Hepatoprotective effect of rebamipide against methotrexate-induced hepatic intoxication: role of Nrf2/GSK-3β, NF-κβ-p65/JAK1/STAT3, and PUMA/Bax/Bcl-2 signaling pathways

Abstract

Objectives

The fact that methotrexate (MTX) is hepatotoxic is an important reason to limit its clinical use. Rebamipide (REB) has antioxidant and anti-inflammatory properties and is useful for the treatment of gastro-duodenal ulcers. This study investigated the impact and protective mechanisms of REB against MTX-induced hepatotoxicity in rats.

Materials and Methods

Animals were divided into four groups of six rats each: a control group, REB group (REB 100 mg/kg/day, orally), MTX control group (20 mg/kg, single i.p.), and MTX + REB group.

Results

The administration of MTX induced marked hepatic injury in the form of hepatocyte inflammatory swelling, degeneration, apoptosis, and focal necrosis. In parallel, our biochemical investigations revealed a marked hepatic dysfunction associated with the disturbance of the oxidant/antioxidant balance in the group treated with only MTX. Moreover, MTX led to the down-regulation of the hepatic Nrf2 and Bcl-2 expressions along with a marked elevation in the hepatic NF-κβ-p65, GSK-3β, JAK1, STAT3, PUMA, and Bax expressions. On the other hand, co-treatment with REB significantly ameliorated the aforementioned histopathological, biochemical, and molecular defects caused by MTX treatment.

Conclusion

the outcomes of the present study showed REB’s ability to protect from hepatic injury induced by MTX, possibly through its antioxidant, anti-inflammatory, and anti-apoptotic properties. These effects could be attributed to REB’s ability to modulate, at least in part, the Nrf2/GSK-3β,NF-κβ-p65/JAK1/STAT3, and PUMA/Bax/Bcl-2signaling pathways.

Keywords:

• Rebamipide
• Nrf2/GSK-3β
• NF-κβ-p65/JAK1/STAT3
• PUMA/Bax/Bcl-2

Author contributions

All authors contributed equally to this work. FA and EH designed the research study. BA, EH and FA performed the experiments. SA and AA analyzed the data. MM and BA wrote the manuscript. All authors reviewed the final version of the manuscript.

Disclosure statement

The authors declare that they have no conflicts of interest regarding any point in this article.

Additional information

Funding

This work received no financial support for research and publication.