Gong Hongyan, Zheng Fang, Niu Bochao, Wang Bin, Xu Lin, Yang Yunchao, Wang Jiahan, Tang Xiaopeng, Bi Yanlin
MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China.
Department of Anesthesiology, Qingdao Municipal Hospital, Qingdao Hospital of Health and Rehabilitation Sciences University, Qingdao, China.
CNS Neurosci Ther. 2025 May;31(5):e70439. doi: 10.1111/cns.70439.
Ferroptosis plays a critical role in stroke pathophysiology, yet its dynamics during recovery remain unclear. This study aimed to investigate the evolution of ferroptosis throughout post-stroke recovery and evaluate auricular transcutaneous vagus nerve stimulation (atVNS) as a therapeutic intervention, focusing on the involvement of α7 nicotinic acetylcholine receptor (α7nAChR)-mediated mechanisms.
Using a middle cerebral artery occlusion (MCAO) mouse model, we examined ferroptosis-related protein expression (GPX4, ACSL4, TfR) and iron levels across acute to chronic recovery phases. The therapeutic effects of atVNS were evaluated through the assessment of ferroptosis markers, neurogenesis, angiogenesis, cognitive function, and neuroinflammation. α7nAChR knockout mice were used to investigate the receptor's role in atVNS-mediated recovery.
We observed sustained alterations in ferroptosis markers and iron levels throughout post-stroke recovery. atVNS treatment reduced ferroptosis progression by modulating GPX4 and ACSL4 expression, enhanced neurogenesis and angiogenesis, improved cognitive recovery, and reduced neuroinflammation. These beneficial effects were absent in α7nAChR knockout mice, while atVNS increased neuronal α7nAChR expression in wild-type mice.
This study reveals the persistent involvement of ferroptosis in stroke recovery and demonstrates that atVNS provides comprehensive neuroprotection through α7nAChR-dependent mechanisms. These findings establish atVNS as a promising noninvasive therapeutic approach for stroke recovery and highlight α7nAChR signaling as a potential therapeutic target.
铁死亡在中风病理生理学中起关键作用，但其在恢复过程中的动态变化仍不清楚。本研究旨在探讨中风后恢复过程中铁死亡的演变，并评估耳经皮迷走神经刺激（atVNS）作为一种治疗干预措施，重点关注α7烟碱型乙酰胆碱受体（α7nAChR）介导的机制的参与情况。
使用大脑中动脉闭塞（MCAO）小鼠模型，我们检测了从急性到慢性恢复阶段铁死亡相关蛋白表达（GPX4、ACSL4、TfR）和铁水平。通过评估铁死亡标志物、神经发生、血管生成、认知功能和神经炎症来评估atVNS的治疗效果。使用α7nAChR基因敲除小鼠来研究该受体在atVNS介导的恢复中的作用。
我们观察到中风后恢复过程中铁死亡标志物和铁水平持续变化。atVNS治疗通过调节GPX4和ACSL4表达减少了铁死亡进展，增强了神经发生和血管生成，改善了认知恢复，并减轻了神经炎症。这些有益效果在α7nAChR基因敲除小鼠中不存在，而atVNS增加了野生型小鼠中神经元α7nAChR的表达。
本研究揭示了铁死亡在中风恢复中的持续参与，并表明atVNS通过α7nAChR依赖的机制提供全面的神经保护。这些发现确立了atVNS作为一种有前景的中风恢复无创治疗方法，并突出了α7nAChR信号作为潜在治疗靶点的重要性。
