ZINC40099027 Promotes Gastric Mucosal Repair in Ongoing Aspirin-Associated Gastric Injury by Activating Focal Adhesion Kinase.

Abstract

Nonsteroidal anti-inflammatory drugs cause gastric ulcers and gastritis. No drug that treats GI injury directly stimulates mucosal healing. ZINC40099027 (ZN27) activates focal adhesion kinase (FAK) and heals acute indomethacin-induced small bowel injury. We investigated the efficacy of ZN27 in rat and human gastric epithelial cells and ongoing aspirin-associated gastric injury. ZN27 (10 nM) stimulated FAK activation and wound closure in rat and human gastric cell lines. C57BL/6J mice were treated with 300 mg/kg/day aspirin for five days to induce ongoing gastric injury. One day after the initial injury, mice received 900 µg/kg/6 h ZN27, 10 mg/kg/day omeprazole, or 900 µg/kg/6 h ZN27 plus 10 mg/kg/day omeprazole. Like omeprazole, ZN27 reduced gastric injury vs. vehicle controls. ZN27-treated mice displayed better gastric architecture, with thicker mucosa and less hyperemia, inflammation, and submucosal edema, and lost less weight than vehicle controls. Gastric pH, serum creatinine, serum alanine aminotransferase (ALT), and renal and hepatic histology were unaffected by ZN27. Blinded scoring of pFAK-Y-397 immunoreactivity at the edge of ZN27-treated lesions demonstrated increased FAK activation, compared to vehicle-treated lesions, confirming target activation in vivo. These results suggest that ZN27 ameliorates ongoing aspirin-associated gastric mucosal injury by a pathway involving FAK activation. ZN27-derivatives may be useful to promote gastric mucosal repair.