Effect of p-cymene and rosmarinic acid on gastric ulcer healing - Involvement of multiple endogenous curative mechanisms

Phytomedicine. 2021 Jun;86:153497. doi: 10.1016/j.phymed.2021.153497. Epub 2021 Feb 16.

Abstract

Background: p-Cymene and rosmarinic acid are secondary metabolites found in several medicinal plants and spices. Previous studies have demonstrated their anti-inflammatory, antioxidant, and cytoprotective effects.

Purpose: To evaluate their gastroduodenal antiulcer activity, gastric healing and toxicity in experimental models.

Methods: Preventive antiulcer effects were assessed using oral pre-treatment on HCl/ethanol-induced gastric lesions and cysteamine-induced duodenal lesions models. Gastric healing, the underlining mechanisms and toxicity after repeated doses were carried out using the acetic acid-induced gastric ulcer rat model and oral treatment for 14 days.

Results: In the HCl/ethanol-induced gastric ulcer and cysteamine-induced duodenal injury, p-cymene and rosmarinic acid (50-200 mg/kg) decreased significantly the ulcer area, and so prevented lesions formation. In the acetic acid-induced ulcer model, both compounds (200 mg/kg) markedly reduced the ulcerative injury. These effects were related to an increase in the levels of reduced glutathione (GSH) and interleukin (IL)-10, and due to a decrease in malondialdehyde (MDA), IL-1β, tumor necrosis factor (TNF)-α, total and mitochondrial reactive oxygen species (ROS) levels. Downregulation of factor nuclear kappa B (NFκB) and enhanced expression of suppressor of cytokine signaling (SOCS)3 were also demonstrated. Furthermore, positive vascular endothelial growth factor (VEGF), metalloproteinase (MMP)-2, and cyclooxygenase (COX-2)-stained cells were increased in treated groups. Treatment also upregulated the platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), transforming growth factor (TGF)-β and epidermal growth factor receptor (EGFR) in gastric tissues. In isolated gastric epithelial cells this healing effect seems to be linked to a modulation of apoptosis, proliferation, survival and protein phosphorylation, such as the extracellular signal-regulated kinases (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK). Oral toxicity investigation for 14 days revealed no alterations in heart, liver, spleen, and kidneys weight nor the biochemical and hematological assessed parameters. p-Cymene and rosmarinic acid also protected animals from body weight loss maintaining feed and water intake.

Conclusions: Data altogether suggest low toxicity, antiulcer and gastric healing activities of p-cymene and rosmarinic acid. Antioxidant and immunomodulatory properties seem to be involved in the curative effect as well as the induction of different factors linked to tissue repair.

Keywords: Gastric healing; Gastroduodenal anticulcer; Oral toxicity after repeated doses; Rosmarinic acid; p-Cymene.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / therapeutic use
  • Anti-Ulcer Agents / therapeutic use*
  • Antioxidants / therapeutic use
  • Cinnamates / therapeutic use*
  • Cymenes / therapeutic use*
  • Depsides / therapeutic use*
  • Male
  • Plants, Medicinal
  • Rats
  • Rats, Wistar
  • Stomach Ulcer / drug therapy*

Substances

  • Anti-Inflammatory Agents
  • Anti-Ulcer Agents
  • Antioxidants
  • Cinnamates
  • Cymenes
  • Depsides
  • 4-cymene
  • rosmarinic acid