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NF-κB-iNOS-COX2-TNF α inflammatory signaling pathway plays an important role in methotrexate induced small intestinal

Kasthuri Natarajan1, Premila Abraham1, Rekha Kota2

  • 1Department of Biochemistry, Christian Medical College, Bagayam, Vellore, 632002, Tamil Nadu, India.

Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association
|June 24, 2018
PubMed

Insights

Methotrexate causes gastrointestinal mucositis via NFκB pathway activation. Aminoguanidine protected against this toxicity by inhibiting NFκB and reducing inflammation, suggesting a therapeutic potential.

Area of Science:

  • Gastroenterology
  • Pharmacology
  • Molecular Biology

Background:

  • Methotrexate (MTX) is a widely used anticancer drug.
  • Its clinical utility is limited by gastrointestinal (GI) toxicity, with unclear mechanisms.
  • The NFκB inflammatory pathway's role in MTX-induced mucositis is investigated.

Purpose of the Study:

  • To investigate the role of the NFκB inflammatory pathway in methotrexate-induced gastrointestinal mucositis.
  • To evaluate the protective effects of aminoguanidine against MTX-induced GI toxicity.

Main Methods:

  • GI injury was induced in Wistar rats using consecutive intraperitoneal injections of MTX.
  • Small intestine tissues were analyzed using light microscopy, immunohistochemistry, and immunofluorescence.
  • Protein and mRNA expressions of NFκB and its target genes were analyzed via Western blot and RT-PCR.

Main Results:

  • MTX treatment activated NFκB and promoted its nuclear translocation, confirmed by multiple methods.
  • Increased mRNA expression of NFκB was observed.
  • Elevated protein and mRNA levels of NFκB target genes (TNF-α, iNOS, COX-2, PLA2, HO-1, HSP70, MMPs 2 and 9) were detected.
  • Aminoguanidine pretreatment attenuated MTX-induced NFκB activation and proinflammatory gene expression.
  • Aminoguanidine improved MTX-induced morphological changes in the GI tract.

Conclusions:

  • MTX induces gastrointestinal mucositis through NFκB pathway activation.
  • Aminoguanidine demonstrates protective effects against MTX-induced GI mucositis in rats.
  • Aminoguanidine may be a potential therapeutic agent for mitigating MTX-related gastrointestinal toxicity.
Keywords:
AminoguanidineMethotrexateNFκBRatSmall intestinal injuryiNOS

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