Key Points
- Post-arrest NMN rapidly restored brain NAD⁺ levels
- ATP levels rose nearly 40% vs. controls
- Neurological scores were significantly improved at 48 hours
- Seven-day survival nearly tripled
- NMN reduced hippocampal neuronal damage and upregulated SIRT3
Methods
Thirty-six adult male mice (10–15 weeks) underwent 10 minutes of induced cardiac arrest followed by cardiopulmonary resuscitation (CPR). Mice were then randomly assigned to:
- Control group: Normal saline at 0, 24, and 48 hours after CPR
- NMN group: 60 mg/kg NMN at 0, 24, and 48 hours after CPR
Mice were tested for brain NAD+ and ATP levels, neurological function, 7-day survival, brain injury, and expression of SIRT3 and IL-6 genes.
NMN Rapidly Restores Brain NAD⁺ and Energy After Cardiac Arrest
Following resuscitation, NAD⁺ levels dropped sharply in control mice, falling nearly 50% within two hours. NMN reversed this decline within minutes.
"Systemic NMN administration successfully increased the NAD+ concentration in the brain at 15min post-ROSC… and 2h post-ROSC."
Examples:
- 15 min: Control 141.4 vs. NMN 185.6 pmol/mg
- 2 hours: Control 91.0 vs. NMN 231.2 pmol/mg
At 2 hours, NAD⁺ levels were more than 2× higher with NMN compared to control.
- Control: 91.0 pmol/mg
- NMN: 231.2 pmol/mg
ATP followed the same pattern. At 2 hours post-resuscitation, brain ATP levels were 40% higher in NMN-treated mice:
"NMN significantly increased the ATP levels in the brain 2h post-ROSC (control: 203.6 vs. NMN: 287.0 nmol/g)."
These findings show that NMN rapidly crosses the blood–brain barrier and restores both cellular NAD⁺ pools and mitochondrial ATP in the early recovery window. Research on NAD+ and brain health demonstrates that rapid restoration of NAD+ levels supports multiple neuroprotective pathways, including energy metabolism, DNA repair, and mitochondrial function—all critical for neuronal survival after ischemic injury.
Brain Recovery and Survival Outcomes Improved
Twenty-four hours post-arrest, the NMN group showed a trend toward better neurological performance. Notably, 44% of NMN treated mice recovered full neurological function compared to 17% of control.
"At 24h post-CA, surviving mice in the NMN group showed a trend toward improved NFS… Notably, NMN administration increased the number of mice without any neurological sequelae."
NMN also conferred a robust survival benefit. The 7-day survival rate reached 61% in the NMN group compared with 22% in controls.
"The 7-day survival rate was significantly higher in the NMN group… control: 22.2% vs. NMN: 61.1%."
These results suggest that NMN therapy enhanced both neurological outcomes and survival following cardiac arrest.
Reduced Neurological Injury
To assess neuroprotection, hippocampal neuron integrity was measured using Fluoro-Jade C (FJC) staining, which showed 60% less neuronal degeneration.
"NMN group showed a trend toward fewer FJC-positive areas following single NMN administration after ROSC."
By 48 hours, neuronal injury had worsened in controls, while NMN treatment markedly limited this progression.
"NMN attenuated the delayed neuronal injury at 48 h post-CA, as evidenced by a significant reduction in FJC-positive areas."
These findings match the improvements in neurological function and survival.
Activated SIRT3 and Anti-Inflammatory Shift
SIRT3, a key NAD⁺-dependent enzyme supporting mitochondrial repair, was significantly upregulated by NMN.
- Sirt3 mRNA increased by ~50% vs. controls (1.5 vs. 1.0).
- SIRT3 protein levels nearly doubled (34.5 vs. 17.7 pg/mg)
In parallel, NMN reduced inflammatory signaling:
"Moreover, NMN significantly downregulated relative IL-6 expression."
Together, these data show that NMN activates mitochondrial-protective SIRT3 pathways while suppressing IL-6–driven inflammation.
Conclusion
This study shows that NMN has strong protective effects in the brain immediately after cardiac arrest.
"NMN administration post-ROSC increased NAD+ and ATP levels in the brain, improved neurological function and survival, and attenuated histological neuronal injury."
Because NMN works by replenishing NAD⁺ and activating SIRT3 pathways tied to mitochondrial health and inflammation, it may represent a promising therapy for post-CA brain injury. Research on NAD+ delivery methods for neuroprotection continues to explore optimal administration routes and timing for maximizing brain bioavailability, suggesting that targeted delivery strategies could further enhance the therapeutic potential demonstrated in this cardiac arrest model.
