Ren Bingkai, Kang Junwei, Dong Xiaoyang, Huang Lianghua, Wu Xiao, Tang Yunliang
Department of Rehabilitation, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
First Department of Rehabilitation Medicine, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China.
Neurocrit Care. 2025 Sep 4. doi: 10.1007/s12028-025-02351-9.
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.
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.
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.
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.
创伤性脑损伤（TBI）是一种严重威胁生命的事件。除神经功能缺损外，它还可导致认知功能的长期损害。迷走神经（VN）在中枢神经系统和外周之间提供了一条直接的通信通道，通过电刺激迷走神经（VNS）调节炎症反射在改善神经退行性疾病的病理方面显示出疗效。我们的目的是研究VNS对TBI大鼠模型认知障碍的影响及其潜在机制。
在控制性皮质撞击前1周，将雄性大鼠的左侧VN植入VNS电极。线粒体通透性转换孔阻滞剂环孢素A（CsA）和干扰素基因刺激剂（STING）激动剂2'3'-cGAMP通过鼻内给药或脑室内注射给予。VNS后的评估包括莫里斯水迷宫、尼氏染色、苏木精-伊红染色、蛋白质免疫印迹法、定量聚合酶链反应、线粒体膜电位和酶联免疫吸附测定。
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，减少了胞质线粒体DNA的积累，减弱了环状GMP-AMP合酶（cGAS）-STING途径，抑制了含核苷酸结合域、富含亮氨酸重复序列家族、含pyrin结构域3（NLRP3）炎性小体的激活，并部分逆转了TBI引起的海马神经元损伤和丢失。然而，给予2'3'-cGAMP显著消除了VNS的这些作用。此外，CsA也显示出神经保护作用，包括改善认知障碍、降低cGAS、磷酸化STING的水平，并抑制NLRP3炎性小体和包含裂解的半胱天冬酶-1、凋亡相关斑点样蛋白（ASC）和N端gasdermin D的焦亡相关成分的表达。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。
刺激VN通过调节线粒体DNA/cGAS/STING/NLRP3途径减轻TBI模型大鼠的焦亡和神经炎症级联反应。
