# Molecular hydrogen attenuates sepsis-induced cognitive dysfunction through regulation of tau phosphorylation.
> 分子状水素による敗血症関連脳症における認知機能障害の抑制：タウリン酸化調節を介したメカニズムの検討


## Abstract

Using a cecal ligation and puncture mouse model of sepsis-associated encephalopathy (SAE), this study examined whether 2% H2 inhalation (60 min at 1 h and 6 h post-surgery) could alleviate cognitive deficits and hippocampal tau pathology. Animals receiving H2 showed improved 7-day survival and better performance in novel object recognition and Y-maze tasks. Histological analysis revealed greater preservation of CA1 hippocampal neurons and higher dendritic spine density, including mushroom-type spines. Biochemically, H2 reduced tau phosphorylation at AT8 (pSer202, pThr205) and T22 epitopes, lowered tau oligomer levels, and decreased TTBK1 expression along with GSK3β (Tyr216) phosphorylation. Parallel experiments with the TTBK1 inhibitor HY-15769 reproduced comparable neuroprotective outcomes, supporting the hypothesis that H2-mediated cognitive protection in SAE involves suppression of the TTBK1–tau phosphorylation axis.

### Mechanism

H2 suppresses TTBK1 expression and GSK3β (Tyr216) phosphorylation, thereby reducing hyperphosphorylation of tau at AT8 and T22 epitopes and limiting tau oligomer accumulation in the hippocampus, which preserves neuronal integrity and dendritic spine density.

## Bibliographic

- **Authors**: Qi B, Song Y, Chen C, Zhao L, Ma W, Meng S, et al.
- **Journal**: Int Immunopharmacol
- **Year**: 2023
- **PMID**: [36538853](https://pubmed.ncbi.nlm.nih.gov/36538853/)
- **DOI**: [10.1016/j.intimp.2022.109603](https://doi.org/10.1016/j.intimp.2022.109603)
- **Study type**: animal study
- **Delivery route**: inhalation
- **Effect reported**: positive
- **H2 concentration**: 2%

## 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 36538853. https://h2-papers.org/en/papers/36538853
> **Source**: PubMed PMID [36538853](https://pubmed.ncbi.nlm.nih.gov/36538853/)