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Background: We previously described the gastroprotective effect of 2-phenylquinoline (2-PQ), the main alkaloid isolated from the bark of Galipea longiflora (Rutaceae). However, despite the significant and promising results, the pharmacological mechanisms of the gastroprotection induced by 2-PQ have not been investigated.Purpose: To evaluate the mechanisms underlying the gastroprotective effects of 2-PQ.Study Design: We used an in vivo mouse ulcer model and in vitro methodologies involving H⁺/K⁺-ATPase and L929 murine fibroblasts.Methods: The gastroprotective activity of 2-PQ (10-100 mg/kg, orally, p.o) was assessed against gastric ulcer induced by 60% ethanol/0.03 M hydrochloric acid (HCl) in mice or that induced by indomethacin (80 mg/kg, p.o) in rats. The cytotoxicity was assessed in L929 murine fibroblasts. Ulcerated tissues were analyzed histologically, histochemically, and biochemically. The antisecretory activity of 2-PQ was evaluated in vivo and in vitro.Results: 2-PQ showed no cytotoxicity, reduced the lesion area induced by ethanol/HCl (log half-maximal effective dose, ED50 = 1.507), and the histological evaluation supported these results. Furthermore, 2-PQ reduced indomethacin-induced gastric ulceration. The gastroprotection was accompanied by normalization of superoxide dismutase (SOD) and glutathione-S-transferase (GST) activity, an intense increase in reduced glutathione (GSH) levels, and reduction in lipid peroxide (LPO) and tumor necrosis factor (TNF)-α levels in the gastric mucosa. The antisecretory properties of 2-PQ were confirmed by the decreased volume and total acidity of the gastric juice, and it reduced histamine- or pentagastrin-stimulated gastric acid secretion. However, 2-PQ did not change the in vitro H⁺/K⁺-ATPase activity or the content of gastric-adhered mucous in mice. In addition, pretreatment with N-ethylmaleimide, NG-nitro-l-arginine methyl esters, yohimbine, or indomethacin reversed the gastroprotective effect of 2-PQ, suggesting nitric oxide, nonprotein sulfhydryl compounds, α-2-receptors, and prostaglandin were involved.Conclusion: 2-PQ provides gastroprotection by reducing oxidative damage and inhibiting acid secretion mediated by histaminergic and gastrinergic regulatory pathways. [ABSTRACT FROM AUTHOR]