Novel gastroprotective role of Alogliptin: Modulating the GDNF/PI3K/Akt/GSK3β, SDF-1/CXCR4, and CREB/COX-2/PGE2 signalling pathways to ameliorate diclofenac-induced peptic ulcer in rats.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain and inflammation, yet their clinical utility is limited by their propensity to induce gastric injury. Alogliptin, a dipeptidyl peptidase-4 inhibitor, exerts pleiotropic effects beyond glucagon-like peptide-1 enhancement, including preservation of stromal cell-derived factor-1 (SDF-1) from degradation, and modulation of glial cell-derived neurotrophic factor (GDNF), a key mediator of gastrointestinal barrier integrity. However, its protective role against NSAID-induced gastric injury has not yet been investigated. Therefore, this study aimed to evaluate the gastroprotective effect of alogliptin against diclofenac-induced gastric ulcer, with emphasis on mucosal repair pathways, oxidative stress, inflammation, and apoptosis. Rats were randomly allocated into four groups: a control group receiving saline for 14 days; Diclofenac group administered diclofenac (50 mg/kg/day, i.p., days 8-14) to induce gastric ulceration; and two pretreatment groups receiving either omeprazole (20 mg/kg/day, p.o.) or alogliptin (40 mg/kg/day, p.o.) for 14 days, concomitantly with diclofenac administration during days 8-14. Alogliptin significantly reduced the ulcer index and preserved gastric mucosal architecture, surpassing omeprazole across most evaluated parameters. Mechanistically, alogliptin restored GDNF/PI3K/Akt signaling, enhanced p-GSK3β/p-CREB, increased COX-2/PGE2 expression, and reestablished SDF-1/CXCR4, collectively supporting mucosal regeneration. Furthermore, Alogliptin suppressed NF-κB/TNF-α-driven inflammation, mitigated oxidative stress, as evidenced by decreased MDA and increased SOD activity, and shifted the apoptotic balance toward cell survival by reducing Bax and elevating Bcl-2 levels. Ultimately, alogliptin exerts multifaceted gastroprotective effects against diclofenac-induced gastric ulcer by enhancing mucosal defense and orchestrating anti-inflammatory, antioxidant, and anti-apoptotic mechanisms through interplay between GDNF/PI3K/Akt, CREB/COX-2/PGE2, and SDF-1/CXCR4 trajectories.