# Lactulose ameliorates cerebral ischemia-reperfusion injury in rats by inducing hydrogen by activating Nrf2 expression.
> ラクツロースによる腸内細菌発酵を介した水素産生とNrf2活性化が脳虚血再灌流傷害を軽減する


## Abstract

This study examined whether oral lactulose administration could protect against cerebral ischemia-reperfusion (I/R) injury in rats via intestinal bacterial fermentation and hydrogen generation. Using a middle cerebral artery occlusion model in Sprague-Dawley rats, intragastric lactulose significantly elevated breath hydrogen levels. Treated animals demonstrated improved neurological scores, reduced infarct volume on TTC staining, better-preserved neurons on Nissl staining, and fewer TUNEL-positive apoptotic cells. Biochemical analyses revealed decreases in malondialdehyde, caspase-3 activity, 3-nitrotyrosine, and 8-hydroxy-2-deoxyguanosine, alongside increased superoxide dismutase activity. These effects exceeded those of edaravone. RT-PCR and Western blot confirmed upregulation of Nrf2 in brain tissue. Antibiotic co-administration suppressed hydrogen production and abolished the neuroprotective effects, supporting the conclusion that lactulose-derived hydrogen and Nrf2 activation are the principal mediators of the observed protection.

### Mechanism

Hydrogen generated by gut bacterial fermentation of lactulose selectively scavenges reactive oxygen species and upregulates Nrf2 expression in brain tissue, thereby suppressing oxidative stress markers and caspase-3-mediated apoptosis following cerebral ischemia-reperfusion.

## Bibliographic

- **Authors**: Zhai X, Chen X, Shi J, Shi D, Ye Z, Liu W, et al.
- **Journal**: Free Radic Biol Med
- **Year**: 2013
- **PMID**: [23954468](https://pubmed.ncbi.nlm.nih.gov/23954468/)
- **DOI**: [10.1016/j.freeradbiomed.2013.08.004](https://doi.org/10.1016/j.freeradbiomed.2013.08.004)
- **Study type**: animal study
- **Delivery route**: hydrogen-rich water
- **Effect reported**: positive

## Delivery context

Hydrogen-rich water is a low-risk delivery route, but the achievable systemic hydrogen dose is bounded. For clinical applications, inhalation is the most efficient route; inhalation, however, carries explosion risk, and concentration matters (empirical LFL of 10% applies to inhalation environments; high-concentration devices are documented in the Consumer Affairs Agency accident database and are not recommended).

## Safety notes

Hydrogen-rich water is a low-risk delivery route, but the achievable systemic hydrogen dose is bounded. For clinical applications, inhalation is the most efficient route; inhalation, however, carries explosion risk, and concentration matters (empirical LFL of 10% applies to inhalation environments; high-concentration devices are documented in the Consumer Affairs Agency accident 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)
- [Inhalation safety threshold lineage](https://h2-papers.org/en/safety-notes/lineage)

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> **Cite as**: H2 Papers — PMID 23954468. https://h2-papers.org/en/papers/23954468
> **Source**: PubMed PMID [23954468](https://pubmed.ncbi.nlm.nih.gov/23954468/)