Protective Effects of Exogenous Melatonin Against Methotrexate-Induced Intestinal Injury

Abstract

Methotrexate is widely used as a chemotherapeutic agent for leukemia and other malignancies. The efficacy of this drug is often limited by mucositis and intestinal injury, which are the major causes of morbidity in children and adults. We investigated whether melatonin, a powerful antioxidant, could have a protective effect. The rats were pretreated with melatonin (20 and 40 mg/kg body weight) daily 1 h before the MTX (7 mg/kg body weight) administration for three consecutive days. After the final dose of MTX, the rats were sacrificed, and the small intestine was used for light microscopy and biochemical assays. Intestinal homogenates were used for assay of oxidative stress parameters malondialdehyde and protein carbonyl content and myeloperoxidase activity, a marker of neutrophil infiltration, as well as for the activities of the antioxidant enzymes. Pretreatment with melatonin had a dose-dependent protective effect on MTX-induced alterations in small intestinal morphology. Morphology was saved to some extent with 20 mg melatonin pretreatment, and near-normal morphology was achieved with 40 mg melatonin pretreatment. Biochemically, pretreatment with melatonin significantly attenuated MTX-induced oxidative stress and restored the activities of the antioxidant enzymes. The results of the present study demonstrate that supplementation by exogenous melatonin significantly reduces MTX-induced small intestinal damage, indicating that it may be beneficial in ameliorating MTX-induced enteritis in humans.