Intranasal administration with NAD+ profoundly decreases brain injury in a rat model of transient focal ischemia.
Excessive poly(ADP-ribose) polymerase-1 (PARP-1) activation plays a significant role in ischemic brain damage. Increasing evidence has supported the hypothesis that PARP-1 induces cell death by depleting intracellular NAD+. Based on our in vitro finding that NAD+ treatment can abolish PARP-1-mediated cell death, we hypothesized that NAD+ administration may decrease ischemic brain injury. In this study, we used a rat model of transient focal ischemia to test this hypothesis. We observed that intranasal NAD+ delivery significantly increased NAD+ contents in the brains. Intranasal delivery with 10 mg/kg NAD+ at 2 hours after ischemic onset profoundly decreased infarct formation when assessed either at 24 or 72 hours after ischemia. The NAD+ administration also significantly attenuated ischemia-induced neurological deficits. In contrast, intranasal administration with 10 mg/kg nicotinamide did not decrease ischemic brain damage. These results provide the first in vivo evidence that NAD+ metabolism is a new target for treating brain ischemia, and that NAD+ administration may be a novel strategy for decreasing brain damage in cerebral ischemia and possibly other PARP-1-associated neurological diseases.
Ying
Weihai
W
Department of Neurology, University of California at San Francisco and San Francisco Veterans Affairs Medical Center; 4150 Clement Street, San Francisco, CA 94121, USA. shine863@gmail.com
Wei
Guangwei
G
Wang
Dongmin
D
Wang
Qing
Q
Tang
Xiannan
X
Shi
Jian
J
Zhang
Peng
P
Lu
Huafei
H
D000281:Administration, Intranasal; D000818:Animals; D004195:Disease Models, Animal; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D009243:NAD / Q000008:administration & dosage / Q000627:therapeutic use*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1