title: NAD(+) administration decreases ischemic brain damage partially by blocking autophagy in a mouse model of brain ischemia.
abstract: Nicotinamide adenine dinuleotide (NAD(+)) plays critical roles in multiple biological functions. Previous studies have indicated that NAD(+) treatment decreases oxidative stress-induced death of primary neurons and astrocytes. Intranasal administration of NAD(+) also reduces brain damage in a rat model of transient focal brain ischemia. However, the mechanisms underlying this protective effect remain unknown. In this study, we used a mouse model of brain ischemia to test our hypothesis that NAD(+) decreases ischemic brain damage partially by preventing autophagy. Adult male mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 90min, and NAD(+) was administered intraperitoneally (i.p.) immediately after reperfusion started. We found that administration with 50mg/kg NAD(+) led to significant decreases in infarct size, edema formation, and neurological deficits at 48h after ischemia. NAD(+) administration also significantly decreased brain ischemia-induced autophagy in the cortex and hippocampus. We further found that prevention of autophagy by 3-methyladenine (3-MA), a selective autophagy inhibitor, significantly reduced ischemic brain damage, suggesting an important role of autophagy in the ischemic brain injury in our animal model. Collectively, our findings have suggested that NAD(+) administration decreases ischemic brain damage at least partially by blocking autophagy. This is the first suggested mechanism regarding the protective effects of NAD(+) in cerebral ischemia, which further highlights the promise of NAD(+) for treating brain ischemia.
authors.affiliation: Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China.
authors.forename: Chaobo
authors.initials: C
authors.lastname: Zheng
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Weiliang
authors.initials: W
authors.lastname: Xia
authors.forename: Shengtao
authors.initials: S
authors.lastname: Shi
authors.forename: Jianrong
authors.initials: J
authors.lastname: Liu
authors.forename: Weihai
authors.initials: W
authors.lastname: Ying
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D020520:Brain Infarction / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D009243:NAD / Q000627:therapeutic use*
chemical_list: D009243:NAD