期刊
MOLECULAR NEUROBIOLOGY
卷 59, 期 8, 页码 4879-4891出版社
SPRINGER
DOI: 10.1007/s12035-022-02903-6
关键词
Ischemic stroke; BBB; NMNAT1; NAD(+); SIRT1
资金
- National Natural Science Foundation of China [81971231]
- Scientific Research Project from the Educational Department of Liaoning Province [JYTQN2020011]
- Natural Science Foundation of Liaoning Province [201602319]
This study investigates the potential role of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) in blood-brain barrier (BBB) damage after ischemic stroke. The results suggest that recombinant human NMNAT1 (rh-NMNAT1) can reduce infarct volume, improve functional outcome, and decrease BBB permeability. The protective effects of rh-NMNAT1 may be mediated through the regulation of nicotinamide adenine dinucleotide (NAD(+))/NADH ratio and Sirtuin 1 (SIRT1) level. Rh-NMNAT1 treatment can also decrease the levels of acetylated nuclear factor-kappa B, acetylated p53, and matrix metalloproteinase-9 in ischemic microvessels. The findings indicate that NMNAT1 may be a potential therapeutic target for reducing BBB disruption after ischemic stroke.
The molecular mechanisms of blood-brain barrier (BBB) disruption in the early stage after ischemic stroke are poorly understood. In the present study, we investigated the potential role of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) in ischemia-induced BBB damage using an animal middle cerebral artery occlusion (MCAO) model of ischemic stroke. Recombinant human NMNAT1 (rh-NMNAT1) was administered intranasally and Sirtuin 1 (SIRT1) siRNA was administered by intracerebroventricular injection. Our results indicate that rh-NMNAT1 reduced infarct volume, improved functional outcome, and decreased BBB permeability in mice after ischemic stroke. Furthermore, rh-NMNAT1 prevented the loss of tight junction proteins (occludin and claudin-5) and reduced cell apoptosis in ischemic microvessels. NMNAT1-mediated BBB permeability was correlated with the elevation of nicotinamide adenine dinucleotide (NAD(+))/NADH ratio and SIRT1 level in brain microvascular endothelial cells. In addition, rh-NMNAT1 treatment significantly decreased the levels of acetylated nuclear factor-kappa B, acetylated p53, and matrix metalloproteinase-9 in ischemic microvessels. Moreover, the protective effects of rh-NMNAT1 could be reversed by SIRT1 siRNA. In conclusion, these findings indicate that rh-NMNAT1 protects BBB integrity after cerebral ischemia via the NAD(+)/SIRT1 signaling pathway in brain microvascular endothelial cells. NMNAT1 may be a novel potential therapeutic target for reducing BBB disruption after ischemic stroke.
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