents, brimonidine and ETOPS. Y-79 and WERI-Rb-1 human retinoblastoma cells (≷10E6/ml) were aliquoted into separate culture plates with the putative neuroprotective agents in the presence and absence of TNF-alpha (0.5ng/ml). Brimonidine (10uM) and ETOPS (2mM) were referenced against pentoxifylline (25ug/ml), MK-801 (10uM), and 3-ABA (10mM). FL1/FL2 plots were compensated for necrosis to identify true apoptotic populations. Results: 24 hour studies showed brimonidine retarded cell death about two and a half fold, as compared to cytokine-treated positive controls. ETOPS treated samples exhibited an approximate four-fold decrease in cell death, as compared to TNF-positive controls. Conclusions: Brimonidine is effective in ameliorating cell death induced by TNF-alpha, a primary inflammatory cytokine detected in many neurodegenerative diseases of the CNS. To an even greater degree, ETOPS, a novel caged nitroxide, was effective in preventing retinal cell death. Albeit by different mechanisms of action, each of these agents may prove to be effective in minimizing retinal damage if used early.
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