Characterization of mechanisms underlying the effects of esomeprazole on the impairment of gastric ulcer healing with addition of NSAID treatment

BackgroundThe efficacy of proton pump inhibitors in patients at high risk of gastrointestinal injury receiving non-steroidal anti-inflammatory drugs is currently debated.AimsTo evaluate the effects of esomeprazole on the impairment of gastric ulcer healing associated with non-steroidal anti-inflammatory drug treatment.MethodsGastric ulcers were induced in rats by acetic acid. Four days later, animals were treated daily with equivalent acid-inhibiting doses of esomeprazole or famotidine, alone or in combination with indomethacin. At day 3 or 7 of treatment, ulcerated tissues were processed to assess: ulcer area; malondialdehyde; prostaglandin E2; nuclear factor-kB; proliferating cell nuclear antigen and caspase-3 (Western blot).ResultsIn indomethacin-treated animals, esomeprazole was more effective than famotidine or the antioxidant melatonin in promoting ulcer healing. Malondialdehyde levels were increased by indomethacin, and this effect was counteracted by esomeprazole, but not famotidine. Esomeprazole and famotidine, given alone or in combination with indomethacin, increased proliferating cell nuclear antigen expression. Increased levels of prostaglandin E2 were detected in ulcerated tissues. Ulcer prostaglandin E2 production was reduced by indomethacin, alone or in combination with esomeprazole or famotidine, while it was enhanced when esomeprazole or famotidine were tested alone. The activation of caspase-3 was induced by indomethacin, and this effect was prevented by esomeprazole, but not famotidine. In the presence of indomethacin, esomeprazole, but not famotidine, enhanced nuclear factor-kB activation in gastric ulcers.ConclusionsEsomeprazole counteracts the detrimental action of indomethacin on ulcer repair through both acid-dependent and acid-independent effects. The acid-independent actions are related to decrease in tissue oxidation and apoptosis and to enhancement of nuclear factor-kB activation.