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

• Published in: ASN neuro 2023-01, Vol.15 (1), p.17590914231198983-17590914231198983
• Main Authors: Kawamura, Takuya, Singh Mallah, Gagandeep, Ardalan, Maryam, Chumak, Tetyana, Svedin, Pernilla, Jonsson, Lina, Jabbari Shiadeh, Seyedeh Marziyeh, Goretta, Fanny, Ikeda, Tomoaki, Hagberg, Henrik, Sandberg, Mats, Mallard, Carina
• Format: Article
• Language: English
• Subjects: alarmins; Animal models; Brain damage; Brain injury; Caspase-3; damage; disruption; expression; High mobility group proteins; Hippocampus; hmgb1; HMGB1 protein; hypothermia; Hypoxia; hypoxic-ischemic encephalopathy; infant; Ischemia; localization; mediator; Mobility; mobility group box-1; NAD; nad(+) metabolism; Neonates; Neuroprotection; Neurosciences; Neurosciences & Neurology; Neurovetenskaper; Newborn babies; nicotinamide adenine dinucleotide; Original Papers; protein sir2; SIRT1 protein; sirtuins; therapy; Traumatic brain injury
• ISSN: 1759-0914; 1759-0914
• DOI: 10.1177/17590914231198983

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 Statement Neonatal 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 Abstract This is a visual representation of the abstract.