Nicotinamide mononucleotide inhibits post-ischemic NAD+ degradation and dramatically ameliorates brain damage following global cerebral ischemia

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for multiple cellular metabolic reactions and has a central role in energy production. Brain ischemia depletes NAD+ pools leading to bioenergetics failure and cell death. Nicotinamide mononucleotide (NMN) is utilized by the NAD+ salvage pathway enzyme, nicotinamide adenylyltransferase (Nmnat) to generate NAD+. Therefore, we examined whether NMN could protect against ischemic brain damage. Mice were subjected to transient forebrain ischemia and treated with NMN or vehicle at the start of reperfusion or 30 min after the ischemic insult. At 2, 4, and 24 h of recovery, the proteins poly-ADP-ribosylation (PAR), hippocampal NAD+ levels, and expression levels of NAD+ salvage pathway enzymes were determined. Furthermore, animal’s neurologic outcome and hippocampal CA1 neuronal death was assessed after six days of reperfusion. NMN (62.5 mg/kg) dramatically ameliorated the hippocampal CA1 injury and significantly improved the neurological outcome. Additionally, the post-ischemic NMN treatment prevented the increase in PAR formation and NAD+ catabolism. Since the NMN administration did not affect animal’s temperature, blood gases or regional cerebral blood flow during recovery, the protective effect was not a result of altered reperfusion conditions. These data suggest that administration of NMN at a proper dosage has a strong protective effect against ischemic brain injury.

NAD replenishment with nicotinamide mononucleotide protects blood–brain barrier integrity and attenuates delayed tissue plasminogen activator‐induced haemorrhagic transformation after cerebral ischaemia

“…These results, together with previous findings on the effects of NMN in brain ischaemic injury Zhao et al, 2014;Park et al, 2016), suggest that NMN may be a promising agent for the treatment of ischaemic stroke.…”

“…The mice that died before the 24 h time point were included only in the experiment of post 24 h mortality rate; these mice were not included in the other analyses. In previous studies, NMN was administered to mice at doses of~1 00 mg·kg À1 (Park et al, 2016) to 500 mg·kg À1 (Long et al, 2015;Uddin et al, 2016). However, most studies applied the dose of 300 mg·kg À1 Yoshino et al, 2011;Zhang et al, 2011;Stein and Imai, 2014;Zhao et al, 2015b;de Picciotto et al, 2016;Wei et al, 2017); therefore, we used 300 mg·kg À1 in this study.…”

“…The administration of nicotinamide mononucleotide (NMN) or nicotinamide riboside, two NAD precursors, as a supplement is able to enhance NAD levels and is used to treat high-fat-induced obesity/fatty liver (Yoshino et al, 2011;Uddin et al, 2016;Zhou et al, 2016). We and other groups have demonstrated that NMN protects against post-ischaemic NAD degradation and decreases brain damage after cerebral ischaemia Zhao et al, 2014;Park et al, 2016).…”

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

“…This is supported by recent in vivo work in zebrafish larvae and mice showing that expression of a bacterial NMN-deamidase, which consumes NAD but does not have NAD synthesis activity, rescues axonal defects and promotes axon survival (Di Stefano et al, 2017). On the other hand, NMN preserves hippocampus-dependent spatial memory after forebrain ischemia (Park et al, 2016) and reduces edema, oxidative stress, inflammation, and neuronal death in a mouse collagenase-induced intracerebral hemorrhage (cICH) model (Wei et al, 2017b). …”

Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3‐dependent mechanism in male mice

“…Administration of NMN to animals that represent the transgenic model of Alzheimer’s disease showed improved mitochondrial bioenergetic functions and reduced fragmentation (Long et al, ). We carried out dose‐dependent experiments of NMN administration following global cerebral ischemia that showed an NMN‐induced inhibition of postischemic NAD + catabolism and dramatic amelioration of ischemic cell death (Park et al, ). Therefore, we decided to study the mechanisms of NMN protection by exploring the downstream effects of NMN administration on mitochondrial NAD + levels, protein acetylation, and modulation of mitochondrial dynamics.…”