Intranasal administration of a PARG inhibitor profoundly decreases ischemic brain injury.
Cumulative evidence has indicated a critical role of poly(ADP-ribose) polymerase-1 activation in ischemic brain damage. Poly(ADP-ribose) glycohydrolase (PARG) is a key enzyme in poly(ADP-ribose) catabolism. Our previous studies showed that PARG inhibitors, gallotannin (GT) and nobotanin B, can profoundly decrease oxidative cell death in vitro. Here, we tested the hypothesis that intranasal delivery of GT can decrease ischemic brain damage by inhibiting PARG. Intranasal delivery of 25 mg / kg GT within 5 hours after a 2-hour focal brain ischemia markedly decreased the infarct formation and neurological deficits of rats. The GT administration also increased poly(ADP-ribose) in the ischemic brains, suggesting that GT acts as a PARG inhibitor in vivo. Furthermore, the GT treatment abolished nuclear translocation of apoptosis-inducing factor (AIF) in the ischemic brains, suggesting that prevention of AIF translocation may contribute to the protective effects of GT. In contrast, intravenous injection of GT, at 2 hours after ischemic onset, did not reduce ischemic brain damage. Collectively, our findings suggest that PARG inhibition can significantly decrease ischemic brain injury, possibly by blocking AIF translocation. This study also highlights distinct merits of intranasal drug delivery for treating CNS diseases.
Wei
Guangwei
G
Department of Neurology, San Francisco Veterans Affairs Medical Center and the University of California at San Francisco, San Francisco, CA 94121, USA.
Wang
Dongmin
D
Lu
Huafei
H
Parmentier
Sophie
S
Wang
Qing
Q
Panter
S Scott
SS
Frey
William H
WH
Ying
Weihai
W
D000281:Administration, Intranasal; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D047348:Hydrolyzable Tannins / Q000008:administration & dosage* / Q000627:therapeutic use; D007275:Injections, Intravenous; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D047348:Hydrolyzable Tannins; C075603:nobotanin B; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase