Mechanisms of protection by pantoprazole against NSAID-induced gastric mucosal damage

Abstract

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.

ADMINISTRATION OF H2 BLOCKERS IN NSAID INDUCED GASTROPATHY IN RATS: effect on histopathological changes in gastric, hepatic and renal tissues

“…Moreover, rats treated with the combination of ranitidine and diclofenac showed decreased production of gastric acid and also decreased incidence of gastric ulcers. This may be attributed to the ranitidine's antioxidative potential as has been reported in previous studies (7,20,23) . Histologically too, ranitidine was observed to reduce gastric and liver damage which may be due to inhibition of neutrophil activation as observed in earlier studies (21,22) .…”

“…Previous studies have reported that NSAIDs may also induce gastric damage by acid-independent mechanisms such as by increasing oxidative stress parameters viz. increase in mucosal myeloperoxidase levels, together with increase in mucosal malondialdehyde and reduced glutathione concentration (7,20,23) . Malondialdehyde is an end product of the peroxidation of polyunsaturated fatty acids and related esters within cell membranes, such that the measurement of this compound represents a suitable index of oxidative tissue damage (15) .…”

Quercetin and Ellagic Acid in Gastric Ulcer Prevention: An Integrated Scheme of the Potential Mechanisms of Action From in Vivo Study

“…PPIs have a gastroprotective effect, independent on their antisecretory actions [73], which is probably mediated by inhibition of neutrophil functions as well as antioxidant actions [74]. The effect of PPIs on HO-1 induction remain controversial; Becker et al [75] showed that both Omeprazole and Lansoprazole strongly induce HO-1 expression in gastric epithelial cells in vitro, while Takagi et al [76] mentioned that Omeprazole weakly induces the expression of HO-1 in gastric epithelial cell lines.…”

Beneficial Effects of Camellia Oil (<i>Camellia oleifera</i> Abel.) on Hepatoprotective and Gastroprotective Activities

“…Omeprazole, pantoprazole and lansoprazole are widely used as clinical treatments for gastric and duodenal ulcers (27,28). Administration of lansoprazole prevents gastric mucosal injury by indomethacin, piroxicam or ketoprofen by reducing cyclooxygenase-2 (COX-2) mRNA expression in SD rats (29).…”