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Hydrogen gas alleviates blood-brain barrier impairment and cognitive dysfunction of septic mice in an Nrf2-dependent pathway.

Nrf2依存的経路を介した水素ガスによる敗血症マウスの血液脳関門障害および認知機能障害の軽減

Abstract

Sepsis-associated encephalopathy (SAE) involves blood-brain barrier (BBB) disruption leading to cognitive impairment and elevated mortality. Using a cecal ligation and puncture (CLP) model in female wild-type and Nrf2-knockout C57BL/6J mice, this study examined whether 2% H2 inhalation (60 min at 1 h and 6 h post-CLP) could protect the BBB via Nrf2 signaling. In wild-type animals, H2 improved 7-day survival, reduced escape latency in the Morris water maze, lowered cortical levels of TNF-α, IL-6, HMGB1, MDA, and 8-iso-PGF2α, and elevated IL-10, SOD, and CAT. BBB integrity markers—ZO-1 and VE-cadherin—were upregulated, while brain water content, Evans blue extravasation, and dextran leakage decreased. β-catenin phosphorylation was also modulated. None of these effects were observed in Nrf2-knockout mice or in bEnd.3 cells treated with the Nrf2 inhibitor ML385, confirming that Nrf2 and its downstream antioxidant pathways are required for H2-mediated BBB preservation and cognitive protection in sepsis.

Mechanism

H2 activates Nrf2 and its downstream antioxidant pathways, suppressing pro-inflammatory cytokines and oxidative stress markers, thereby reducing BBB permeability and preserving tight junction proteins ZO-1 and VE-cadherin in septic brain tissue.

Bibliographic

Authors

Feng J, Lian N, Yang M, Xie K, Wang G, Wang CY, et al.

Journal

Int Immunopharmacol

Year

2020

PMID

32447221

DOI

10.1016/j.intimp.2020.106585

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

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  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.
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• Molecular hydrogen attenuates sepsis-induced cognitive dysfunction through regulation of tau phosphorylation.
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• 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