Xenin-25 Attenuates Indomethacin-Induced Gastric Injury in Rats by Modulating Inflammatory, Antioxidant, and Apoptotic Processes: The Role of Vagal Afferent Fibers

Nonsteroidal anti-inflammatory drug (NSAID)-induced gastric injury is closely linked to oxidative stress, inflammation, and apoptosis. Xenin-25, a 25–amino acid peptide widely distributed in the gastrointestinal tract and central nervous system, regulates motility, secretion, and feeding. This study investigated whether its gastroprotective effects in an indomethacin-induced ulcer model depend on vagal afferent fibers using a capsaicin-denervation approach. Male Sprague-Dawley rats were randomly assigned to the following groups (n = 7 each): control ulcer, ulcer-treated Xenin-25 (0.2, 2, or 20 µg/kg, subcutaneously (s.c.)), ulcer with VAD, and ulcer with VAD plus Xenin-25 (2µg/kg, s.c.). VAD was induced by bilateral perivagal capsaicin, followed by three weeks of recovery. Ulcers were produced with indomethacin (25 mg/kg, s.c.), and Xenin-25 or saline was given immediately and at 2 h. Animals were sacrificed at 4 h under anesthesia. Gastric tissues were assessed for malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO), and caspase-3 levels, as well as mRNA expression of nuclear factor kappa B(NF-κB), Bcl-2, and Bax. Histopathological evaluation included hematoxylin–eosin staining. Ulcer-induction significantly increased MDA and MPO levels and decreased GSH content, with marked upregulation of NF-κB and Bax and downregulation of Bcl-2 (p < 0.01–0.001). Xenin-25 ameliorated oxidative stress, normalized inflammatory and apoptotic markers, and reduced macroscopic and histopathological scores (p < 0.001 vs. ulcer). While Xenin-25 protective effects were largely preserved in VAD rats, reductions in MDA levels and lesion length were attenuated. Xenin-25 ameliorates NSAID-induced gastric injury through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, and vagal afferent integrity partially contributes to its efficacy.