Pharmacological inhibition of soluble epoxide hydrolase or genetic deletion reduces diclofenac-induced gastric ulcers

Life Sci. 2017 Jul 1;180:114-122. doi: 10.1016/j.lfs.2017.05.018. Epub 2017 May 15.

Abstract

Aims: This research was conducted to evaluate the hypothesis that gastric ulcers caused by the NSAID diclofenac sodium (DCF) can be prevented by the soluble epoxide hydrolase inhibitor TPPU.

Main methods: Mice were administered a single dose of 10, 30 or 100mg/kg of DCF. Once an ulcerative dose of DCF was chosen, mice were pretreated with TPPU for 7days at 0.1mg/kg to evaluate anti-ulcer effects of the sEH inhibitor on anatomy, histopathology, pH, inflammatory markers and epithelial apoptosis of stomachs.

Key findings: Diclofenac caused ulceration of the stomach at a dose of 100mg/kg and a time post dose of 6h. Ulcers generated under these conditions were associated with a significant increase in the levels of TNF-α and IL-6 in serum and increased apoptosis compared to control mice. Pretreatment with TPPU resulted in a decrease of ulceration in mice treated with DCF with a significant decrease in the level of apoptosis, TNF-α and IL-6 in the serum in comparison to diclofenac-treated mice. TPPU did not affect the pH of the stomach, whereas omeprazole elevated the pH of the stomach as expected. A similar anti-ulcer effect was observed in sEH gene knockout mice treated with DCF.

Significance: The sEH inhibitor TPPU decreases the NSAID-induced stomach ulcers.

Keywords: Apoptosis; Diclofenac; IL-6; Soluble epoxide hydrolase inhibitor TPPU; Stomach ulcer; TNF-α.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / toxicity*
  • Anti-Ulcer Agents / pharmacology
  • Apoptosis / drug effects
  • Diclofenac / administration & dosage
  • Diclofenac / toxicity*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Epoxide Hydrolases / genetics
  • Gene Deletion
  • Hydrogen-Ion Concentration
  • Interleukin-6 / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Omeprazole / pharmacology
  • Phenylurea Compounds / pharmacology*
  • Piperidines / pharmacology*
  • Stomach Ulcer / pathology
  • Stomach Ulcer / prevention & control*
  • Time Factors
  • Tumor Necrosis Factor-alpha / blood

Substances

  • 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea
  • Anti-Inflammatory Agents, Non-Steroidal
  • Anti-Ulcer Agents
  • Enzyme Inhibitors
  • Interleukin-6
  • Phenylurea Compounds
  • Piperidines
  • Tumor Necrosis Factor-alpha
  • Diclofenac
  • Epoxide Hydrolases
  • Omeprazole