Xenin-25 Protects Against Indomethacin-Induced Acute Gastric Injury in Rats via Antioxidant and Anti-Inflammatory Actions
Background
Acute gastric injury, often induced by non-steroidal anti-inflammatory drugs (NSAIDs) like indomethacin, is a prevalent and serious condition leading to gastric ulcers, bleeding, and perforations. Current treatments, primarily proton pump inhibitors (PPIs), offer symptomatic relief but often fall short in addressing the underlying oxidative stress, inflammation, and apoptosis that drive mucosal damage. Xenin-25, a neuropeptide, has demonstrated diverse physiological roles, including effects on gastrointestinal function, making it a compelling candidate for novel gastroprotective strategies that target these fundamental pathological processes.
Study Design
Male Sprague-Dawley rats were randomly assigned to control, saline-treated ulcer, and Xenin-25-treated ulcer groups. Gastric ulcers were induced with indomethacin (25 mg/kg, subcutaneously). Xenin-25 (0.2, 2, 20 µg/kg) or saline was administered subcutaneously immediately after and at 2 h following indomethacin injection. To investigate vagal afferent fiber involvement, two additional groups underwent vagal afferent denervation (VAD) via bilateral perivagal capsaicin application (1%). Following a 2-week recovery, VAD rats received ulcer induction, then Xenin-25 (2 µg/kg) or saline. All animals were sacrificed 4 h after ulcer induction for biochemical, molecular, and histopathological analyses.
Results
Indomethacin administration resulted in significant increases in malondialdehyde (MDA) and myeloperoxidase (MPO) levels, accompanied by glutathione depletion. Molecular analysis showed upregulation of nuclear factor-κB (NF-κB) and Bax, alongside downregulation of Bcl2 expression, indicating increased inflammation and apoptosis. Histopathological examination confirmed severe gastric damage.
Xenin-25 treatment markedly attenuated these adverse effects, reducing oxidative stress, inflammatory responses, apoptotic markers, and histopathological gastric damage across all doses tested. Notably, Xenin-25-induced reductions in lesion length, MDA, and MPO levels were abolished in VAD rats. However, all other anti-inflammatory and anti-apoptotic effects of Xenin-25 were preserved even in the absence of vagal afferents, suggesting a dual or direct mechanism of action.
Key Findings
- Indomethacin increased
malondialdehydeandmyeloperoxidaselevels, and alteredNF-κB,Bax,Bcl2expression. - Xenin-25 treatment markedly attenuated oxidative stress, inflammation, and apoptosis markers.
- Xenin-25 reduced histopathological gastric damage in indomethacin-induced injury.
- Xenin-25's reduction in lesion length,
malondialdehyde, andmyeloperoxidasewas abolished in vagal afferent denervated rats. - Other anti-inflammatory and anti-apoptotic effects of Xenin-25 were preserved despite vagal afferent denervation.
Why It Matters
Xenin-25 presents a promising therapeutic agent for acute gastric injury, potentially offering a more comprehensive approach than current symptomatic treatments. Its ability to mitigate oxidative stress, inflammation, and apoptosis directly addresses key pathological drivers of gastric damage. The finding that many of its beneficial effects are independent of vagal afferent fibers suggests a direct action on gastric tissue, which could simplify its clinical translation and broaden its applicability. This preclinical evidence supports further investigation into Xenin-25's potential as a novel gastroprotective strategy, possibly as an adjunct therapy for NSAID-induced gastropathy or other forms of acute mucosal injury.
xenin-25
gastric-injury
indomethacin
inflammation
oxidative-stress
apoptosis