High‐concentration hydrogen inhalation mitigates sepsis‐associated encephalopathy in mice by improving mitochondrial dynamics

Background Sepsis‐associated encephalopathy (SAE) is a neuronal injury with poor prognosis. Mitochondrial dysfunction is critical in SAE development, and hydrogen gas (H2) has a protective effect on septic mice. This study aimed to investigate the effect of high concentration (67%) of H2 on SAE and whether it is related to mitochondrial biogenesis and mitochondrial dynamics. Methods A mouse sepsis model was induced by cecal ligation and puncture. The mice inhalated 67% H2 for 1 h at 1 and 6 h post‐surgery, respectively. The 7‐day survival rate was recorded. Cognitive function was assessed using the Y‐maze test and Morris water maze test. Serum inflammatory factors, antioxidant enzymes, as well as mitochondrial function indexes including mitochondrial membrane potential (MMP) and ATP in the hippocampal tissue were evaluated 24 h after surgery. Mitochondrial dynamic proteins (DRP1 and MFN2) and biosynthetic proteins (PGC‐1α, NRF2, and TFAM) in the hippocampal tissue were detected. Moreover, the morphology of mitochondria was observed by transmission electron microscopy. Results Inhalation of 67% H2 improved the 7‐day survival rates and recognition memory function of septic mice, alleviated brain antioxidant enzyme activity (SOD and CAT), and reduced serum proinflammatory cytokine levels. H2 inhalation also enhanced the expression of MFN2 and mitochondrial biogenesis‐related factors (PGC‐1α, NRF2, and TFAM) and decreased the expression of fission protein (DRP1), leading to improvement in mitochondrial function, as evidenced by MMP and ATP levels. Conclusions Inhalation of high concentration (67%) of H2 in septic mice improved the survival rate and reduced neuronal injury. Its mechanism might be mediated by enhancing mitochondrial biogenesis and mitochondrial dynamics. High concentration (67%) of hydrogen gas inhalation exerts a protective effect on sepsis‐associated encephalopathy, and the mechanism may be improving mitochondrial function through the promotion of mitochondrial biogenesis and the improvment of mitochondrial dynamics.