南京医科大学第一附属医院Ming Lu，Xiao Lu和南京医科大学Lei Cao合作，近期取得重要工作进展。他们研究提出，迷走神经刺激通过小胶质细胞NLRP3炎症小体α7nAchR依赖性失活作为缺血性卒中一种有前景的神经保护作用。相关研究成果2024年3月19日在线发表于《药理学报》杂志上。

据介绍，缺血性脑卒中是世界范围内致残和死亡的主要因素，其治疗需要迫切关注。先前的研究表明，迷走神经刺激（VNS）通过抑制神经炎症和细胞凋亡来对缺血性中风发挥神经保护作用。

研究人员评估了VNS干预缺血性卒中的时机，以及VNS诱导的神经保护的潜在机制。小鼠接受短暂性大脑中动脉闭塞（tMCAO）60分钟。暴露颈椎水平的左侧迷走神经，并将其连接到与低频电刺激器相连的电极上。在tMCAO前、中、后分别给予VNS 60分钟(Pre-VNS, Dur-VNS, Post-VNS)。再灌注后24小时评估神经功能。研究人员发现，所有三种VNS都能显著防止tMCAO诱导的损伤，这可以通过改善神经功能和减少梗死体积来证明。

此外，Pre-VNS对缺血性损伤最为有效。研究人员发现tMCAO激活了大脑缺血核心和半影区域的小胶质细胞，随后NLRP3炎症小体激活诱导了神经炎症，最终引发了神经元死亡。VNS治疗保留了半影区α7nAChR的表达，抑制了NLRP3炎症小体的激活和随后的神经炎症，挽救了大脑神经元。使用基因操作，包括Chrna7敲除小鼠和小胶质细胞Chrna7过表达小鼠，以及使用α7nAChR抑制剂甲基亚乌头碱和激动剂PNU-282987的药物干预，进一步验证了α7nAChR在缺血性卒中小胶质细胞NLRP3炎症小体激活中的作用。

总之，这项研究证明了VNS作为一种安全有效的缺血性卒中治疗策略的潜力，并提出了一种靶向小胶质细胞NLRP3炎症小体的新方法，该方法可用于治疗其它炎症相关疾病。

附：英文原文

Title: Vagus nerve stimulation as a promising neuroprotection for ischemic stroke via α7nAchR-dependent inactivation of microglial NLRP3 inflammasome

Author: Xia, Xiao-mei, Duan, Yu, Wang, Yue-ping, Han, Rui-xue, Dong, Yin-feng, Jiang, Si-yuan, Zheng, Yu, Qiao, Chen, Cao, Lei, Lu, Xiao, Lu, Ming

Issue&Volume: 2024-03-19

Abstract: Ischemic stroke is a major cause of disability and death worldwide, and its management requires urgent attention. Previous studies have shown that vagus nerve stimulation (VNS) exerts neuroprotection in ischemic stroke by inhibiting neuroinflammation and apoptosis. In this study, we evaluated the timing for VNS intervention in ischemic stroke, and the underlying mechanisms  of VNS-induced neuroprotection. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60min. The left vagus nerve at cervical level was exposed and attached to an electrode connected to a low-frequency electrical stimulator. Vagus nerve stimulation (VNS) was given for 60min before, during and after tMCAO (Pre-VNS, Dur-VNS, Post-VNS). Neurological function was assessed 24h after reperfusion. We found that all the three VNS significantly protected against the tMCAO-induced injury evidenced by improved neurological function and reduced infarct volume. Moreover, the Pre-VNS was the most effective against the ischemic injury. We found that tMCAO activated microglia in the ischemic core and penumbra regions of the brain, followed by the NLRP3 inflammasome activation-induced neuroinflammation, which finally triggered neuronal death. VNS treatment preserved α7nAChR expression in the penumbra regions, inhibited NLRP3 inflammasome activation and ensuing neuroinflammation, rescuing cerebral neurons. The role of α7nAChR in microglial NLRP3 inflammasome activation in ischemic stroke was further validated using genetic manipulations, including Chrna7 knockout mice and microglial Chrna7 overexpression mice, as well as pharmacological interventions using the α7nAChR inhibitor methyllycaconitine and agonist PNU-282987. Collectively, this study demonstrates the potential of VNS as a safe and effective strategy to treat ischemic stroke, and presents a new approach targeting microglial NLRP3 inflammasome, which might be therapeutic for other inflammation-related diseases.

DOI: 10.1038/s41401-024-01245-4

Source: https://www.nature.com/articles/s41401-024-01245-4