Vagus Nerve Stimulation Attenuates Cognitive Impairment in Traumatic Brain Injury via the mtDNA/cGAS-STING/NLRP3 Inflammasome Axis.

IF 3.6 3区医学 Q2 CLINICAL NEUROLOGY

Neurocritical Care Pub Date : 2025-09-04 DOI:10.1007/s12028-025-02351-9

Bingkai Ren, Junwei Kang, Xiaoyang Dong, Lianghua Huang, Xiao Wu, Yunliang Tang

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Abstract

Background: Traumatic brain injury (TBI) is a major life-threatening event. In addition to neurological deficits, it can lead to long-term impairments of cognitive function. The vagus nerve (VN) provides a direct communication conduit between the central nervous system and the periphery, and modulation of the inflammatory reflex via electrical stimulation of the vagus nerve (VNS) shows efficacy in ameliorating pathology in neurodegenerative diseases. Our objective was to investigate the impact and underlying mechanism of VNS for cognitive impairment in a rat model of TBI.

Methods: Male rats were implanted with VNS electrodes on the left VN 1 week prior to controlled cortical impact. Mitochondrial permeability transition pore blocker cyclosporin A (CsA) and stimulator of interferon genes (STING) agonist 2'3'-cGAMP were delivered by intranasal administration or intraventricular injection. Post-VNS assessments included Morris water maze, Nissl staining, hematoxylin and eosin staining, Western blotting, quantitative polymerase chain reaction, mitochondrial membrane potential, and enzyme-linked immunosorbent assay.

Results: We found that VNS treatment significantly improved cognitive impairment, increased mitochondrial membrane potential, reduced accumulation of cytosolic mitochondrial DNA, attenuated cyclic GMP-AMP synthase (cGAS)-STING pathway, suppressed nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation, and partially reversed hippocampus neuronal damage and loss caused by TBI. However, 2'3'-cGAMP delivery significantly abrogated these effects of VNS. In addition, CsA also showed neuroprotective effects, including improved cognitive impairment, decreased levels of cGAS, phosphorylated STING, and suppressed the expressions of NLRP3 inflammasome and pyroptosis-pertinent components containing cleaved Caspase-1, ASC, and N-terminal Gasdermin D. CsA also inhibited interleukin-1β and interleukin-18 proinflammatory cytokine concentration.

Conclusions: Stimulation of the VN attenuates the pyroptosis and neuroinflammatory cascades in the rat of the TBI model by regulating the mitochondrial DNA/cGAS/STING /NLRP3 pathway.

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迷走神经刺激通过mtDNA/cGAS-STING/NLRP3炎症小体轴减轻外伤性脑损伤的认知障碍

背景：创伤性脑损伤（TBI）是危及生命的重大事件。除了神经功能缺陷外，它还会导致认知功能的长期损害。迷走神经（VN）是中枢神经系统和外周神经系统之间的直接交流通道，通过电刺激迷走神经（VNS）调节炎症反射在神经退行性疾病的病理改善中显示出有效的效果。我们的目的是研究VNS对脑外伤大鼠模型认知障碍的影响及其潜在机制。方法：在控制性皮质撞击前1周，在雄性大鼠的左下丘脑植入VNS电极。线粒体通透性过渡孔阻断剂环孢素A （CsA）和干扰素基因刺激剂（STING）激动剂2'3'-cGAMP分别经鼻或脑室注射给药。vns后评估包括Morris水迷宫、尼氏染色、苏木精和伊红染色、Western blotting、定量聚合酶链反应、线粒体膜电位和酶联免疫吸附测定。结果：我们发现VNS治疗显著改善了认知障碍，增加了线粒体膜电位，减少了细胞质线粒体DNA的积累，减弱了环GMP-AMP合成酶(cGAS)-STING途径，抑制了核苷酸结合结构域、富含亮氨酸的家族、含pyrin结构域-3 （NLRP3）炎性体的激活，部分逆转了脑损伤引起的海马神经元损伤和丢失。然而，2'3'-cGAMP递送显著消除了VNS的这些影响。此外，CsA还具有神经保护作用，包括改善认知障碍，降低cGAS水平，磷酸化STING，抑制NLRP3炎症小体和含有裂解Caspase-1， ASC和n端Gasdermin d的焦热相关成分的表达。CsA还抑制白细胞介素-1β和白细胞介素-18促炎细胞因子浓度。结论：VN刺激通过调节线粒体DNA/cGAS/STING /NLRP3通路减轻TBI模型大鼠的焦亡和神经炎症级联反应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neurocritical Care 医学-临床神经学

CiteScore

7.40

自引率

8.60%

发文量

221

审稿时长

4-8 weeks

期刊介绍： Neurocritical Care is a peer reviewed scientific publication whose major goal is to disseminate new knowledge on all aspects of acute neurological care. It is directed towards neurosurgeons, neuro-intensivists, neurologists, anesthesiologists, emergency physicians, and critical care nurses treating patients with urgent neurologic disorders. These are conditions that may potentially evolve rapidly and could need immediate medical or surgical intervention. Neurocritical Care provides a comprehensive overview of current developments in intensive care neurology, neurosurgery and neuroanesthesia and includes information about new therapeutic avenues and technological innovations. Neurocritical Care is the official journal of the Neurocritical Care Society.