迷走神经刺激通过调控M1/M2小胶质细胞极化减轻神经炎症改善癫痫大鼠认知功能

doi:10.13418/j.issn.1001-165x.2023.5.09

中国临床解剖学杂志 ›› 2023, Vol. 41 ›› Issue (5): 550-556.doi: 10.13418/j.issn.1001-165x.2023.5.09

迷走神经刺激通过调控M1/M2小胶质细胞极化减轻神经炎症改善癫痫大鼠认知功能

李永格¹，　周舒^1，2，　刘庆春¹，　未小明¹，　张冬¹，　马凤巧¹

1.河南省南阳市南阳医学高等专科学校基础医学部, 南阳 473000； 2.云南省昆明市昆明医科大学
生物医学工程研究中心, 昆明 650000

收稿日期:2023-02-01 出版日期:2023-09-25 发布日期:2023-10-16
作者简介:李永格（1981-），男，湖北汉川人，副教授，研究方向：癫痫发生机制及治疗，E-mail：liyongge19810719@aliyun.com
基金资助:
河南省科技攻关项目（212102310837）；河南省高校青年骨干教师项目（2018GGJS253）；南阳市基础与前沿项目（JCQY026）

Vagus nerve stimulation reduces neuroinflammation through microglia M1/M2 polarization regulation to improve cognitive function of epileptic rats

Li Yongge¹, Zhou Shu^{1, 2}, Liu QingChun¹, Wei Xiaoming¹, Zhang Dong¹, Ma Fengqiao¹

1. Department of Basic Medicine, Nanyang Medical College, Nanyang 473000, Henan Province, China; 2. Biomedical Engineering Research Center, Kunming Medical University, Kunming 650000, Yunnan Province, China

Received:2023-02-01 Online:2023-09-25 Published:2023-10-16

摘要/Abstract

摘要： 目的　探讨迷走神经刺激（VNS）对难治性癫痫大鼠认知功能的影响及可能机制。方法　通过腹腔注射氯化锂-皮罗卡品建立难治性癫痫大鼠模型。模型制作成功大鼠随机分为模型组（18只）与VNS组（15只），另外设对照组（20只）。对照组与模型组只分离迷走神经并植入刺激器，但不给予刺激；VNS组采取连续4周迷走神经电刺激。观察大鼠癫痫发作情况；Morris水迷宫实验检测大鼠认知功能；Nissl染色观察大鼠海马组织病理形态；ELISA检测大鼠海马组织TNF-ɑ、IL-6和IL-10表达；免疫荧光染色法与Western-blot分别检测大鼠海马组织M1型小胶质细胞标记物（iNOS）和M2型小胶质细胞标记物（Arg1）相对表达。结果 ①与对照组相比，模型组大鼠癫痫发作等级及发作持续时间明显增加（P<0.05）；通过VNS连续干预4周后，大鼠癫痫发作等级及发作持续时间明显降低（P<0.05）。②模型组大鼠逃避潜伏期时间明显长于对照组，而穿越原平台的次数明显少于对照组（P<0.05）；通过VNS连续干预4周后，癫痫大鼠逃避潜伏期时间明显缩短，而穿越原平台的次数明显增加（P<0.05）。③对照组大鼠海马神经元形态正常；模型组大鼠海马神经元损伤严重，数量明显减少（P<0.05）；VNS组大鼠海马神经元损伤相比模型组明显减轻，数量明显增加（P<0.05）。④模型组大鼠海马组织TNF-ɑ、IL-6相对表达明显高于对照组，而IL-10相对表达明显降低（P<0.05）；通过VNS连续干预4周后，癫痫大鼠海马组织TNF-ɑ、IL-6相对表达明显降低，而IL-10相对表达明显增加（P<0.05）。⑤与对照组相比，模型组大鼠海马组织iNOS相对表达明显增加，而Arg1相对表达明显减少（P<0.05）；与模型组相比，VNS组大鼠海马组织iNOS相对表达明显减少，而Arg1相对表达明显增加（P<0.05）。结论 VNS具有改善难治性癫痫大鼠认知功能障碍的作用，其机制可能是通过促进M2型小胶质细胞极化，减轻中枢炎性反应，保护海马神经元。

