Pylorus ligation-induced hyperacidity: synergistic prophylactic effects of linagliptin and L-arginine via up-regulation of EP4 receptor subtype and improvement of vascular endothelial damage

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2024-02, Vol.397 (2), p.1127-1139
• Main Authors: Asaad, Gihan F., Saleh, Dalia O., Mostafa, Rasha E., Hassan, Azza, Jaleel, Gehad Abdel
• Format: Article
• Language: English
• Subjects: Animals; Archives & records; Arginine; Arginine - pharmacology; Biomedical and Life Sciences; Biomedicine; Caspase-3; Chronic illnesses; Gastric juice; Gastric Mucosa; Gene expression; Inflammation; Ketamine; Laboratory animals; Ligation; Linagliptin - metabolism; Linagliptin - pharmacology; Linagliptin - therapeutic use; Medical research; Neurosciences; Nitric oxide; Pepsin; Pharmacology; Pharmacology/Toxicology; Proteins; Pylorus - surgery; Rats; Stomach; Stomach Ulcer - drug therapy; Stomach Ulcer - etiology; Stomach Ulcer - prevention & control; Tumor necrosis factor-α; Ulcers; Up-Regulation; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-023-02667-3

Gastric hyperacidity and ulceration are chronic diseases characterized by repeated healing followed by re-exacerbation. The study aims to protect against gastric hyperacidity without interfering with gastric acid secretion. Pylorus ligation–induced hyperacidity is commonly utilized in the induction of gastric ulcers. Forty-two rats were distributed into seven groups ( n  = 6). Group I comprised sham-operated group. Group II served as pylorus-ligation group. Groups III–VII were given oral Linagliptin (LN; 3 and 6 mg/kg), L-arginine (LA; 150 and 300 mg/kg) and their combination (LN 3 + LA 150 mg/kg), respectively for 7 days. On the 8 th day, groups II–VII were subjected to pylorus-ligation. Treatment of pylorus-ligated rats with LN, LA and their combination improved the gastric hyperacidity as exhibited by a marked reduction in the gastric juice volume, total and free acidities and pepsin contents with a noticeable increase in pH. Pre-treatment with LN, LA and their combination showed a marked alleviation in the gastric inflammatory indicators evidenced by reduction in the gastric levels of MCP-1and Il-1β as well as elevation of eNOS levels versus the sham-operated group. A marked up-regulation in the gastric gene expression of PGE, EP4 and VEGF accompanied by an improvement of the histopathologic pictures/scores, and TNF-α and caspase-3 immuno-staining were also recorded. By estimating the combination-index, it can be concluded that combining LN with LA exhibited prophylactic synergistic effects in ameliorating pylorus ligated-induced hyperacidity, mainly via up-regulation of EP4 receptor and improvement of vascular endothelial damage through VEGF expression in gastric mucosa.