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

IF 4.8 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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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.