High Concentration Hydrogen Protects Sepsis-Associated Encephalopathy by Enhancing Pink1/Parkin-Mediated Mitophagy and Inhibiting cGAS-STING-IRF3 Pathway

IF 5 1区医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2025-02-27 DOI:10.1111/cns.70305

Yan Cui, Jianfeng Liu, Yu Song, Chen Chen, Yuehao Shen, Keliang Xie

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Abstract

Background

Sepsis-associated encephalopathy (SAE) leads to increased mortality. Hydrogen (H₂) has been proven to be effective in protecting against SAE. This study aimed to investigate the protective mechanism of a high concentration of H₂ (HCH) (67%) against SAE.

Methods

A mouse sepsis model was established via cecal ligation and puncture (CLP). 67% H₂ was inhaled for 1 h at 1 h and 6 h after the operation. First, mice were randomly divided into 5 groups: Sham, CLP, CLP + CQ (a mitophagy inhibitor), CLP + H₂, and CLP + H₂ + CQ. Seven-day survival, cognitive function, and hippocampal damage were assessed. Then, mice were randomly divided into four groups: Sham, CLP, CLP + UA (a mitophagy agonist), and CLP + H₂. Seven-day survival was recorded, cognitive function was assessed via Y-maze and Morris water maze tests, and hippocampal damage was evaluated via Nissl staining. Phosphorylated tau, inflammatory factors, ATP, and antioxidant enzyme levels and mitochondrial membrane potential (MMP) were detected. Mitochondria were observed via transmission electron microscopy. The protein levels of the PINK1/Parkin pathway and STING-TBK-IRF3 pathway were detected via western blotting.

Results

HCH inhalation improves 7-day survival and cognitive function in septic mice and reduces brain tissue damage, proinflammatory cytokine levels, and phosphorylated tau levels. These effects were reversed by a mitophagy inhibitor. HCH significantly improves mitochondrial function, enhances PINK1/Parkin-mediated mitophagy, and reduces the activity of the STING-TBK-IRF3 pathway in brain tissue.

Conclusions

HCH inhalation effectively improved the survival rate of septic mice, alleviated SAE, and reduced tau phosphorylation. The mechanism may involve HCH enhancing PINK1/Parkin-mediated mitophagy, which inhibits the activity of the cGAS-STING-IRF3 pathway, thereby reducing neuroinflammation.

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高浓度氢通过增强Pink1/ parkin介导的有丝分裂和抑制cGAS-STING-IRF3途径保护败血症相关脑病

背景败血症相关脑病（SAE）导致死亡率增加。氢气（H2）已被证明在防止SAE方面是有效的。本研究旨在探讨高浓度H2 (HCH)（67%）对SAE的保护机制。方法采用盲肠结扎穿刺法（CLP）建立小鼠脓毒症模型。术后1 h、6 h分别吸入67% H2 1 h。首先，将小鼠随机分为5组：Sham、CLP、CLP + CQ（一种线粒体自噬抑制剂）、CLP + H2和CLP + H2 + CQ。评估7天生存率、认知功能和海马损伤。然后，将小鼠随机分为4组：Sham、CLP、CLP + UA（一种线粒体自噬激动剂）和CLP + H2。记录7天生存率，通过y迷宫和Morris水迷宫评估认知功能，通过尼氏染色评估海马损伤。检测磷酸化tau蛋白、炎症因子、ATP、抗氧化酶水平和线粒体膜电位（MMP）。透射电镜观察线粒体。western blotting检测PINK1/Parkin通路和STING-TBK-IRF3通路的蛋白水平。结果吸入六氯环己烷可提高脓毒症小鼠的7天存活率和认知功能，降低脑组织损伤、促炎细胞因子水平和磷酸化tau水平。这些作用被一种线粒体自噬抑制剂逆转。HCH显著改善线粒体功能，增强PINK1/ parkinson介导的线粒体自噬，降低脑组织STING-TBK-IRF3通路的活性。结论吸入六氯环己烷可有效提高脓毒症小鼠的存活率，减轻SAE，降低tau蛋白磷酸化。其机制可能涉及HCH增强PINK1/ parkinson介导的有丝分裂，从而抑制cGAS-STING-IRF3通路的活性，从而减少神经炎症。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.