Antiulcer activity of proanthocyanidins is mediated via suppression of oxidative, inflammatory, and apoptotic machineries

Abstract

Gastric ulcer (GU) is a lesion in the gastric mucosa associated with excessive oxidative damage, inflammatory response, apoptotic events, and irritation which may develop into cancer. However, medications commonly used in GU treatment cannot normalize gastric mucosa, while causing several adverse effects. Proanthocyanidins (PAs) are dietary flavonoids with numerous biological and pharmacological activities. In the current investigation, we studied the potential anti-ulcerative activity of PAs against acidified ethanol (HCl/ethanol)-caused gastric ulceration. Fifty male albino Wistar rats were allocated into five equal groups: control, HCl/ethanol (3 mL/kg), lansoprazole (LPZ, 30 mg/kg) + HCl/ethanol, and PAs (100 and 250 mg/kg) + HCl/ethanol. LPZ and PAs were applied one week before gastric ulcer induction. PAs pretreatment notably reduced gastric mucosal macroscopic and microscopic pathological changes in a dose-dependent manner. Additionally, PAs activated the innate antioxidant molecules including glutathione and its derived antioxidants (glutathione peroxidase and glutathione reductase), along with superoxide dismutase and catalase, while attenuating pro-oxidant formation, including malondialdehyde and nitric oxide. Interestingly, PAs supplementation at a higher dose suppressed gastric inflammatory and apoptotic responses, as demonstrated by the reduced levels of interleukin-1β, interleukin-6, tumor necrosis factor alpha, high-mobility group box 1, cyclooxygenase 2, prostaglandin E2, nuclear factor kappa-B, Bcl-2-associated X protein, and caspase-3, while B cell lymphoma 2 was elevated. Hence, PAs could exhibit antiulcer activity by protecting gastric tissue from the development of oxidative damage, inflammatory responses, and apoptosis events associated with ulceration. Practical implications: Gastric ulcer is a lesion in the gastric mucosal layer associated with excessive inflammatory response, apoptotic events, oxidative damage, and irritation, and may develop into cancer with about 5%–10% morbidity rate. However, medications commonly used in GU treatment cannot normalize gastric mucosa, while causing several adverse effects. Therefore, new therapeutic approaches are needed to treat or prevent gastric ulceration. Proanthocyanidins (PAs, condensed tannins) are dietary flavonoids found in abundance in different plant species, including their fruits, bark, and seeds. Due to their potent antioxidative activity, PAs have been applied to prevent or treat oxidative stress-related diseases, including cancer, as well as metabolic, neurodegenerative, cardiovascular, and inflammatory disorders. Here, we examine the potential therapeutic role of proanthocyanidins (PAs) against acidified ethanol-induced gastric ulcer in rats through evaluating oxidative challenge, inflammatory response, apoptotic events, and histopathological changes in the gastric tissue.