Journal
LIFE SCIENCES
Volume 308, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2022.120939
Keywords
Ethanol; Irbesartan; NLRP3 inflammasome; HMGB1; Apoptosis; Autophagy
Funding
- Taif University Researchers Supporting Project, Taif University, Saudi Arabia [TURSP-2020/29]
- Taif Univer- sity, Saudi Arabia
- Princess Nourah bint Abdulrahman University Researchers Supporting Project, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia [PNURSP2022R91]
- Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
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The study found that irbesartan can alleviate ethanol-induced gastric mucosal injury by suppressing inflammatory and apoptotic signals, while upregulating pro-autophagy events.
Background: Pronounced anti-inflammatory and anti-apoptotic features have been characterized for the angiotensin receptor blocker irbesartan. Yet, its effect on ethanol-induced gastropathy has not been studied. The present work explored the potential modulation of inflammatory, apoptotic, and autophagic events by irbesartan for the attenuation of ethanol-evoked gastric mucosal injury.Methodology: Wistar rats were divided into control, control + irbesartan, ethanol, ethanol + irbesartan, and ethanol + omeprazole groups. Macroscopic examination, histopathology, immunohistochemistry, and biochemical assays were applied to examine the gastric tissues.Key findings: Irbesartan administration (50 mg/kg; by gavage) in ethanol-evoked gastropathy improved the gastric pathological manifestations (area of gastric lesion and ulcer index scores), histopathological changes, and microscopic damage scores. These beneficial effects were interceded by suppression of the HMGB1-associated inflammatory events and the linked downregulation of the nuclear NF-Kappa Bp65 protein expression. In the meantime, curtailing of the NLRP3 inflammasome by irbesartan was observed with consequent decline of the pro-inflammatory cytokine IL-1 beta. In tandem, upregulation of the antioxidant Nrf2 and the cytoprotective PPAR-gamma were seen. Together, suppression of the pro-inflammatory cues and pro-oxidant signals attenuated the pro-apoptotic events as evidenced by Bcl-2 upregulation, Bax downregulation, and caspase 3 dampened activity. Regarding gastric autophagy signals, irbesartan diminished SQSTM-1/p62 accumulation and upregulated Beclin 1. This was associated with gastric AMPK/mTOR pathway activation evidenced by increased AMPK (Ser487) phosphorylation and lowered mTOR (Ser2448) phosphorylation.Conclusion: Suppression of the inflammatory and apoptotic signals and upregulation of the pro-autophagy events may advocate the promising gastroprotective actions of irbesartan against ethanol-induced gastric injury.
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