Mechanisms of protection by pantoprazole against NSAID-induced gastric mucosal damage.
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) can be associated with severe adverse digestive effects. In clinical settings, proton pump inhibitors have proven to be effective in preventing and healing NSAID-induced gastroduodenal lesions. The present study investigates the mechanisms of protection afforded by pantoprazole against gastric injury induced by different NSAIDs in rats. Animals were orally treated with indomethacin (100 micromol/kg), diclofenac (60 micromol/kg), piroxicam (150 micromol/kg) or ketoprofen (150 micromol/kg). Thirty minutes before NSAIDs, animals received pantoprazole 6 or 60 micromol/kg orally. Four hours after NSAIDs, the following parameters were assessed: histomorphometric evaluation of gastric mucosal damage; gastric mucosal levels of myeloperoxidase (MPO), malondialdehyde (MDA), reduced glutathione as an index of non-proteic sulfhydryl compounds (GSH), and prostaglandin E2 (PGE2); mucosal cyclooxygenase-1 and -2 (COX-1, COX-2) mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). Separate experiments were carried out to assay the effects of pantoprazole on gastric acid secretion in pylorus-ligated rats. The in vitro influence of pantoprazole (1-10 microM) on the oxidation of low density lipoproteins (LDLs) induced by copper sulphate was also examined. All NSAIDs elicited mucosal necrotic lesions associated with neutrophil infiltration and reduction of PGE2 levels. Increments of MPO and MDA contents, as well as a decrease in GSH levels, were detected in the gastric mucosa of indomethacin-, piroxicam- or ketoprofen-treated animals. Indomethacin enhanced mucosal COX-2 expression, while not affecting COX-1. At the oral dose of 6 micromol/kg pantoprazole did not affect NSAID-induced mucosal damage, whereas at 60 micromol/kg it markedly reduced injuries provoked by all test NSAIDs. Pantoprazole 60 micromol/kg also reversed the effects of NSAIDs on MPO, MDA, and GSH mucosal contents, without interfering with the decrease in PGE2 levels or indomethacin-induced COX-2 expression. However, at both doses, pantoprazole inhibited acid secretion in pylorus-ligated rats. Furthermore, pantoprazole concentration dependently reduced the in vitro oxidation of LDLs. Our results suggest that besides inhibiting acid secretion, the protection afforded by pantoprazole against NSAID-induced gastric damage depends on a reduction in mucosal oxidative injury, which may also account for an increment of sulfhydryl radical mucosal bioavailability. It is also suggested that pantoprazole does not influence the down-regulation of gastric prostaglandin production associated with NSAID treatment.
Fornai
M
M
Interdepartmental Centre for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
Natale
G
G
Colucci
R
R
Tuccori
M
M
Carazzina
G
G
Antonioli
L
L
Baldi
S
S
Lubrano
V
V
Abramo
A
A
Blandizzi
C
C
Del Tacca
M
M
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D004008:Diclofenac; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D007213:Indomethacin; D008026:Ligation; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D010084:Oxidation-Reduction; D000077402:Pantoprazole; D009195:Peroxidase / Q000378:metabolism; D010894:Piroxicam; D054328:Proton Pump Inhibitors; D011708:Pylorus / Q000601:surgery; D051381:Rats; D017208:Rats, Wistar; D013454:Sulfoxides / Q000494:pharmacology*
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; D008077:Lipoproteins, LDL; D054328:Proton Pump Inhibitors; D013454:Sulfoxides; D010894:Piroxicam; D004008:Diclofenac; D008315:Malondialdehyde; D000077402:Pantoprazole; D009195:Peroxidase; D005978:Glutathione; D009853:Omeprazole; D007213:Indomethacin