title: 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 30min after the ischemic insult. At 2, 4, and 24h 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 (62.5mg/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.
authors.affiliation: Veterans Affairs Maryland Health Care System, 10 North Greene Street, Baltimore, MD 21201, USA.
authors.forename: Ji H
authors.initials: JH
authors.lastname: Park
authors.affiliation: Veterans Affairs Maryland Health Care System, 10 North Greene Street, Baltimore, MD 21201, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Long
authors.affiliation: Veterans Affairs Maryland Health Care System, 10 North Greene Street, Baltimore, MD 21201, USA.
authors.forename: Katrina
authors.initials: K
authors.lastname: Owens
authors.affiliation: Veterans Affairs Maryland Health Care System, 10 North Greene Street, Baltimore, MD 21201, USA; Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, School of Medicine, University of Maryland, Baltimore, 685 West Baltimore Street, MSTF 534, Baltimore, MD 21201, USA. Electronic address: tkristian@anes.umm.edu.
authors.forename: Tibor
authors.initials: T
authors.lastname: Kristian
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009243:NAD / Q000187:drug effects* / Q000378:metabolism; D009536:Niacinamide / Q000378:metabolism; D009537:Nicotinamide Mononucleotide / Q000494:pharmacology*
chemical_list: D009243:NAD; D009537:Nicotinamide Mononucleotide; D009536:Niacinamide
keywords: Nicotinamide mononucleotide; brain; ischemia; mouse; nicotinamide dinucleotide; poly-ADP-ribose