Gastroprotective effect of cilostazol against ethanol- and pylorus ligation-induced gastric lesions in rats

Naunyn Schmiedebergs Arch Pharmacol. 2019 Dec;392(12):1605-1616. doi: 10.1007/s00210-019-01699-y. Epub 2019 Aug 1.

Abstract

Despite the availability of effective antiulcer medications, their suboptimal safety profile ignites the search for alternative/complementary treatments. Drug repositioning is an attractive, efficient, and low-risk strategy. Cilostazol, a clinically used phosphodiesterase 3 inhibitor, has pronounced anti-inflammatory and vasodilatory effects suggesting antiulcer activity. Using ethanol-induced and pyloric ligation-induced gastric ulcer models, we investigated the gastroprotective effect of cilostazol (5 or 10 mg/kg, p.o.) in comparison with the standard antiulcer ranitidine (50 mg/kg, p.o.) in rats. Gastric mucosa was examined macroscopically, histologically, and biochemically for ulcer severity, markers of oxidative stress, proinflammatory cytokines, apoptotic, and cytoprotective mediators. Gastric acidic output, peptic activity, and mucin content were measured in gastric fluids. Pretreatment with cilostazol reduced ulcer number and severity, ameliorated redox status (reduced glutathione and malonaldehyde content), and decreased levels of IL-1β, IL-6, and TNF-훼 in gastric mucosa, in parallel with increases in mucosal defensive factors nitric oxide (NO), prostaglandin E2 (PGE2), and heat-shock protein 70 (HSP70) promoting mucus secretion, tissue perfusion, and regeneration. Histological examination confirmed the beneficial effects of cilostazol in terms of reducing focal necrosis and infiltration of inflammatory cells, as well as increasing mucopolysaccharide content. These beneficial effects are likely secondary to an increase in cAMP and decrease in apoptosis regulator Bcl-2-associated X protein (BAX). Cilostazol, in a dose-dependent effect, exhibited vasodilatory, anti-inflammatory, and antiapoptotic actions in the gastric mucosa resulting in significant antiulcer activity comparable with the standard drug, ranitidine, but devoid of antisecretory activity. Therefore, its use should be dose and ulcer-inducer dependent.

Keywords: BAX; Cilostazol; Gastric ulcer; HSP 70; PGE2; cAMP.

MeSH terms

  • Animals
  • Anti-Ulcer Agents / pharmacology
  • Anti-Ulcer Agents / therapeutic use*
  • Cilostazol / pharmacology
  • Cilostazol / therapeutic use*
  • Cytokines / metabolism
  • Dinoprostone / metabolism
  • Ethanol
  • Gastric Mucosa / drug effects
  • Gastric Mucosa / metabolism
  • Gastric Mucosa / pathology
  • HSP70 Heat-Shock Proteins / metabolism
  • Male
  • Nitric Oxide / metabolism
  • Pylorus / surgery
  • Rats, Wistar
  • Stomach Ulcer / drug therapy*
  • Stomach Ulcer / etiology
  • Stomach Ulcer / metabolism
  • Stomach Ulcer / pathology

Substances

  • Anti-Ulcer Agents
  • Cytokines
  • HSP70 Heat-Shock Proteins
  • Nitric Oxide
  • Ethanol
  • Dinoprostone
  • Cilostazol