# Hydrogen gas promotes neuroprotection and upregulates ATF5 expression in neonatal hypoxic-ischemic brain injury.
> 新生児低酸素虚血性脳損傷における水素ガスの神経保護効果とATF5発現上昇


## Abstract

Using neonatal piglets—whose brain architecture closely parallels that of human newborns—this study examined cell-type-specific responses to hydrogen gas following hypoxic-ischemic (HI) brain injury. Hydrogen gas administration markedly reduced HI-induced apoptosis in cortical neurons and white matter oligodendrocytes, maintaining cell densities comparable to uninjured controls. Concurrently, microglial activation, astrocyte proliferation, and myelin loss were all diminished. RNAscope analysis demonstrated that hydrogen gas elevated expression of the anti-apoptotic transcription factor ATF5 in both neurons and mature oligodendrocytes, pointing to a cell-specific protective mechanism. These results identify ATF5 as a candidate molecular mediator of hydrogen gas-mediated neuroprotection in the neonatal HI setting.

### Mechanism

Hydrogen gas upregulates the anti-apoptotic transcription factor ATF5 in cortical neurons and mature oligodendrocytes, suppressing hypoxia-ischemia-induced apoptosis and thereby preserving cell density in neonatal brain tissue.

## Bibliographic

- **Authors**: Nakamura S, Nakamura Y, Jinnou H, Nakao Y, Yinmon H, Mitsuie T, et al.
- **Journal**: Exp Neurol
- **Year**: 2026
- **PMID**: [41386344](https://pubmed.ncbi.nlm.nih.gov/41386344/)
- **DOI**: [10.1016/j.expneurol.2025.115590](https://doi.org/10.1016/j.expneurol.2025.115590)
- **Study type**: animal study
- **Delivery route**: inhalation
- **Effect reported**: positive

## 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

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.

See also:
- [Inhalation concentration and LFL / UFL](https://h2-papers.org/en/safety-notes/inhalation-concentration)
- [Consumer Affairs Agency accident cases](https://h2-papers.org/en/safety-notes/accident-cases)
- [LFL / UFL terminology](https://h2-papers.org/en/safety-notes/lfl-ufl-explained)
- [Inhalation safety threshold lineage](https://h2-papers.org/en/safety-notes/lineage)

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> **Cite as**: H2 Papers — PMID 41386344. https://h2-papers.org/en/papers/41386344
> **Source**: PubMed PMID [41386344](https://pubmed.ncbi.nlm.nih.gov/41386344/)