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