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Cilostazol protects against gastric ulcers by regulating PPAR-γ, HO-1, PECAM-1, pErk-1, NF-κB, Bcl-2, and cleaved

Nagla A El-Shitany¹, Eman A El-Saidy², Mostafa E El-Naggar²

¹Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt. nagla_fouad@yahoo.com.

Naunyn-Schmiedeberg'S Archives of Pharmacology

|June 17, 2024

Abstract:

Millions of individuals worldwide, across all age groups, suffer from the widespread health issue of gastric ulcers. In many experiments, cilostazol (Cls), a phosphodiesterase-3 inhibitor, was recently shown to have anti-ulcer activity. Notably, Cls increases the expression and transcriptional activity of PPAR-γ in vitro and in vivo. This study aimed to evaluate the protective effect of Cls against ethanol-induced gastric ulcers and clarify the possible underlying mechanisms with an emphasis on the role of PPAR-γ. Male albino rats were treated with ethanol to induce gastric ulcers, or they were pretreated with Cls, omeprazole (Omp), GW9662, or Cls + GW9662 for 14 consecutive days before receiving ethanol. Cls protects against ethanol-induced gastric ulcers. Cls treatment significantly reduced ethanol-induced upregulation of the pro-inflammatory markers (IL-1β, IL-6, TNF-α, and NF-κB), MDA (a marker of lipid peroxidation), and caspase-3 and cleaved caspase-3 (apoptotic markers). On the other hand, Cls treatment counteracted ethanol-induced downregulation of PPAR-γ, pErk-1, HO-1 and GSH (antioxidant markers), PECAM-1 and NO (healing markers), and Bcl-2 (antiapoptotic marker). However, when combined with GW9662, a potent antagonist of PPAR-γ, Cls loses its effects. In conclusion, these results suggest that PPAR-γ and pErk-1 are essential for Cls's protective effects against ethanol-induced gastric ulcers.

Insights

Cilostazol (Cls) effectively protects against gastric ulcers by reducing inflammation and apoptosis. Its protective effects are mediated through the activation of PPAR-γ and pErk-1 pathways, crucial for healing.

Area of Science:

Gastroenterology
Pharmacology
Molecular Biology

Background:

Gastric ulcers affect millions globally, necessitating effective treatments.
Cilostazol (Cls), a phosphodiesterase-3 inhibitor, exhibits potential anti-ulcer properties.
Cls is known to enhance peroxisome proliferator-activated receptor gamma (PPAR-γ) activity.

Purpose of the Study:

To investigate the protective effects of Cls against ethanol-induced gastric ulcers in rats.
To elucidate the underlying mechanisms, focusing on the role of PPAR-γ.
To assess the impact of Cls on inflammatory, apoptotic, antioxidant, and healing markers.

Main Methods:

Ethanol was used to induce gastric ulcers in male albino rats.
Rats were pretreated with Cls, omeprazole (Omp), GW9662 (PPAR-γ antagonist), or Cls + GW9662.
Key markers including inflammatory cytokines, lipid peroxidation, apoptosis, antioxidants, and healing factors were analyzed.

Main Results:

Cls significantly reduced gastric ulcer formation and associated inflammation (IL-1β, IL-6, TNF-α, NF-κB).
Cls inhibited lipid peroxidation (MDA) and apoptosis (caspase-3), while promoting antioxidant (HO-1, GSH) and healing markers (PECAM-1, NO).
The protective effects of Cls were abolished when co-administered with GW9662, indicating the critical role of PPAR-γ.

Conclusions:

Cilostazol demonstrates significant gastroprotection against ethanol-induced ulcers.
PPAR-γ and pErk-1 activation are essential mechanisms underlying Cls's therapeutic effects.
Cls represents a promising therapeutic agent for gastric ulcer treatment.

Read full analysis

Keywords:

Cilostazol Gastric ulcer NF-κB PECAM-1 PPAR-γ pErk-1

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