Parnian Mohammadzadeh
1 
, Behnam Ghorbanzadeh
2* , Mohammad Seydabadi
3, ladan kharaz
1 , Tarang Taghvaei Arabi
4, Fereshteh Beigom Talebpour Amiri
5, Mohammad Shokati sayyad
3, Sara Bayat
4, Gholamreza Houshmand
1,4* 1 Department of Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
2 Department of Pharmacology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
3 Pharmaceutical Sciences Research Center, Department of Pharmacology and Toxicology, School of Pharmacy, Mazandaran University of Medical sciences, Sari, Iran
4 Gut and Liver Research Center, Department of Internal Medicine, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
5 Department of Anatomy, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
Abstract
Purpose: To evaluate the gastroprotective effect of sitagliptin against ethanol-induced gastric ulcers in rats and to investigate the potential involvement of the nitric oxide (NO), cyclic guanosine monophosphate (cGMP), and ATP-sensitive potassium (KATP) channel pathway.Methods: Seventy-seven adult male Wistar rats were randomly allocated into 11 groups (n = 7 per group). Gastric ulcers were induced by oral administration of ethanol (4 ml/kg) following 18–24 hours of fasting. Sitagliptin (25, 50, and 100 mg/kg) was administered orally 30 minutes prior to ethanol exposure. Pharmacological modulators, including stimulators (L-arginine, sildenafil, diazoxide) and inhibitors (Nω-nitro-L-arginine methyl ester hydrochloride, methylene blue, glibenclamide), were administered intraperitoneally 30 minutes prior to sitagliptin. One hour after ethanol administration, rats were sacrificed, gastric lesions were assessed, and tissue samples were analyzed for histopathological changes and inflammatory markers.Results: Sitagliptin at 100 mg/kg significantly reduced gastric ulcer area and inflammatory markers compared to the ethanol-treated group. Co-administration with stimulatory modulators further enhanced these protective effects, whereas inhibitory agents attenuated them.Conclusion: The findings suggest that sitagliptin exerts gastroprotective effects against ethanol-induced gastric injury, possibly involving the NO/cGMP/KATP signaling pathway. These results should be interpreted as a proof-of-concept, and further studies are required to evaluate their clinical relevance.Keywords: ethanol; gastric ulcer; KATP channels; nitric oxide; sitagliptin