# Hydrogen gas inhalation alleviated cerebral ischemia/reperfusion injury by regulating mitophagy in SH-SY5Y cells and mice via PTEN-induced kinase 1/Parkin pathway.
> 水素ガス吸入によるPINK1/Parkin経路を介したミトファジー調節と脳虚血再灌流障害の軽減：SH-SY5Y細胞およびマウスを用いた検討


## Abstract

This study examined the effects of molecular hydrogen (H₂) inhalation on cerebral ischemia-reperfusion injury (CIRI) using both a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model and human neuroblastoma SH-SY5Y cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). In vivo, H₂ inhalation reduced infarct volume, improved neurological deficit scores, decreased histopathological damage, and suppressed neuronal apoptosis while promoting mitophagy. In OGD/R-exposed SH-SY5Y cells, H₂ enhanced cell viability, lowered mitochondrial reactive oxygen species, preserved mitochondrial membrane potential, and activated the PINK1/Parkin mitophagy pathway. Concurrently, the Nrf2/HO-1 antioxidant axis was upregulated and NF-κB-driven inflammatory signaling was attenuated. Pretreatment with the Nrf2-specific inhibitor ML385 (5 μM) substantially reversed these mitochondrial protective and anti-apoptotic outcomes, indicating that Nrf2 activation is integral to H₂-mediated neuroprotection against CIRI.

### Mechanism

H₂ activates the PINK1/Parkin pathway to promote selective clearance of damaged mitochondria (mitophagy), upregulates the Nrf2/HO-1 antioxidant axis, and suppresses NF-κB inflammatory signaling, collectively reducing oxidative stress and neuronal apoptosis in ischemia-reperfusion conditions.

## Bibliographic

- **Authors**: Wang Z, Feng WB, Zhou J, Huang L, Fang C, Yuan J, et al.
- **Journal**: J Stroke Cerebrovasc Dis
- **Year**: 2026 (2026-04-26)
- **PMID**: [42049119](https://pubmed.ncbi.nlm.nih.gov/42049119/)
- **DOI**: [10.1016/j.jstrokecerebrovasdis.2026.108645](https://doi.org/10.1016/j.jstrokecerebrovasdis.2026.108645)
- **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 42049119. https://h2-papers.org/en/papers/42049119
> **Source**: PubMed PMID [42049119](https://pubmed.ncbi.nlm.nih.gov/42049119/)