We have previously shown that nesfatin-1 exerts neuroprotective and anti-apoptotic effects, and alleviates indomethacin-induced acute gastric ulcer1,2,3. We aimed to investigate the anti-inflammatory effects of nesfatin-1 in a chronic gastric ulcer model and the involvement of cycloxygenase (COX) pathway in nesfatin-1-afforded gastroprotection. Experimental protocols were approved by the Marmara University Animal Ethics Committee. Under anesthesia (100 mg/kg ketamine+10mg/kg chlorpromazine; intraperitoneally, ip) fasted male Sprague Dawley rats (250-300g) underwent a midline laparotomy, and half a milliliter of acetic acid (80%; ulcer groups; n=40) or saline (control groups; n=40) was applied on serosal surface of stomachs for 1 min. Control or ulcer groups were treated daily with either ip saline or nesfatin-1 (0.3 μg/kg; for 3 days). Nesfatin-1-treatment was preceded with ip saline, COX-2 inhibitor NS-398 (2 mg/kg), COX-1 inhibitor ketorolac (3 mg/kg) or non-selective COX inhibitor indomethacin (5 mg/kg) for 3 days. Rats were decapitated at the end of third day and their trunk blood was collected for the measurements of TNF-α, IL-1β and IL-10 using ELISA. Gastric lesions were scored macroscopically, and gastric samples were analyzed for levels of malondialdehyde (MDA; indicator of lipid peroxidation), antioxidants glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT), luminol and lucigenin-enhanced chemiluminescence (CL; measure of reactive oxygen metabolites) and myeloperoxidase activity (MPO; indicating neutrophil infiltration). Mann-Whitney U and ANOVA tests were used for statistical analysis. Induction of ulcer resulted in increased macroscopic scores (p<0.01) along with elevated gastric MDA, CL levels and MPO activity (p<0.001); while nesfatin-1 treatment abolished these elevations (p<0.05-0.001). Depleted GSH, SOD and CAT levels (p<0.001) in the saline-treated ulcer group were preserved in the nesfatin-1-treated ulcer group (p<0.01, p<0.001). Increased levels of serum TNF-α, IL-1β, IL-10 in the saline-treated ulcer group as compared to control group (p<0.05-0.001) were significantly decreased in nesfatin-1-treated ulcer group (p<0.05-0.01). Inhibition of COX-1, COX-2 or both reversed most of the alterations induced with nesfatin-1, but COX-2-blockade (p<0.05-0.001) was consistently more effective to abolish all nesfatin-1-induced changes. Our results suggest that nesfatin-1 ameliorates ulcer-induced inflammatory response through the modulation of oxidant-antioxidant balance. Since selective pharmacological inhibition of COX-1 or COX-2 suppresses the antioxidant/anti-inflammatory effects of nesfatin-1, it appears that nesfatin-1 decreases inflammatory mediators and neutrophil migration by a COX-dependent, and especially COX-2-dependent mechanism during the ulcer healing stage.