Inhibition of poly(ADP-ribose) polymerase inhibits ischemia/reperfusion induced neurodegeneration in retina via suppression of endoplasmic reticulum stress.
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-eIF2α-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-eIF2α-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.
College of Life Sciences, Wuhan University, Wuhan 430072, China.
Chuanzhou
C
Li
Leilei
L
Wang
Timothy S
TS
Kern
Ling
L
Zheng
D000818:Animals; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000209:etiology; D009457:Neuroglia / Q000201:enzymology / Q000473:pathology; D019384:Nucleic Acid Synthesis Inhibitors / Q000008:administration & dosage*; D009930:Organic Chemicals / Q000008:administration & dosage; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015427:Reperfusion Injury / Q000150:complications*; D012162:Retinal Degeneration / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D051742:Transcription Factor CHOP / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D009930:Organic Chemicals; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497249:DDIT3 protein, human; C502278:GPI 15427