Therapeutic Effect of Nicotinamide Mononucleotide for Hypoxic-Ischemic Brain Injury in Neonatal Mice

A clinical challenge remains in the treatment of hypoxic-ischemic brain injury in newborns. Nicotinamide adenine dinucleotide (NAD+) has beneficial effects in animal models of adult stroke. Here, we aimed to understand the short- and long-term neuroprotective effects of NAD+-promoting substance nicotinamide mononucleotide (NMN) in a well-established brain injury model in neonatal mice. Postnatal day (PND) 9 male and female mice were subjected to cerebral hypoxia-ischemia and treated with saline or NMN (50 mg/kg) immediately after hypoxia-ischemia. At different time points after hypoxia-ischemia, hippocampal NAD+, caspase-3 activity, protein expression of SIRT1, SIRT6, release of high mobility group box-1 (HMGB1), long-term neuropathological outcome, short-term developmental behavior, and long-term motor and memory function were evaluated. Neonatal hypoxia-ischemia reduced NAD+ and SIRT6 levels, but not SIRT1, in the injured hippocampus, while HMGB1 release was significantly increased. NMN treatment normalized hippocampal NAD+ and SIRT6 levels, while caspase-3 activity and HMGB1 release were significantly reduced. NMN alleviated tissue loss in the long-term and improved early developmental behavior, as well as motor and memory function. This study shows that NMN treatment provides neuroprotection in a clinically relevant neonatal animal model of hypoxia-ischemia in mice suggesting as a possible novel treatment for neonatal brain injury.Summary StatementNeonatal hypoxia-ischemia reduces nicotinamide adenine dinucleotide (NAD+) and SIRT6 levels in the injured hippocampus.Hippocampal high mobility group box-1 (HMGB1) release is significantly increased after neonatal hypoxia-ischemia.Nicotinamide mononucleotide (NMN) treatment normalizes hippocampal NAD+ and SIRT6 levels, with significant decrease in caspase-3 activity and HMGB1 release.NMN improves early developmental behavior, as well as motor and memory function. Graphical AbstractThis is a visual representation of the abstract.