Sitagliptin Impairs Healing of Experimentally Induced Gastric Ulcers Via inhibition of iNOS and COX-2 Expression

Gastric ulcer healing is a complex process that is regulated by several promoting factors including COX-2 and iNOS. Diabetes mellitus is usually associated with delayed gastric ulcer healing. Hence, the current study was designed to investigate the effect of sitagliptin (dipeptidyl peptidase-4 inhibitor) on gastric ulcer healing and expression of iNOS and COX-2 in rat stomach.The study was conducted on 30 rats divided into three equal groups. Group 1 served as normal control group. Gastric ulcer was induced, by serosal application of acetic acid, in group 2 (ulcer model group) and group 3 (sitagliptin-treated group). Sitagliptin was administrated from day 3 to day 10 in group 3. All rats were sacrificed on day 10 and stomachs were removed for pathological examination and immunohistochemical assessment of COX-2 and iNOS expression. Pathological examination revealed that gastric ulcer healing was significantly impaired in the sitagliptin-treated group as evidenced by the significantly larger ulcerated area and ulcer base maturation impairment.COX-2 and iNOS expression as well as mean MVD were significantly diminished in the sitagliptin-treated group as compared to the ulcer model group. A significant positive correlation was found between COX-2 and iNOS implying their synergistic action. We conclude that sitagliptin significantly impairs gastric ulcer healing in rats possibly through inhibition of iNOS and COX-2 expression. Our results raise the question of whether sitagliptin is advisable in diabetic patients with pre-existing gastric ulcer. Our preliminary experimental findings need to be substantiated by future human studies.