TY - JOUR
T1 - Inhibition of poly(ADP-ribose) polymerase inhibits ischemia/reperfusion induced neurodegeneration in retina via suppression of endoplasmic reticulum stress
AU - Li, Chuanzhou
AU - Wang, Leilei
AU - Kern, Timothy S.
AU - Zheng, Ling
N1 - Funding Information:
The authors acknowledge Eisai, Inc. (Woodcliff Lake, NJ, USA) for providing GPI 15427 used in the present study. This work was Supported by the National Basic Research Program of China (2009CB918304 and 2012CB524901), the Natural Science Foundation of China (No. 81100687), Program for New Century Excellent Talents in University (NECT-10-0623), and the Doctoral Independent Research Program of Wuhan University (No. 204276401).
PY - 2012/6/29
Y1 - 2012/6/29
N2 - 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 80-90mm Hg for 60min followed by reperfusion, and mice were treated with GPI 15427 (40mg/kg -1 day -1, orally) 2days before or 1day 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.
AB - 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 80-90mm Hg for 60min followed by reperfusion, and mice were treated with GPI 15427 (40mg/kg -1 day -1, orally) 2days before or 1day 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.
KW - ER stress
KW - Ischemia and reperfusion
KW - Neuroprotection
KW - PARP
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U2 - 10.1016/j.bbrc.2012.05.109
DO - 10.1016/j.bbrc.2012.05.109
M3 - Article
C2 - 22640737
AN - SCOPUS:84862842660
SN - 0006-291X
VL - 423
SP - 276
EP - 281
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -