PARP Inhibitor Protects Against Chronic Hypoxia/Reoxygenation-Induced Retinal Injury by Regulation of MAPKs, HIF1α, Nrf2, and NFκB.

摘要: Purpose In the eye, chronic hypoxia/reoxygenation (H/R) contributes to development of a number ocular disorders. H/R induces production reactive oxygen species (ROS), leading poly(ADP-ribose) polymerase-1 (PARP1) activation that promotes inflammation, cell death, and disease progression. Here, we analyzed protective effects PARP1 inhibitor olaparib in H/R-induced retina injury investigated signaling mechanisms involved. Methods A rat retinal model was used detect histologic biochemical changes retina. Results induced reductions thickness most layers, which were prevented by olaparib. Furthermore, caused increased levels Akt glycogen synthase kinase-3β phosphorylation, further olaparib, contributing protection. By contrast, c-Jun N-terminal kinase p38 mitogen-activated protein kinases (MAPK) phosphorylation reduced via phosphatase 1 (MKP-1) expression. addition, hypoxia-inducible factor 1α (HIF1α) decreased possibly contributed VEGF Nuclear (erythroid-derived 2)-like 2 (Nrf2) expression slightly activated factor-κB (NFκB) also through (Ser536) acetylation (Lys310) p65 subunit, although this significantly Conclusions Olaparib degenerative morphology. The probably involved Nrf2 ROS reduction, as well normalization HIF1α related inflammation NFκB dephosphorylation/inactivation, inhibition-MKP-1 activation-p38 MAPK inhibition pathway. PARP inhibitors represent potential therapeutics disease.