Li Shi-Ting, Pan Jing, Hua Xu-Ming, Liu Hong, Shen Sa, Liu Jia-Fu, Li Bin, Tao Bang-Bao, Ge Xiao-Li, Wang Xu-Hui, Shi Juan-Hong, Wang Xiao-Qiang
Department of Neurosurgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
CNS Neurosci Ther. 2014 Feb;20(2):154-64. doi: 10.1111/cns.12182. Epub 2014 Jan 8.
Several lines of evidence demonstrated that endothelial nitric oxide synthase (eNOS) confers protective effects during cerebral ischemia. In this study, we explored the underlying cellular and molecular mechanisms of neuroprotection by eNOS.
A series of in vivo and in vitro ischemic models were employed to study the role of eNOS in maintaining neuronal survival and to identify the downstream factors.
The current data showed that pretreatment with a specific eNOS inhibitor, L-N5-(1-iminoethyl) ornithine (L-NIO), aggravated the neuronal loss in the rat cerebral ischemic model, accompanied by reduction in brain-derived neurotrophic factor (BDNF) level, which was consistent with the findings in an oxygen-glucose deprivation model (OGD) with two neuronal cells: primary rat cortical neurons and human neuroblastoma SH-SY5Y cells. Furthermore, the extensive neuronal loss induced by L-NIO was totally abolished by exogenous BDNF in both in vitro and in vivo models. On the other hand, eNOS overexpression through an adenoviral vector exerted a prominent protective effect on the neuronal cells subject to OGD, and the protective effect was totally abrogated by a neutralizing anti-BDNF antibody.
Collectively, our results indicate that the neuroprotection of neuron-derived eNOS against the cerebral ischemia was mediated through the regulation of BDNF secretion. In conclusion, our discovery provides a novel explanation for the neuroprotective effect of eNOS under pathological ischemic conditions such as stroke.
多项证据表明，内皮型一氧化氮合酶（eNOS）在脑缺血期间具有保护作用。在本研究中，我们探讨了eNOS发挥神经保护作用的潜在细胞和分子机制。
采用一系列体内和体外缺血模型来研究eNOS在维持神经元存活中的作用，并确定其下游因子。
目前的数据表明，用特异性eNOS抑制剂L-N5-（1-亚氨基乙基）鸟氨酸（L-NIO）预处理会加重大鼠脑缺血模型中的神经元损失，同时脑源性神经营养因子（BDNF）水平降低，这与在原代大鼠皮质神经元和人神经母细胞瘤SH-SY5Y细胞这两种神经元细胞的氧糖剥夺模型（OGD）中的发现一致。此外，在体外和体内模型中，外源性BDNF完全消除了L-NIO诱导的广泛神经元损失。另一方面，通过腺病毒载体过表达eNOS对遭受OGD的神经元细胞发挥了显著的保护作用，而这种保护作用被一种中和抗BDNF抗体完全消除。
总体而言，我们的结果表明，神经元源性eNOS对脑缺血的神经保护作用是通过调节BDNF分泌介导的。总之，我们的发现为eNOS在中风等病理性缺血条件下的神经保护作用提供了一种新的解释。
