The effect of metformin on indomethacin-induced gastric ulcer: Involvement of nitric oxide/Rho kinase pathway

Eur J Pharmacol. 2021 Feb 5:892:173812. doi: 10.1016/j.ejphar.2020.173812. Epub 2020 Dec 17.


Gastric ulcer is a very common disease that represent an economic burden. Non-steroidal anti-inflammatory drugs induce ulcer in old patients and in patients with comorbidities. Indomethacin is widely used to induce gastric ulcer in animal models. Diabetic patients are highly susceptible to develop gastric ulcer. Metformin, the first line medication for the treatment of type II diabetes melilites that have many off label uses in non-diabetic patients, has been recently reported to have anti-inflammatory activities. Therefore, this research was conducted to assess the possible healing effects of metformin on gastric ulcers induced by indomethacin in rats. Indomethacin (48 mg/kg) single dose increased stomach acidity, ulcer index and induced histopathological changes. Indomethacin also decreased mucin levels and increased the activity of tumor necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB), Rho-associated protein kinas-1 (ROCK-1) and decreased the levels of the protective nitric oxide (NO). After the induction of ulcer, rats were treated by omeprazole (30 mg/kg) or metformin (50, 100 or 200 mg/kg). Omeprazole and metformin were found to decrease stomach acidity and ulcer index, restored the histological features and increased mucin levels. Both also decreased the levels of NF-κB, TNF-α, ROCK-1 and increased NO. Metformin exerted ulcer healing effects comparable to that of omeprazole. This can be attributed, at least partly, to its anti-inflammatory activity and increasing NO levels.

Keywords: Antioxidant; Diabetes; Gastric ulcer; Metformin; Nitric oxide/Rho kinase pathway.

MeSH terms

  • Animals
  • Anti-Ulcer Agents / pharmacology*
  • Disease Models, Animal
  • Gastric Mucosa / drug effects*
  • Gastric Mucosa / enzymology
  • Gastric Mucosa / pathology
  • Indomethacin
  • Male
  • Metformin / pharmacology*
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism*
  • Omeprazole / pharmacology
  • Proton Pump Inhibitors / pharmacology
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Stomach Ulcer / chemically induced
  • Stomach Ulcer / drug therapy*
  • Stomach Ulcer / enzymology
  • Stomach Ulcer / pathology
  • Tumor Necrosis Factor-alpha / metabolism
  • Wound Healing / drug effects*
  • rho-Associated Kinases / metabolism*


  • Anti-Ulcer Agents
  • NF-kappa B
  • Proton Pump Inhibitors
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Metformin
  • ROCK1 protein, rat
  • rho-Associated Kinases
  • Omeprazole
  • Indomethacin