Liang Jia, Wang Peng, Wei Jia, Bao Cuifen, Han Donghe
Key Laboratory of Molecular Cell Biology and New Drug Development, Liaoning Medical University, Jinzhou, 121001, People's Republic of China.
Neurochem Res. 2015 Jun;40(6):1102-10. doi: 10.1007/s11064-015-1569-2. Epub 2015 Apr 5.
Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) is a nicotinamide adenine dinucleotide biosynthetic enzyme. It has been shown to be neuroprotective against neonatal excitotoxicity-induced brain injury, but its role in ischemic stroke is unclear. In this study, the role of NMNAT1 in oxygen-glucose deprivation (OGD)-induced primary cultured neuronal cell injury and mouse middle cerebral artery occlusion-induced cerebral ischemic injury and its regulation on AMP-activated protein kinase (AMPK) activation were evaluated. The results showed that NMNAT1 overexpression reduced cell death and apoptosis both in vitro and in vivo. Conversely, NMNAT1 knockdown exacerbated cell death and apoptosis. Furthermore, NMNAT1 overexpression regulated neuron survival via AMPK activation, as NMNAT1 overexpression enhanced AMPK activity in OGD-treated cortical neurons, and AMPK inhibitor blocked LV-NMNAT1-induced neuroprotection in OGD-treated cortical neurons. In addition, NMNAT1 overexpression could reduce brain infarction size and improve behavioral outcomes in mice with ischemic stroke. These results suggested that up-regulation of NMNAT1 could induce neuroprotection against ischemic injury through AMPK activation and indicated that NMNAT1 is a potential therapeutic target for stroke.
烟酰胺单核苷酸腺苷酸转移酶1（NMNAT1）是一种烟酰胺腺嘌呤二核苷酸生物合成酶。已证明它对新生儿兴奋性毒性诱导的脑损伤具有神经保护作用，但其在缺血性卒中中的作用尚不清楚。在本研究中，评估了NMNAT1在氧糖剥夺（OGD）诱导的原代培养神经元细胞损伤和小鼠大脑中动脉闭塞诱导的脑缺血损伤中的作用及其对AMP激活蛋白激酶（AMPK）激活的调节。结果表明，NMNAT1过表达在体外和体内均减少了细胞死亡和凋亡。相反，NMNAT1敲低加剧了细胞死亡和凋亡。此外，NMNAT1过表达通过激活AMPK调节神经元存活，因为NMNAT1过表达增强了OGD处理的皮质神经元中的AMPK活性，并且AMPK抑制剂阻断了LV-NMNAT1诱导的OGD处理的皮质神经元中的神经保护作用。此外，NMNAT1过表达可减少缺血性卒中小鼠的脑梗死面积并改善行为结果。这些结果表明，NMNAT1的上调可通过激活AMPK诱导对缺血性损伤的神经保护作用，并表明NMNAT1是卒中的潜在治疗靶点。
