Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
CNS Neurosci Ther. 2012 Nov;18(11):918-26. doi: 10.1111/cns.12011.
Decreased baroreflex sensitivity is associated with poor outcome in many cardiovascular diseases including stroke, but the molecular mechanism underlying this relationship is unclear. This work was designed to test the hypothesis that acetylcholine (ACh) and α7 nicotinic ACh receptor (α7nAChR) mediate the protection of arterial baroreflex against stroke.
Sinoaortic denervation (SAD) was used to impair the function of arterial baroreflex, and anticholinesterase agents were used to activate the cholinergic system and increase endogenous ACh. Middle cerebral artery occlusion (MCAO) was performed in the α7nAChR knockout (KO) mice and Sprague-Dawley rats.
We found decreased expression of vesicular ACh transporter (VAChT) and α7nAChR in rat brain after SAD. In rats subjected to MCAO, neostigmine significantly reduced the infarct size. The protective effects of neostigmine were abolished by selective nAChR antagonist vecuronium but not by mAChR antagonist anisodamine. In addition, the effect of neostigmine disappeared in α7nAChR KO mice. In cultured neurons, ACh inhibited cell death induced by H(2) O(2) . In cultured microglial cells, ACh decreased the release of proinflammatory cytokines induced by lipopolysaccharide. These in vitro effects were blocked by selective α7nAChR antagonists.
Taken together, these findings indicate that the ACh-α7nAChR involved in the protective effects of arterial baroreflex against ischemic stroke.
在包括中风在内的许多心血管疾病中，血压反射敏感性降低与预后不良相关，但这种关系的分子机制尚不清楚。本研究旨在验证以下假说，即乙酰胆碱（ACh）和α7 烟碱型乙酰胆碱受体（α7nAChR）介导了动脉血压反射对中风的保护作用。
通过主动脉弓神经切除术（SAD）损害动脉血压反射功能，使用抗胆碱酯酶药物激活胆碱能系统并增加内源性 ACh。在α7nAChR 基因敲除（KO）小鼠和 Sprague-Dawley 大鼠中进行大脑中动脉闭塞（MCAO）。
我们发现 SAD 后大鼠大脑中囊泡 ACh 转运体（VAChT）和 α7nAChR 的表达减少。在 MCAO 大鼠中，新斯的明显著减少梗死面积。新斯的明的保护作用被选择性 nAChR 拮抗剂维库溴铵而非 mAChR 拮抗剂山莨菪碱所阻断。此外，新斯的明的作用在 α7nAChR KO 小鼠中消失。在培养的神经元中，ACh 抑制 H2O2 诱导的细胞死亡。在培养的小胶质细胞中，ACh 减少脂多糖诱导的促炎细胞因子释放。这些体外作用被选择性的 α7nAChR 拮抗剂阻断。
综上所述，这些发现表明，ACh-α7nAChR 参与了动脉血压反射对缺血性中风的保护作用。
