Antiulcer activity and mechanism of action of the hydroethanolic extract of leaves of Terminalia argentea Mart. In different in vivo and in vitro experimental models

Terminalia argentea Mart. (Combretaceae) is a deciduous tree commonly found in Brazil, Bolivia, and Paraguay. It occurs in all regions of Brazil and is widespread in the Amazon, Cerrado, Pantanal, Atlantic Rain Forest, and Caatinga Biomes. In the traditional medicine of Brazil, people widely use tea or decoction of its leaf materials for treating gastritis, ulcers, wound healing, and inflammation.The current study aims to evaluate the gastroprotective and ulcer-healing activities of the hydroethanolic extract of T. argentea leaves (HETa) and investigate the underlying mechanisms of action through in vivo and in vitro experiments.We extracted the leaves of T. argentea with a 70% hydroethanolic solution (HETa) and performed phytochemical analysis using high-performance liquid chromatography (HPLC) and electrospray ionization mass spectrometry (ESI-MSn). We researched the antiulcer activity using in vivo and in vitro experiments, administering three doses (2, 10, and 50 mg/kg) and different concentrations of 1, 5, and 20 μg/mL, respectively. We verified the acute antiulcer activity using chemical models (acidified ethanol (EtOH/HCl) and indomethacin (IND)) and physiological models (water-immersion stress (WRS)). To induce chronic ulcers, used acetic acid and treated the animals for seven days. To investigate the mechanism of action, conducted assays of antioxidant activity, measured the dosage of inflammatory cytokines, quantified mucus, treated with inhibitors (IND, L-NAME, glibenclamide, and yohimbine), performed histopathological analysis, and measured gastric acid secretion. Furthermore, we performed in vitro experiments on murine macrophage cell lines (RAW 264-7 cells) to quantify nitrite/nitrate and cytokine production and on V79-4 cells to verify cell proliferation/migration.We conducted HPLC and ESI-MSn analyses to obtain a fingerprint of the chemical composition of the HETa, revealing the presence of phenolics (caffeoyl ellagic acid), flavonoids (rutin, quercetin xyloside, quercetin rhamnoside, quercetin glucoside, quercetin galloyl xyloside, quercetin), and tannins (terminalin), respectively. The three doses of HETa reduced acute and chronic ulcers in different models. The mechanism of action involves increasing mucus production and angiogenesis, and it partially involves prostaglandins, nitric oxide, K+ATP channels, and α2-adrenergic receptors. HETa also exhibited antioxidant potential, reducing myeloperoxidase (MPO) activity, and increasing glutathione (GSH) levels. Moreover, it demonstrated anti-inflammatory action by reducing nitrite/nitrate levels and pro-inflammatory cytokine concentrations in vivo, and it increased in vitro proliferation/migration of fibroblasts.The study shows that HETa presents a potent preventive and curative antiulcer effect in different ulcer models, supporting the popular use of homemade preparations of T. argentea leaves. The preventive and gastric healing ulcer activity of HETa involves multiple targets, including increasing the gastric mucus barrier, antioxidant defenses, and anti-inflammatory effects on gastric mucosa repair. Phytochemical analysis identified the presence of phenolic compounds, flavonoids, and tannins in HETa, and the antiulcer activity may be attributable to the combined effect of these constituents.