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Jason D. Dapper, Samuel D. Crish, Wan-Heng Wang, Iok-Hou Pang, David J. Calkins; p38 MAPK Inhibitors Reduce Retinal Ganglion Cell Degeneration in the Microbead Occlusion Model of Ocular Hypertension. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2607.
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p38 mitogen-activated protein kinase (MAPK) signaling is relevant to age-related neurodegenerative diseases, and downstream effects of p38 MAPK activation are associated with retinal ganglion cell (RGC) degeneration in glaucoma and other optic nerve insults. Because p38 MAPK inhibitors may protect against neurodegeneration in other disorders, we tested their efficacy in preventing RGC degeneration during microbead-induced ocular hypertension in rats.
We induced unilateral ocular hypertension in 6-8 month Brown Norway rats by injection of polystyrene microbeads into the anterior chamber; the opposing eye received an equal volume saline injection. For a period of 4-6 weeks, two cohorts received twice daily topical application of p38 MAPK inhibitors, BIRB-796 and RO-3206145, while a control cohort received topical saline. Forty-eight hours prior to sacrifice and perfusion with 4% paraformaldehyde, rats received bilateral intravitreal injection of fluorescent cholera toxin beta subunit (CTB). We measured anterograde transport to the superior colliculus (SC) by quantification of CTB signal in coronal brain sections and RGC axon survival in optic nerve cross-sections. Retinas from each cohort were dissected into halves, with one half processed for mRNA extraction and quantitative PCR and the other cut into cross-sections for immunohistochemistry.
Microbead injection elevated ocular pressure by 30-35% in all cohorts. In the control group, elevated pressure induced a 35% loss of CTB signal in the SC and a 30% decrease in axon survival in the optic nerve. Treatment with BIRB-796 and RO-3206145 increased intact CTB signal to 87% and 95%, respectively, and prevented axon loss entirely. The p38 MAPK inhibitors also decreased expression of Timp3, Hspb1, and CP mRNA in retina from microbead eyes compared to the control group and diminished immuno-labeling for phosphorylated Tau and Hsp27, two downstream targets of activated p38 MAPK.
These results support the hypothesis that p38 MAPK activation contributes to the progression of RGC degeneration in glaucoma. The use of p38 MAPK inhibitors confers protection of the RGC pathway both distally and proximally from stressors associated with ocular hypertension through down-regulation of downstream targets generally associated with MAPK activation and disease progression.
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