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

被引:7
作者
Kawamura, Takuya [1 ,2 ]
Mallah, Gagandeep Singh [1 ]
Ardalan, Maryam [1 ]
Chumak, Tetyana [1 ]
Svedin, Pernilla [1 ]
Jonsson, Lina [1 ]
Shiadeh, Seyedeh Marziyeh Jabbari [1 ]
Goretta, Fanny [1 ]
Ikeda, Tomoaki [2 ]
Hagberg, Henrik [3 ]
Sandberg, Mats [4 ]
Mallard, Carina [1 ,5 ]
机构
[1] Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Ctr Perinatal Med & Hlth, Gothenburg, Sweden
[2] Mie Univ, Dept Obstet & Gynecol, Tsu, Japan
[3] Inst Clin Sci, Ctr Perinatal Med & Hlth, Gothenburg, Sweden
[4] Univ Gothenburg, Inst Biomed, Sahlgrenska Acad, Gothenburg, Sweden
[5] Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Box 432, S-40530 Gothenburg, Sweden
关键词
sirtuins; alarmins; infant; therapy; hypoxic-ischemic encephalopathy; nicotinamide adenine dinucleotide; MOBILITY GROUP BOX-1; NAD(+) METABOLISM; PROTEIN SIR2; HMGB1; DAMAGE; LOCALIZATION; HYPOTHERMIA; DISRUPTION; EXPRESSION; MEDIATOR;
D O I
10.1177/17590914231198983
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
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页数:17
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