Preclinical efficacy of melatonin to reduce methotrexate-induced oxidative stress and small intestinal damage in rats.
BACKGROUND
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.


OBJECTIVE
The present study investigates whether melatonin, a powerful antioxidant, could have a protective effect.


METHODS
Rats were pretreated with melatonin (20 and 40 mg/kg body weight) daily 1 h before methotrexate (7 mg/kg body weight) administration for three consecutive days. After the final dose of methotrexate, 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.


RESULTS
Pretreatment with melatonin had a dose-dependent protective effect on methotrexate (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 (P < 0.01 for MDA, P < 0.001 for protein carbonyl content) and restored the activities of the antioxidant enzymes (glutathione reductase P < 0.05, superoxide dismutase P < 0.01).


CONCLUSIONS
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.
Department of Biochemistry, Christian Medical College, Bagayam, Vellore 632002, Tamil Nadu, India.
Viswa Kalyan
VK
Kolli
Premila
P
Abraham
Bina
B
Isaac
N
N
Kasthuri
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D008550:Melatonin / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D008727:Methotrexate / Q000009:adverse effects*; D052016:Mucositis / Q000139:chemically induced / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000964:Antimetabolites, Antineoplastic; D000975:Antioxidants; D008550:Melatonin; D008727:Methotrexate