title: Characterization of mechanisms underlying the effects of esomeprazole on the impairment of gastric ulcer healing with addition of NSAID treatment.
abstract: BACKGROUND
  The efficacy of proton pump inhibitors in patients at high risk of gastrointestinal injury receiving non-steroidal anti-inflammatory drugs is currently debated.
  
  
  OBJECTIVE
  To evaluate the effects of esomeprazole on the impairment of gastric ulcer healing associated with non-steroidal anti-inflammatory drug treatment.
  
  
  METHODS
  Gastric 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 E(2); nuclear factor-kB; proliferating cell nuclear antigen and caspase-3 (Western blot).
  
  
  RESULTS
  In 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 E(2) were detected in ulcerated tissues. Ulcer prostaglandin E(2) 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.
  
  
  CONCLUSIONS
  Esomeprazole 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.
authors.affiliation: Interdepartmental Centre for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa, Pisa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Colucci
authors.forename: M
authors.initials: M
authors.lastname: Fornai
authors.forename: L
authors.initials: L
authors.lastname: Antonioli
authors.forename: N
authors.initials: N
authors.lastname: Ghisu
authors.forename: M
authors.initials: M
authors.lastname: Tuccori
authors.forename: C
authors.initials: C
authors.lastname: Blandizzi
authors.forename: M
authors.initials: M
authors.lastname: Del Tacca
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D000897:Anti-Ulcer Agents / Q000008:administration & dosage*; D000975:Antioxidants / Q000008:administration & dosage; D053148:Caspase 3 / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D064098:Esomeprazole / Q000008:administration & dosage*; D015738:Famotidine / Q000008:administration & dosage; D007213:Indomethacin / Q000008:administration & dosage; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008550:Melatonin / Q000008:administration & dosage; D016328:NF-kappa B / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D000975:Antioxidants; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D008315:Malondialdehyde; D015738:Famotidine; D053148:Caspase 3; D008550:Melatonin; D015232:Dinoprostone; D064098:Esomeprazole; D007213:Indomethacin