关键词: , 迷走神经刺激；　难治性癫痫；　M1/M2型小胶质细胞；　认知功能

Abstract: Objective To explore the effect of vagus nerve stimulation (VNS) on cognitive function in rats with intractable epilepsy and its possible mechanism. Methods The intractable epilepsy rat model was established by intraperitoneal injection of lithium chloride pilocarpine. The rats were randomly divided into a model group (18 rats), a VNS group (15 rats) and a control group (20 rats). The vagus nerve was separated and the stimulator was implanted, but no stimulation for the rats in the control group and model group, while the rats in the VNS group underwent vagus nerve stimulation for 4 weeks. The seizure of rats was detected. Morris water mate test was used to detect the cognitive function of rats. The pathological morphology of hippocampus was observed by Nissl staining. The expression levels of TNF-ɑ, IL-6 and IL-10 in the hippocampus were detected by ELISA. The relative expressions of iNOS, Arg1 were detected by immunofluorescence staining and Western blot, respectively. Results ①The seizure grade and duration were significantly higher in the model group than those in the control group (P<0.05). After continuous intervention with VNS for 4 weeks, the seizure grade and duration in the model group were significantly decreased (P<0.05). ②The escape latency time of rats in the model group was significantly longer than that in the control group, and the times of crossing platform was significantly less than that in the control group (P<0.05). After continuous intervention with VNS for 4 weeks, the escape latency time of epileptic rats was significantly reduced, and the times of crossing platform increased (P<0.05). ③The morphology of hippocampal neurons was normal in the control group. The hippocampal neurons in the model group were severely damaged, and the number of neurons was decreased (P<0.05). Compared with the model group, the damage of hippocampal neurons in the VNS group was significantly reduced, and the number of neurons was increased (P<0.05). ④The relative expression of TNF-ɑ and IL-6 in the hippocampus of model group were significantly higher than those in the control group, the relative expression of IL-10 was significantly decreased (P<0.05). After continuous intervention with VNS for 4 weeks, the relative expression of TNF-ɑ and IL-6 in the hippocampus of epileptic rats were significantly decreased, the relative expression of IL-10 was significantly increased (P<0.05). ⑤ Compared with the control group, the relative expression of iNOS in the hippocampus of the model group was significantly increased , while the relative expression of Arg1 was decreased significantly(P<0.05). Compared with the model group, the relative expression of iNOS in the hippocampus of the VNS group was significantly decreased, while the relative expression of Arg1 was significantly increased (P<0.05). Conclusions VNS can significantly improve the cognitive dysfunction of rats with intractable epilepsy, and its mechanism may be through promoting the polarization of M2 microglia to reduce the inflammatory reaction of central nervous system, and protect hippocampal neurons.

Key words: Vagus nerve stimulation; , , Intractable epilepsy, 　M1/M2 microglia, 　Cognitive function

中图分类号:

R285.5

李永格, 周舒, 刘庆春, 未小明, 张冬, 马凤巧. 迷走神经刺激通过调控M1/M2小胶质细胞极化减轻神经炎症改善癫痫大鼠认知功能[J]. 中国临床解剖学杂志, 2023, 41(5): 550-556.

Li Yongge, Zhou Shu, Liu QingChun, Wei Xiaoming, Zhang Dong, Ma Fengqiao . Vagus nerve stimulation reduces neuroinflammation through microglia M1/M2 polarization regulation to improve cognitive function of epileptic rats[J]. Chinese Journal of Clinical Anatomy, 2023, 41(5): 550-556.

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迷走神经刺激通过调控M1/M2小胶质细胞极化减轻神经炎症改善癫痫大鼠认知功能

Vagus nerve stimulation reduces neuroinflammation through microglia M1/M2 polarization regulation to improve cognitive function of epileptic rats

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