Hydrogen gas alleviates sepsis-induced neuroinflammation and cognitive impairment through regulation of DNMT1 and DNMT3a-mediated BDNF promoter IV methylation in mice.
水素ガス吸入が敗血症誘発性神経炎症および認知障害に及ぼす影響：DNMT1・DNMT3aを介したBDNFプロモーターIVメチル化調節機序の解明
Abstract
Sepsis-associated encephalopathy (SAE) contributes to both acute and persistent cognitive deficits. Using a cecal ligation and perforation (CLP) model in C57BL/6 mice, this study examined whether 2% hydrogen gas (H2) inhalation influences SAE through epigenetic regulation. H2 inhalation reduced hippocampal pro-inflammatory cytokines (TNF-α, IL-6, HMGB1) and downregulated DNMT1 and DNMT3a expression without affecting DNMT3b. Quantitative methylation analysis revealed hypomethylation at 5 CpG sites within BDNF promoter IV, accompanied by elevated BDNF protein levels. Morris water maze assessments conducted from day 4 to day 10 post-surgery demonstrated shortened escape latency and increased platform crossings in H2-treated septic mice, indicating improved spatial memory. These findings suggest that H2 inhalation modulates hippocampal BDNF expression through DNMT1- and DNMT3a-dependent promoter IV methylation changes, thereby attenuating SAE-related cognitive impairment.
Mechanism
H2 inhalation suppresses DNMT1 and DNMT3a expression in the hippocampus, inducing hypomethylation at five CpG sites of BDNF promoter IV, which elevates BDNF levels and reduces neuroinflammation and cognitive deficits in septic mice.
Bibliographic
- Authors
- Yu M, Qin C, Li PY, Zhang YJ, Wang Y, Zhang JH, et al.
- Journal
- Int Immunopharmacol
- Year
- 2021
- PMID
- 33773206
- DOI
- 10.1016/j.intimp.2021.107583
Tags
Delivery context
In air, molecular hydrogen is reported to be combustible across approximately **4% (LFL, lower flammability limit) to 75% (UFL, upper flammability limit)**. Among high-concentration hydrogen inhalers, 66% output sits inside this range, and even pure-hydrogen (100%) output forms a 4–75% concentration-gradient layer at the device–air boundary (the UFL 75% paradox). Engineering principle would therefore call for operation below LFL (the classical 4%); that figure, however, was measured under closed, pre-mixed, static conditions. For the open, dynamic inhalation environment, the empirical value reported in the literature is **10%**, which is the figure referenced in practice as the operating ceiling. The 66% / 100% output devices are recorded in the Japanese Consumer Affairs Agency accident-information database, and from these considerations are not recommended.
Safety notes
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