Antral ulcers induced by alendronate, a nitrogen-containing bisphosphonate, in rat stomachs - prophylactic effect of rebamipide

We demonstrated the development of antral ulcers induced in rats by alendronate and investigated the pathogenic factors involved in this model. Animals fasted for 18 h were given alendronate p.o., and then re-fed normally and killed on various days up to 7 days later. Alendronate caused non-hemorrhagic damage in both the corpus and antrum of fasted rats, but after refeeding for 3 days the lesions in the corpus healed completely, while those in the antrum developed into large ulcers with increased vascular permeability. The development of antral ulcers was accompanied by an increase in MPO activity and lipid peroxidation as well as a decrease in SOD activity and GSH content in the mucosa. Histologically, the damage did not penetrate the muscularis mucosa, yet severe edema and neutrophil infiltration were observed in the submucosa. Neither omeprazole nor indomethacin had any effect, while allopurinol and SOD reduced the severity of these ulcers. Rebamipide dose-dependently suppressed the ulcerogenic response to alendronate, with a concomitant reversal of the increased vascular permeability, MPO activity and lipid peroxidation as well as the reduced SOD activity and GSH content. These results suggest that alendronate did not cause gross damage in the stomach of fasted rats, yet produced large ulcers in the antrum with severe edema after refeeding. The pathogenesis of these ulcers may be explained by impairment of the mucosal anti-oxidative system and does not involve acid/peptic digestion and deficiency of prostaglandins. Rebamipide prevents the antral ulcers, probably due to its anti-oxidative as well as anti-inflammatory actions.