Ramelteon Protects Intestinal Tissue Against Injury Caused by Methotrexate Via Showing Anti-apoptotic, Antiinflammatory and Antioxidant Properties

Abstract

Objective:Methotrexate (MTX), a drug used in the treatment of autoimmune diseases and cancers, is a folic acid antagonist, but it has toxic effects on the gastrointestinal system (GIS). In this study, we examined the anti-inflammatory, antioxidant and anti-apoptotic effects of Ramelteon (RAM), a melatonin receptor agonist, on the MTX-induced toxicity in the intestinal tissue of rats.Methods:Thirty-two male Wistar albino rats were randomly divided into 4 groups; Control group, MTX group, MTX + RAM group, and RAM group. Single-dose 0.1 mL 20 mg/kg MTX, saline or 0.1 mL 10 mg/kg RAM orally was administered for 7 days. Animals were sacrificed at the end of 7 days after the last drug administration. Then, intestinal tissues were collected for biochemical, histopathological and immunohistochemical analyses.Results:While normal histological findings and biochemical parameters were observed in the control and RAM groups, in the MTX group, mononuclear cell infiltrations, hemorrhagic areas, degenerations in the submucosa and Lieberkuhn crypts were observed in the intestinal sections. Caspase-3 (Cas-3) and tumor necrosis factor-alpha (TNF-α) expressions, total oxidant status (TOS) and oxidative stress index (OSI) increased and total antioxidant status (TAS) decreased in the MTX group. RAM treatment decreased Cas-3 and TNF-α expressions, TOS, OSI levels and increased TAS levels.Conclusion:In this study, RAM showed anti-apoptotic, antioxidant and anti-inflammatory effects on MTX-induced toxicity in intestinal tissue. Therefore, it was suggested that RAM might be used in MTX-like toxicities to alleviate the side effects on the GIS.

Keywords

• intestinal injury
• inflammation
• methotrexate
• oxidative stress
• ramelteon