title: A preclinical study on the protective effect of melatonin against methotrexate-induced small intestinal damage: effect mediated by attenuation of nitrosative stress, protein tyrosine nitration, and PARP activation.
abstract: OBJECTIVE
  One of the major toxic side effects of methotrexate (MTX) is enterocolitis. To date, there is no efficient standard treatment for this side effect. Nitrosative stress is reported to play a critical role in MTX-induced mucositis. The purpose of this study is to investigate whether pretreatment with melatonin, an inhibitor of nitro-oxidative stress, prevents MTX-induced mucositis in rats.
  
  
  METHODS
  Rats were pretreated with melatonin (20 and 40 mg/kg body weight) i.p. daily 1 h before MTX (7 mg/kg body weight) administration for three consecutive days. After the final dose of MTX, the rats were killed and the small intestines were used for analysis.
  
  
  RESULTS
  The small intestines of MTX-treated rats showed moderate to severe injury. The villi were distorted, blunted, and atrophied and focally absent in various segments of the small intestines. Crypt abscesses were also found, suggesting an inflammatory response. Pretreatment with melatonin had a dose-dependent protective effect on MTX-induced mucositis. Morphology was saved to a moderate extent with 20 mg melatonin pretreatment, and near-normal morphology was achieved with 40 mg melatonin pretreatment. Damage to the villi and crypt abscess was reduced. The villi/crypt ratio was almost restored. Melatonin pretreatment protected the small intestines from MTX-induced damage by attenuating nitrosative stress, protein tyrosine nitration and PARP expression.
  
  
  CONCLUSIONS
  Because of its versatility in protecting against nitro-oxidative stress and reducing inflammation, we suggest that melatonin could be beneficial in ameliorating MTX-induced enteritis in humans.
authors: Department of Biochemistry, Christian Medial College, Bagayam, Vellore 632002, Tamil Nadu, India.
authors: Viswa Kalyan
authors: VK
authors: Kolli
authors: Indirani
authors: I
authors: Kanakasabapathy
authors: Minnie
authors: M
authors: Faith
authors: Hemalatha
authors: H
authors: Ramamoorthy
authors: Bina
authors: B
authors: Isaac
authors: Kasthuri
authors: K
authors: Natarajan
authors: Premila
authors: P
authors: Abraham
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004760:Enterocolitis / Q000139:chemically induced / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008550:Melatonin / Q000008:administration & dosage / Q000494:pharmacology*; D008727:Methotrexate / Q000633:toxicity*; D009566:Nitrates / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D009566:Nitrates; D014443:Tyrosine; D011065:Poly(ADP-ribose) Polymerases; D008550:Melatonin; D008727:Methotrexate