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Molecular hydrogen attenuates sepsis-induced neuroinflammation through regulation of microglia polarization through an mTOR-autophagy-dependent pathway.

mTOR-オートファジー経路を介したミクログリア極性化制御による分子状水素の敗血症関連神経炎症抑制効果

Abstract

Sepsis-associated encephalopathy (SAE) causes cognitive dysfunction and elevates morbidity and mortality. Using a cecal ligation and puncture (CLP) mouse model alongside LPS-stimulated BV-2 microglial cells, this study examined how hydrogen inhalation affects SAE and its underlying mechanism. In vivo, hydrogen inhalation improved Morris Water Maze performance, including escape latency and platform-crossing frequency. Both animal and cell experiments showed reductions in TNF-α, IL-6, and HMGB1, alongside increases in IL-10 and TGF-β. M1 microglia polarization was suppressed while M2 polarization was enhanced. In BV-2 cells, hydrogen decreased the p-mTOR/mTOR and p62 levels while increasing p-AMPK/AMPK and LC3II/LC3I ratios, as well as TREM-2 and Beclin-1 expression. Application of the mTOR activator MHY1485 abolished these protective effects, confirming that the mTOR-autophagy pathway mediates hydrogen's anti-neuroinflammatory actions.

Mechanism

Hydrogen activates AMPK and suppresses mTOR, thereby promoting autophagy (elevated LC3II/LC3I and Beclin-1, reduced p62), which drives microglial polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype, reducing neuroinflammatory cytokine release.

Bibliographic

Authors

Zhuang X, Jiang Y, Zhao S, Wang Y, Su L, Xie K, et al.

Journal

Int Immunopharmacol

Year

2020

PMID

32058932

DOI

10.1016/j.intimp.2020.106287

Tags

Delivery context

For inhalation applications of molecular hydrogen, the lower flammability limit (LFL) deserves careful handling. The classical 4% figure applies to closed-system mixtures; the practical inhalation-environment threshold is 10%. Even pure-hydrogen output (the UFL 75% paradox) passes through the flammable range at the air–gas boundary. High-concentration (66% / 100%) inhalers are documented in the Japanese Consumer Affairs Agency accident-information database and are not recommended.

Safety notes

See also:

• Inhalation concentration and LFL / UFL
• Consumer Affairs Agency accident cases
• LFL / UFL terminology
• Inhalation safety threshold lineage

Other papers on the same disease / condition

• The protective effects of molecular hydrogen in sepsis-associated encephalopathy: current status.
  2026 ・ Eur J Pharmacol ・ mixed routes ・ not assessed
• Mitochondrial dysfunction, neuroinflammation, and associated mechanisms in sepsis-associated encephalopathy: from pathogenesis to emerging therapeutics.
  2026 ・ Front Neurosci ・ not specified ・ not assessed
• Effect of molecular hydrogen treatment on Sepsis-Associated encephalopathy in mice based on gut microbiota.
  2023 ・ CNS Neurosci Ther ・ mixed routes ・ positive
• Molecular hydrogen attenuates sepsis-induced cognitive dysfunction through regulation of tau phosphorylation.
  2023 ・ Int Immunopharmacol ・ inhalation ・ positive
• Inhaled molecular hydrogen reduces hippocampal neuroinflammation, glial reactivity and ameliorates memory impairment during systemic inflammation.
  2023 ・ Brain Behav Immun Health ・ inhalation ・ positive
• Hydrogen-rich saline regulates NLRP3 inflammasome activation in sepsis-associated encephalopathy rat model.
  2023 ・ Int Immunopharmacol ・ injection / infusion ・ positive
• Emerging Trends and Hot Spots in Sepsis-Associated Encephalopathy Research From 2001 to 2021: A Bibliometric Analysis.
  2022 ・ Front Med (Lausanne) ・ not specified ・ not assessed
• Hydrogen Gas Alleviates Sepsis-Induced Brain Injury by Improving Mitochondrial Biogenesis Through the Activation of PGC-α in Mice.
  2021 ・ Shock ・ inhalation ・ positive