Tang Hao, Wen Jun, Wang Ling, Yang Qinghuan, Qin Ting, Ren Yu, Zhao Yong, Li Changqing, Li Jiani, Cao Hui, Xu Jianfeng, Yang Qin
Department of Neurology, The Frist Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, China.
Neurochem Int. 2025 Mar;184:105950. doi: 10.1016/j.neuint.2025.105950. Epub 2025 Feb 17.
Vagus nerve stimulation (VNS) can promote neurofunctional recovery following cerebral ischemic stroke (CIS), but the underlying mechanism remains unclear. PANoptosis, a novel form of inflammatory programmed cell death, may play a role in the progression of CIS. Our previous studies have indicated that Sirt1 exerts neuroprotection against CIS by modulating various programmed cell death pathways. It needs to be clarified whether and how VNS regulates PANoptosis through Sirt1, thereby affecting the recovery of CIS. This study aims to clarify the role of VNS in modulating neuronal PANoptosis following CIS, and elucidate its underlying mechanisms. Models of middle cerebral artery occlusion/reperfusion (MCAO/R) in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) in primary neurons were established to assess the occurrence of neuronal PANoptosis following CIS. Circulating Sirt1 levels were measured in two independent cohorts of acute ischemic stroke (AIS) patients. VNS was administered to activate Sirt1, and its effects on PANoptosis and neurological recovery were evaluated. We found that neuronal PANoptosis was induced following CIS, which was reversed via VNS intervention. Sirt1 levels in serum of AIS patients were significantly increased, and positively correlated with infarct volume and National Institutes of Health Stroke Scale scores. In contrast, Sirt1 was downregulated in brain tissue from rodent models and AIS patients. This discrepancy in expression levels can be attributed to the increased generation of Sirt1 by peripheral macrophages. VNS upregulated Sirt1 expression, while the Sirt1 inhibitor EX527 negated the effects of VNS on PANoptosis, infarct volume, and neurofunctional recovery. These findings indicate that VNS may inhibit PANoptosis and promote neurofunctional recovery following CIS in a Sirt1-dependent manner, which may be a new potential target for stroke therapy. Sirt1 may also serve as a blood biomarker for patient stratification with independent prognostic value in AIS patients.
迷走神经刺激（VNS）可促进脑缺血性卒中（CIS）后的神经功能恢复，但其潜在机制仍不清楚。PANoptosis是一种新型的炎症程序性细胞死亡形式，可能在CIS的进展中起作用。我们之前的研究表明，Sirt1通过调节各种程序性细胞死亡途径对CIS发挥神经保护作用。VNS是否以及如何通过Sirt1调节PANoptosis从而影响CIS的恢复尚需阐明。本研究旨在阐明VNS在调节CIS后神经元PANoptosis中的作用，并阐明其潜在机制。建立大鼠大脑中动脉闭塞/再灌注（MCAO/R）模型和原代神经元氧糖剥夺/复氧（OGD/R）模型，以评估CIS后神经元PANoptosis的发生情况。在两个独立的急性缺血性卒中（AIS）患者队列中测量循环Sirt1水平。给予VNS以激活Sirt1，并评估其对PANoptosis和神经功能恢复的影响。我们发现CIS后诱导了神经元PANoptosis，而VNS干预可逆转这种情况。AIS患者血清中的Sirt1水平显著升高，且与梗死体积和美国国立卫生研究院卒中量表评分呈正相关。相比之下，啮齿动物模型和AIS患者脑组织中的Sirt1表达下调。这种表达水平的差异可归因于外周巨噬细胞产生Sirt1增加。VNS上调Sirt1表达，而Sirt1抑制剂EX527消除了VNS对PANoptosis、梗死体积和神经功能恢复的影响。这些发现表明，VNS可能以Sirt1依赖的方式抑制CIS后的PANoptosis并促进神经功能恢复，这可能是卒中治疗的一个新的潜在靶点。Sirt1也可能作为AIS患者分层的血液生物标志物，具有独立的预后价值。
