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. 2024 Sep;30(9):e70021.
doi: 10.1111/cns.70021.

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

Yan Cui  1   2 , Shuqi Meng  2   3 , Nannan Zhang  2 , Jingya Liu  2   3 , Lina Zheng  2 , Wanjie Ma  2 , Yu Song  2 , Zhiwei Wang  2 , Yuehao Shen  2 , Jianfeng Liu  2   3 , Keliang Xie  2   3
Affiliations

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

Yan Cui et al. CNS Neurosci Ther. 2024 Sep.

Abstract

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.

Keywords: hydrogen; mitochondrial biogenesis; mitochondrial dynamics; sepsis‐associated encephalopathy.

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Conflict of interest statement

The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper.

Figures

FIGURE 1
FIGURE 1
67% H2 inhalation improved the 7‐day survival rate and MSS score of septic mice. (A) Experimental flow chart. (B) 7‐day survival rate of mice; the values are expressed as the survival rates (n = 20, log‐rank test). ## p < 0.01 vs. Sham group, **p < 0.01 vs. CLP group. (C) Murine sepsis score (n = 6). ***p < 0.001 compared between two groups.
FIGURE 2
FIGURE 2
67% H2 inhalation improved cognitive dysfunction in mice with sepsis. (A) Trajectory plot of the seventh day after training. (B) Escape latency during training in mice of each group. ***p < 0.01 vs. Sham group, ## p < 0.01, ### p < 0.001 vs.CLP group. (C) Time ratio of mice in the quadrant where the platform is located on 7th day after training. (D) The number of times the mice crossed the platform on 7th day after training. (E) Times in the novel arms in the Y‐maze test. All the data were expressed as means ± SD (n = 6 per group). ***p < 0.001 compared with two groups.
FIGURE 3
FIGURE 3
67% H2 inhalation ameliorated brain injury in septic mice. (A) Nissl staining of hippocampus (×200). (B) The number of abnormal neurons was calculated based on Nissl staining. (C) HE staining of brain tissue. (D–F) Serum TNF‐α, IL‐1β, and HMGB1. All the data were expressed as means ± SD (n = 6 per group). The red arrows represent the obvious differences. ***p < 0.01 compared with two groups.
FIGURE 4
FIGURE 4
67% H2 inhalation alleviated mitochondrial dysfunction of septic mice. (A) The JC‐1 aggregate/monomer ratio was used to assess the MMP. (B) The ATP content was detected based on fluorescein. (C) Hippocampal CAT. (D) Hippocampal CAT. (E) The morphology of mitochondria was observed by transmission electron microscopy. The red arrows represent the obvious differences. All the data were expressed as means ± SD (n = 6 per group). ***p < 0.01 compared with two groups.
FIGURE 5
FIGURE 5
67% H2 improved the mitochondrial dynamics in septic mice. (A–C) The expression of DRP1 and MFN2 was detected by western blotting. (D) Drp1 was observed by immunofluorescence staining. All the data were expressed as means ± SD (n = 6 per group). ***p < 0.01 compared with two groups.
FIGURE 6
FIGURE 6
67% H2 improved the mitochondrial biogenesis in septic mice. (A–D) The expression of mitochondrial biogenesis‐related proteins (PGC‐1α, NRF2, and TFAM) was assayed by western blotting. (E) NRF2 was observed by immunofluorescence staining. All the data were expressed as means ± SD (n = 6 per group). ***p < 0.01 compared with two groups.
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