Abstract Body: Background: Nicotinamide adenine dinucleotide (NAD+) depletion after cardiac arrest (CA) contributes to neuronal injury. Systemic administration of nicotinamide mononucleotide (NMN) following CA restores brain NAD+ and alleviates post-CA brain injury (PCABI) in mice. However, the mechanisms by which NMN contributes to the alleviation of PCABI remain elusive.

Hypothesis: NMN restores mitochondrial metabolism and activates Sirtuin-3 (SIRT3), a key regulator of mitochondrial function and neuroinflammation, after CA.

Aims: This study aimed to investigate brain ATP, SIRT3, and neuroinflammation following systemic administration of NMN after CA.

Methods: A murine model of CA was used. Mice received intraperitoneal NMN (60 mg/kg) (NMN group) or saline (control group) immediately after the return of spontaneous circulation, with additional doses at 24 and 48 h after CA. Brain tissue was harvested at 2 and 6 h after CA, and brain NAD+, ATP, SIRT3, and IL-6 were analyzed.

Results: Brain NAD+ levels decreased 2 h post-CA (sham 169.7 ± 4.3 vs. control 91.0 ± 8.7 pmol/mg tissue, p < 0.001), whereas NMN significantly increased brain NAD+ levels compared to the control group (231.2 ± 11.8 pmol/mg tissue, p < 0.001). NMN significantly increased brain ATP levels 2 h post-CA compared to the control group (control 203.6 ± 28.4 vs. NMN 287.0 ± 21.9 nmol/g tissue, p = 0.048). Moreover, NMN increased brain SIRT3 (control 17.7 ± 3.6 vs. NMN 34.5 ± 4.4 pg/mg tissue, difference 16.8 [95% CI, 4.1 to 29.6], p = 0.01). NMN downregulated the hippocampal Il6 expression (relative expression: control 1.0 ± 0.2 vs. NMN 0.4 ± 0.1, difference -0.6 [95% CI, -1.1 to -0.03], p = 0.04) 6 h post-CA. IL-6 protein level showed a trend toward a decrease in the brain with NMN (control 0.95 [IQR 0.74–1.37] vs. NMN 0.56 [IQR 0.46–1.28] pg/mg tissue, p = 0.24).

Conclusions: Post-CA systemic administration of NMN replenishes brain NAD+ and preserves mitochondrial function at least in part through SIRT3 enhancement and reduced inflammation. NMN is a simple yet attractive approach for improving outcomes after CA.