Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 5, pp 1209–1218 | Cite as

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

  • Viswa Kalyan Kolli
  • Indirani Kanakasabapathy
  • Minnie Faith
  • Hemalatha Ramamoorthy
  • Bina Isaac
  • Kasthuri Natarajan
  • Premila AbrahamEmail author
Original Article



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.


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.


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.


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.


Anticancer drug Methotrexate Melatonin Small intestine Nitrosative stress 



The authors would like to thank CSIR, New Delhi, for the financial support. Mr. Viswa Kalyan Kolli is a senior research fellow on the project.

Conflict of interest



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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Viswa Kalyan Kolli
    • 1
  • Indirani Kanakasabapathy
    • 2
  • Minnie Faith
    • 1
  • Hemalatha Ramamoorthy
    • 1
  • Bina Isaac
    • 2
  • Kasthuri Natarajan
    • 1
  • Premila Abraham
    • 1
    Email author
  1. 1.Department of BiochemistryChristian Medial College, BagayamVelloreIndia
  2. 2.Department of AnatomyChristian Medial College, BagayamVelloreIndia

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