Regenerative Neurogenesis After Ischemic Stroke Promoted by Nicotinamide Phosphoribosyltransferase–Nicotinamide Adenine Dinucleotide Cascade

Yan Zhao, Yun-Feng Guan, Xiao-Ming Zhou, Guo-Qiang Li, Zhi-Yong Li, Can-Can Zhou, Pei Wang, Chao-Yu Miao
2015 Stroke  
N icotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells, and nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme for NAD biosynthesis in mammal. 1 Nampt catalyzes the reaction between nicotinamide and 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide (NMN), an intermediate in the biosynthesis of NAD. 1 Classically, NAD acts as a coenzyme and metabolite playing a fundamental role in electron transfer chain and energy generation
more » ... ATP production) through oxidative phosphorylation. 2 Recent work has revealed an entirely different role of NAD as a critical signaling regulator. 3,4 Moreover, with the identification of a group of NADconsuming proteins, 3 such as the sirtuins, poly(ADP-ribose) polymerases, and cyclic ADP-ribose synthases, Namptregulated NAD pool has drawn much attention as a substrate and a regulator in cell signaling and cellular homeostasis, such as metabolism, 5,6 circadian rhythms, 7 immunity, 8 and cell death. 9 Nampt-NAD cascade plays critical roles in cerebral ischemic injury. Cerebral ischemia caused brain NAD depletion followed by brain cell death. 10 Replenishment of NAD conferred a marked neuroprotection against ischemic cell death. 10 We and other groups have shown that Nampt is mainly localized on neurons rather than glial cells, 11,12 and both intercellular and extracellular Nampt display potent neuroprotection in ischemic stroke models. [11] [12] [13] We also showed that induction of autophagy Background and Purpose-Nicotinamide adenine dinucleotide (NAD) is a ubiquitous fundamental metabolite. Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme for mammalian NAD salvage synthesis and has been shown to protect against acute ischemic stroke. In this study, we investigated the role of Nampt-NAD cascade in brain regeneration after ischemic stroke. Methods-Nampt transgenic (Nampt-Tg) mice and H247A mutant enzymatic-dead Nampt transgenic (ΔNampt-Tg) mice were subjected with experimental cerebral ischemia by middle cerebral artery occlusion. Activation of neural stem cells, neurogenesis, and neurological function recovery were measured. Besides, nicotinamide mononucleotide and NAD, two chemical enzymatic product of Nampt, were administrated in vivo and in vitro. Results-Compared with wild-type mice, Nampt-Tg mice showed enhanced number of neural stem cells, improved neural functional recovery, increased survival rate, and accelerated body weight gain after middle cerebral artery occlusion, which were not observed in ΔNampt-Tg mice. A delayed nicotinamide mononucleotide administration for 7 days with the first dose at 12 hours post middle cerebral artery occlusion did not protect acute brain infarction and neuronal deficit; however, it still improved postischemic regenerative neurogenesis. Nicotinamide mononucleotide and NAD + promoted proliferation and differentiation of neural stem cells in vitro. Knockdown of NAD-dependent deacetylase sirtuin 1 (SIRT1) and SIRT2 inhibited the progrowth action of Nampt-NAD axis, whereas knockdown of SIRT1, SIRT2, and SIRT6 compromised the prodifferentiation effect of Nampt-NAD axis. Conclusions-Our data demonstrate that the Nampt-NAD cascade may act as a centralizing switch in postischemic regeneration through controlling different sirtuins and therefore represent a promising therapeutic target for long-term recovery of ischemic stroke. contributed equally. The online-only Data Supplement is available with this article at
doi:10.1161/strokeaha.115.009216 pmid:26060246 fatcat:ubbtk5v2frddhdm4saf73d7nsu