Post-treatment with a novel PARG inhibitor reduces infarct in cerebral ischemia in the rat.
Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD(+)) by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). Overactivation of the poly(ADP-ribose) pathway increases nicotinamide and decreases cellular NAD(+)/ATP, which leads to cell death. Blocking poly(ADP-ribose) metabolism by inactivating PARP has been shown to reduce ischemia injury. We investigated whether disrupting the poly(ADP-ribose) cycle by PARG inhibition could achieve similar protection. We demonstrate that either pre- or post-ischemia treatment with 40 mg/kg of N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide, a novel PARG inhibitor, significantly reduces brain infarct volumes by 40-53% in a rat model of focal cerebral ischemia. Our result provides the first evidence that PARG inhibitors can ameliorate ischemic brain damage in vivo, in support of PARG as a new therapeutic target for treating ischemia injury.
Lu
Xi-Chun M
XC
Guilford Pharmaceuticals Inc, 6611 Tributary Street, Baltimore, MD 21224, USA.
Massuda
Edmond
E
Lin
Qian
Q
Li
Weixing
W
Li
Jia-He
JH
Zhang
Jie
J
D000818:Animals; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004396:Coloring Agents / Q000493:pharmacokinetics; D003958:Diamide / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion / Q000379:methods; D013778:Tetrazolium Salts / Q000493:pharmacokinetics; D013997:Time Factors
D004396:Coloring Agents; D004791:Enzyme Inhibitors; D013778:Tetrazolium Salts; D003958:Diamide; C009591:triphenyltetrazolium; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase