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

• Effect of treatment with nicotinamide mononucleotide on forebrain ischemia is examined.
• Nicotinamide mononucleotide administration ameliorates both histologic and neurologic outcome.
• Treated animals show normalized post-ischemic NAD levels and inhibition of poly-ADP-ribosylation.

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.