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Bongsu Kim, Rania Kusibati, Tyler Heisler-Taylor, Colleen M Cebulla; The Effect of Oral AZD6244 on Photoreceptor Survival in Murine Experimental Retinal Detachment. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3626.
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© ARVO (1962-2015); The Authors (2016-present)
Signaling through ERK1/2 is neuroprotective in some retinal damage models. However, it is unclear whether this pathway is protective for photoreceptors during retinal detachment (RD). We tested the hypothesis that blocking ERK1/2 signaling in a murine RD model would increase apoptosis and photoreceptor cell death.
AZD6244 (10mg/kg), a MEK inhibitor was prepared in a strawberry jelly (100ul) with 0.8% DMSO as a vehicle. Starting at day -1, the jelly with the drug or vehicle (control) was administrated and consumed daily by trained, single-housed C57Bl/6 mice. At day 0, retinal detachment was created by subretinal hyaluronic acid (10mg/ml) injection in the left eye. Eyes were harvested and fixed at day 3 (n=4 per group) and 7 (n=5 per group). Apoptosis in the outer nuclear layer (ONL) was tested by TUNEL assay. Photoreceptor cell death was evaluated by a normalized ONL thickness ratio measurement. Phosphorylation of retinal ERK (pERK) was evaluated with immunofluorescence.
Oral delivery of AZD6244 blocked pERK accumulation in Müller glia in detached retina. At day 3, the number of TUNEL positive ONL cells per area was significantly increased by 3.22 fold in AZD6244 treated RD eyes compared to vehicle treated RD eyes (2035.64 ± 453.96 vs 631.30 ± 195.41, respectively, P=0.009) while it was not changed in control eyes. However, apoptosis was not significantly different at day 7 between the two groups. ONL thickness was not significantly different at the two timepoints tested.
Oral delivery of MEK inhibitor AZD6244 blocked Müller pERK accumulation and significantly increased photoreceptor cell apoptosis in a murine RD model at the timepoint of maximal apoptosis, suggesting a neuroprotective role for the ERK1/2 pathway.
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