Regenerative neurogenesis after ischemic stroke promoted by Nampt-NAD cascade

摘要

Aim 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 enzy- matic-dead Nampt transgenic ~ Nampt-Tg） mice were subjected with experimental cerebral ischemia by middle cere- bral artery occlusion （ MCAO）. Activation of neural stem cells （ NSCs）, neurogenesis and neurological function re- covery were measured. Besides, nicotinamide mononucleotide （ NMN） and NAD, two chemical enzymatic product of Nampt, were administrated iu vivo and iu vitro. Results Compared with WT mice, Nampt-Tg mice showed en- hanced number of NSCs, improved neural functional recovery, increased survival rate and accelerated body weight gain after MCAO, which were not observed in Nampt-Tg mice. A delayed NMN administration for 7 days with the first dose at 12 hours post MCAO did not protect acute brain infarction and neuronal deficit; however, it still im- proved post-ischemic regenerative neurogenesis. NMN and NAD ＋ promoted proliferation and differentiation of NSCs iu vitro. Knockdown of NAD-dependent deacetylase sirtuin 1 ~ SIRT1 ~ and SIRT2 inhibited the pro-growth action of Nampt-NAD axis, while knockdown of SIRT1, SIRT2 and SIRT6 compromised the pro-differentiation effect of Nampt-NAD axis. Conclusions Our data demonstrate that the Nampt-NAD cascade may act as a centrali- zing switch in post-ischemic regeneration through controlling different sirtuins and therefore represent a promising therapeutic target for long-term recovery of ischemic stroke.