Poly(ADP-ribose) polymerase (PARP) inhibitors have neuroprotective effects after retinal ischemia and reperfusion (I/R) injury, but mechanisms of this action are not clear. A second generation PARP inhibitor, GPI 15427, was administrated to mice to investigate the possible mechanisms underlying its neuroprotective effects after retinal I/R injury. Ischemia was induced by increasing intraocular pressure to 80-90 mm Hg for 60 min followed by reperfusion, and mice were treated with GPI 15427 (40 mg/kg(-1) day(-1), orally) 2 days before or 1 day after injury. Histopathology caused by the retinal I/R injury was estimated by TUNEL assay and histological analyses. Relative gene expressions were evaluated by RT-PCR, Western blotting and immunohistological studies. GPI 15427 inhibited the retinal I/R-induced PARP activation and glial cell activation. GPI 15427 also significantly inhibited the I/R-induced neurodegeneration, as well as increase in TUNEL-positive cells. I/R-induced PERK-eIF2 alpha-CHOP activation and Bip over-expression were inhibited by GPI 15427, while it did not suppress I/R-induced CHOP over-expression and degeneration of retinal capillaries. Our results suggest that GPI 15427 inhibited retinal I/R-induced neurodegeneration and glial cell activation, and this was associated with an effect of the drug to suppress PERK-eIF2 alpha-CHOP activation and Bip over-expression. These results provide evidence that GPI 15427 inhibits retinal I/R injury at least in part via inhibition of endoplasmic reticulum stress. (C) 2012 Elsevier Inc. All rights reserved.