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

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.

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Acknowledgments

The authors are grateful to Prof. Dr. Nermeen Al- Shafeey, Department of Pathology, National Research Centre, for her kind support in carrying out the histological studies.

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Helmy Moawad supervised the study. Sally A El Awdan designed and supervised the carry out of experiments and collection of data. Nada A Sallam interpreted results and wrote the manuscript. Wafaa El-Eraky conceived and supervised the study. Mohammed A Alkhawlani carried out experiments, collected data, interpreted results, and participated in writing the manuscript. All authors approved manuscript.

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Correspondence to Nada A. Sallam.

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Animal care and use protocol was approved by the Ethics committee of Faculty of Pharmacy, Cairo University (PT 1713) in accordance with the International Standards and the Ethical Guidelines on Animal Welfare (DIRECTIVE 2010/63/EU).

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Moawad, H., El Awdan, S.A., Sallam, N.A. et al. Gastroprotective effect of cilostazol against ethanol- and pylorus ligation–induced gastric lesions in rats. Naunyn-Schmiedeberg's Arch Pharmacol 392, 1605–1616 (2019). https://doi.org/10.1007/s00210-019-01699-y

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Keywords

  • Cilostazol
  • Gastric ulcer
  • PGE2
  • cAMP
  • HSP 70
  • BAX