Systemic nicotinamide mononucleotide administration to mitigate post-cardiac arrest brain injury in mice

Abstract

Post-cardiac arrest brain injury (PCABI) is the leading cause of death and disability following cardiac arrest (CA). Nicotinamide adenine dinucleotide (NAD+) depletion after CA contributes to neuronal injury, while nicotinamide mononucleotide (NMN) replenishes NAD+ and may provide neuroprotection via sirtuin activation. This study aimed to investigate the effects of systemic NMN administration on neurological function, survival, and sirtuin-3 (SIRT3) levels in the brain post-CA. In adult male mice (C57BL/6NCrSlc, 10–15 weeks old), 10-min CA was induced by intravenous potassium chloride injection followed by cardiopulmonary resuscitation. NMN (60 mg/ kg body weight) or normal saline (control) was randomly administered by intraperitoneal injection immediately after the return of spontaneous circulation (ROSC) and 24 and 48 h post-CA. Brain NAD+ and adenosine triphosphate (ATP) levels, neurological function score (NFS), survival, histological neuronal injury, and brain gene expression and protein levels were measured. Brain NAD+ levels decreased at 2 h post-ROSC and NMN significantly increased brain NAD+ and ATP levels. At 48 h post-CA, surviving mice in the NMN group exhibited significantly higher NFS (control: 8 [IQR: 4–12] vs. NMN: 12 [IQR: 9–12], p = 0.03) and less severe hippocampal neuronal injury compared with controls. Moreover, the NMN group showed significantly higher 7-day survival rate (control: 22.2% [4/18] vs. NMN: 61.1% [11/18], p = 0.03) and brain SIRT3 levels (control: 17.7 ± 3.6 vs. NMN: 34.5 ± 4.4 pg/mg protein, p = 0.01). In conclusion, systemic NMN administration after ROSC attenuates PCABI. The increased brain ATP levels and SIRT3 upregulation may suggest the usefulness of NMN for improving mitochondrial function and contributing to neuroprotection. NAD+ supplementation with NMN is a promising therapeutic approach against PCABI.