Protective effects of perindopril against indomethacin-induced gastric mucosal damage through modulation of DDAH-1/ADMA and ACE-2/ANG-(1-7) signaling pathways

Abstract

Indomethacin is a widely used nonsteroidal anti-inflammatory drug; however, its clinical utility is accompanied by serious adverse reactions including peptic ulcers. The current study aims to investigate the protective potential of perindopril against indomethacin-induced gastric injury in rats. Perindopril (4 mg/kg) was administered orally for 7 days and indomethacin (60 mg/kg, single oral dose) was administered on the 7^th day, 1 h after perindopril administration. Pantoprazole was used as a standard agent. Ulcer index (UI), preventive index ratio (PI), histopathological examination, oxidative stress, and inflammatory biomarkers were investigated. Perindopril significantly decreased UI while increased PI and counteracted histopathological aberrations induced by indomethacin. It alleviated indomethacin-induced oxidative stress by lowering NO while increasing GSH content and superoxide dismutase activity. Perindopril significantly downregulated TNF-α and asymmetric dimethylarginine (ADMA), while significantly upregulated COX-2, PGE-2, dimethylarginine dimethylaminohydrolase-1 (DDAH-1), ANG-(1-7), and ACE-2 expression. Together, these findings suggest the gastroprotective effects of perindopril through modulation of DDAH-1/ADMA and ACE-2/ANG-(1-7) signaling.

HIGHLIGHTS

• Perindopril attenuated gastric histopathological damage.

• It increased GSH content and SOD activity while decreased NO content.

• It modulated gastric ADMA and DDAH-1 activity.

• It reduced TNF-α, while increased COX-2 and PGE-2 expression.

• It upregulated ACE-2 activity and ANG-(1-7) protein expression.

Keywords:

• Perindopril
• indomethacin
• gastric ulcer
• oxidative stress
• ADMA
• ACE-2

Acknowledgments

“The authors would like to extend their sincere appreciation to Taif University Researchers Supporting Project number (TURSP-2020/56), Taif University, Taif, Saudi Arabia. The authors are grateful to Dr. Mohamed A. Khattab, Faculty of Veterinary Medicine, Cairo University, Egypt for his generous assistance in histopathological examination of tissues and Dr. Hany A. Omar for his kind help in the careful checking for language, grammar, and style.”

Author contributions

Conceived and designed study: YTM, IAN, AAA and WRM. Performed the experiments:

YTM, WRM. Data analysis: YTM, AAA and WRM. Reagents/materials analysis tools: YTM and IAN. Writing, review and editing: YTM, IAN, AAA and WRM. WRM was responsible for correspondence to journal submission. All authors read and approved the final version of the manuscript and all data were generated in-house and no paper mill was used.

Disclosure statement

The authors declare that there are no conflicts of interest.

Additional information

Funding

Taif University offered a fund through Taif University Researchers Supporting Project number [TURSP-2020/56], Taif, Saudi Arabia.