Usnea longissima, a medicinal lichen of Anatolia (Turkey), is used in the treatment of gastric ulcer in local folk medicine. In this paper, the gastroprotective effect of usnic acid (UA) isolated from Usnea longissima was investigated in the indomethacin-induced gastric ulcers in rats at doses of 25, 50, 100 and 200 mg/kg body weight. The gastric lesions were significantly reduced by all doses of UA as compared with the indomethacin (25 mg/kg body weight) treated group. In the stomach tissues of treated animals, the in vivo antioxidant levels were evaluated. The administration of indomethacin caused a significant decrease in the levels of superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH), and an increase in the lipid peroxidation (LPO) level (p < 0.05). The administration of all doses of UA reversed the trend, inducing a significant increase of SOD, GSH and GPx levels and a reduction in LPO level in tissues. However, catalase (CAT), glutathione reductase (GR) and myeloperoxidase (MPx) activities, increased by indomethacin, were found to be lower in the UA- and ranitidine-treated groups. The gastric mucosal constitutive NO synthase (cNOS) and inducible NO symbase (iNOS) activities were also investigated in tissues of UA- (100mg/kg), ranitidine- (50mg/kg) and indomethacin-treated rat groups. The administration of UA and ranitidine increased the cNOS activity and lowered the iNOS activity as compared with indomethacin-treated group. These results suggest that the gastroprotective effect of UA can be attributed to its reducing effect on the oxidative damage and neutrophil infiltration in tissues. (c) 2005 Elsevier Ireland Ltd. All rights reserved.