Zhao Bing, Zhang Meng, Han Xue, Zhang Xia-Yan, Xing Qiong, Dong Xu, Shi Qiao-Juan, Huang Peng, Lu Yun-Bi, Wei Er-Qing, Xia Qiang, Zhang Wei-Ping, Tang Chun
Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China ; Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China.
PLoS One. 2013 Dec 31;8(12):e85403. doi: 10.1371/journal.pone.0085403. eCollection 2013.
Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) in neuron has been known as a protective factor against cerebral ischemia through its enzymatic activity, but the role of central extracellular NAMPT (eNAMPT) is not clear. Here we show that eNAMPT protein level was elevated in the ischemic rat brain after middle-cerebral-artery occlusion (MCAO) and reperfusion, which can be traced to at least in part from blood circulation. Administration of recombinant NAMPT protein exacerbated MCAO-induced neuronal injury in rat brain, while exacerbated oxygen-glucose-deprivation (OGD) induced neuronal injury only in neuron-glial mixed culture, but not in neuron culture. In the mixed culture, NAMPT protein promoted TNF-α release in a time- and concentration-dependent fashion, while TNF-α neutralizing antibody protected OGD-induced, NAMPT-enhanced neuronal injury. Importantly, H247A mutant of NAMPT with essentially no enzymatic activity exerted similar effects on ischemic neuronal injury and TNF-α release as the wild type protein. Thus, eNAMPT is an injurious and inflammatory factor in cerebral ischemia and aggravates ischemic neuronal injury by triggering TNF-α release from glia cells, via a mechanism not related to NAMPT enzymatic activity.
神经元中的细胞内烟酰胺磷酸核糖转移酶（iNAMPT）通过其酶活性被认为是一种对抗脑缺血的保护因子，但中枢细胞外烟酰胺磷酸核糖转移酶（eNAMPT）的作用尚不清楚。在此我们表明，大脑中动脉闭塞（MCAO）和再灌注后，缺血大鼠脑中的eNAMPT蛋白水平升高，这至少部分可追溯到血液循环。给予重组NAMPT蛋白会加重MCAO诱导的大鼠脑神经元损伤，而仅在神经元 - 胶质细胞混合培养中加重氧 - 葡萄糖剥夺（OGD）诱导的神经元损伤，在神经元培养中则不然。在混合培养中，NAMPT蛋白以时间和浓度依赖性方式促进TNF-α释放，而TNF-α中和抗体可保护OGD诱导的、NAMPT增强的神经元损伤。重要的是，基本上没有酶活性的NAMPT的H247A突变体对缺血性神经元损伤和TNF-α释放的影响与野生型蛋白相似。因此，eNAMPT是脑缺血中的一种有害和炎症因子，通过触发胶质细胞释放TNF-α，经由一种与NAMPT酶活性无关的机制加重缺血性神经元损伤。
