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O. Perche, M. Doly, I. Ranchon-Cole; Caspase-8 and Caspase-9 Inhibitors Do Not Protect From Light-Induced Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4394.
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To study caspase-8 and -9 involvements in light-induced retinal degeneration.
Wistar rats were raised in dim-cyclic light. In a first set of experiments, 45 days old rats were dark-adapted overnight before being exposed for 24 hours to a 3400 lux-light. Sixteen hours before exposure, they were uninjected or injected with DMSO 2%, caspase-8 inhibitor Z-IETD-FMK (0,2mM) or caspase-9 inhibitor Z-LEHD-FMK (0.2mM). Electroretinograms (ERG) were recorded before exposure and/or treatment, at 1 day (D1) and 15 days (D15) after exposure to the damaging light. Bmax (maximal b-wave amplitude) was derivated from the ERGs. After the last ERG, rats were sacrificed for morphometric analysis. Unexposed animals were processed in parallel. In a second set of experiments, uninjected rats were sacrificed at 0, 2, 4, 6, 12, 24 hours of light-exposure or at D1 to measure caspase-9 activity and expression in the retina.
In unexposed rats, Z-IETD-FMK or Z-LEHD-FMK had no toxic effect on the retina.In uninjected retina, light-exposure induced a decrease of Bmax by 75% and a thinning of ONL by 90%. In DMSO, Z-IETD-FMK or Z-LEHD-FMK groups, light exposure had the same effect than in uninjected group. In uninjected retina, caspase-9 activity was decreased by 50% at 2 and 4 hours of light exposure. Thereafter, it progressively increased to reach 162% at D1. Caspase-9 expression was upregulated to 150% at 2h of light exposure and, then progressively decreased to reach 125% at D1.
Caspase-9 and caspase-8 do not seem to be involved in the degenerative process induced by light exposure. The overexpression of caspase-9 while its activity is the lowest suggests the induction of endogenous inhibitors by light exposure. Further experiments are on course to study caspase-8 activity and expression during light exposure and to better understand the apoptotic mechanism induced by light exposure.
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