Clopidogrel delays gastric ulcer healing in rats

Clopidogrel is not safe enough for the gastric mucosa in patients with high risk of peptic ulcer. This study aimed to explore if clopidogrel delays gastric ulcer healing and elucidate the involved mechanisms. Gastric ulcer was induced in rats and the ulcer size, mucosal epithelial cell proliferation of the ulcer margin, expression of growth factors [epidermal growth factor (EGF), basic fibroblast growth factor] and their receptors, and signal transduction pathways for cell proliferation were measured and compared between the clopidogrel-treated group and untreated controls. For the in vitro part, rat gastric mucosal epithelial cell line (RGM-1 cells) was used to establish EGF receptor over-expressed cells. Cell proliferation and molecular change under EGF treatment (10ng/ml) with and without clopidogrel (10(-6)M) were demonstrated. Ulcer size was significantly larger in the clopidogrel-treated group compared to the control and mucosal epithelial cell proliferation of the ulcer margin was significantly decreased in the clopidogrel-treated group (P<0.05). Clopidogrel (2mg and 10mg/kg/day) significantly decreased ulcer-induced gastric epithelial cell proliferation and ulcer-stimulated expressions of EGF receptor and phosphorylated extracellular signal-regulated kinase (PERK) at the ulcer margin (P<0.05). Clopidogrel (10(-6)M) also inhibited EGF-stimulated EGF receptor, PERK expression, and cell proliferation in RGM-1 cells (P<0.05), and caused much less inhibition of EGF-stimulated cell proliferation in EGF receptor over-expressed RGM-1 cells than in RGM-1 cells (22% vs. 32% reduction). In conclusion, clopidogrel delays gastric ulcer healing in rats via inhibiting gastric epithelial cell proliferation, at least by inhibition of the EGF receptor-ERK signal transduction pathway.