Abstract
Proton pump inhibitors exert their preventive and healing effects on gastropathy induced by nonsteroidal anti-inflammatory drug (NSAIDs) by a dual action: the antisecretory and the antioxidant effect. The latter was investigated by using esomeprazole against indomethacin-induced gastric mucosa lesions in rats and assessed by a histomorphometric analysis. Treatment by intragastric gavage were 1% methocel as vehicle; esomeprazole 10, 30, or 60 µmol/kg; indomethacin 100 µmol/kg; and esomeprazole 10, 30, or 60 µmol/kg plus indomethacin 100 µmol/kg. The evaluation of glutathione (GSH) levels and respiratory chain complex activities [nicotinamide adenine dinucleotide, reduced (NADH)-ubiquinone oxidoreductase, succinate dehydrogenase, cytochrome C reductase, cytochrome oxidase] was performed in the isolated gastric mucosa. Esomeprazole (10–60 µmol/kg) dose dependently reversed, up to complete recovery, the inhibitory effect of indomethacin on GSH levels (approximately 60% inhibition) and mitochondrial enzyme activities (inhibition ranging from 60% to 75%). Indomethacin-induced mucosal injuries were reduced by esomeprazole. Thus, in addition to inhibiting acid secretion, the gastroprotective effect of esomeprazole can be ascribed to a reduction in gastric oxidative injury.
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Agastya G, West BC, Callahan JM (2000) Omeprazole inhibits phagocytosis and acidification of phagolysosomes of normal human neutrophils in vitro. Immunopharmacol Immunotoxicol 22:357–372
Anderson ME (1985) Determination of glutathione and glutathione disulfide in biological samples. Methods Enzymol 113:548–555
Banerjee D, Maity B, Bauri AK, Bandyopadhyay SK, Chattopadhyay S (2007) Gastroprotective properties of Myristica malabarica against indomethacin-induced stomach ulceration: a mechanistic exploration. J Pharm Pharmacol 59:1555–1565
Biswas K, Bandyopadhyay U, Chattopadhyay I, Varadaraj A, Ali E, Banerjee RK (2003) A novel antioxidant and antiapoptotic role of omeprazole to block gastric ulcer through scavenging of hydroxyl radical. J Biol Chem 278:10993–11001
Blandizzi C, Natale G, Gherardi G, Lazzeri G, Marveggio MC, Colucci R, Carignani D, Del Tacca M (1999) Acid-independent gastroprotective effects of lansoprazole in experimental mucosal injury. Dig Dis Sci 44:2039–2050
Blandizzi C, Fornai M, Colucci R, Natale G, Lubrano V, Vassalle C, Antonioli L, Lazzeri G, Del Tacca M (2005) Lansoprazole prevents experimental gastric injury induced by non-steroidal anti-inflammatory drugs through a reduction of mucosal oxidative damage. World J Gastroenterol 11:4052–4060
Fernandez-Checa JC, Kaplowitz N, Garcia-Ruiz C, Colell A, Miranda M, Marì M, Ardite E, Morales A (1997) GSH transport in mitochondria: defense against TNF-induced oxidative stress and alcohol-induced defect. Am J Physiol 273:G7–G17
Fornai M, Natale G, Colucci R, Tuccori M, Carazzina G, Antonioli L, Baldi S, Lubrano V, Abramo A, Blandizzi C, Del Tacca M (2005) Mechanisms of protection by pantoprazole against NSAID-induced gastric mucosal damage. Naunyn-Schmiedeberg’s Arch Pharmacol 372:79–87
Hassan A, Martin E, Puig-Parellada P (1998) Role of antioxidants in gastric mucosal damage induced by indomethacin in rats. Methods Find Exp Clin Pharmacol 20:849–854
Hiraishi H, Shimada T, Terano A (2000) Involvement of oxidative stress in the pathogenesis of NSAID-induced gastric mucosal damage. J Gastroenterol 35:567–569
Jacob M, Bjarnason I, Simpson RJ (2001) Effects of indomethacin on energy metabolism in rat and human jejunal tissue in vitro. Clin Sci 101:493–498
Janssen M, Dijkmans BAC, Vandenbroucke JP, Biemond I, Lamers CB (1994) Achlorhydria does not protect against benign upper gastrointestinal ulcers during NSAID use. Dig Dis Sci 39:362–365
Koch TR, Petro A, Darrabie M, Opara EC (2004) Effect of the H, K-ATPase inhibitor, esomeprazole magnesium, on gut total antioxidant capacity in mice. J Nutr Biochem 15:522–526
Koch TR, Petro A, Darrabie M, Opara EC (2005) Effects of esomeprazole magnesium on nonsteroidal anti-inflammatory drug gastropathy. Dig Dis Sci 50:86–93
Kwiecien S, Brzozowski T, Konturek SJ (2002) Effects of reactive oxygen species action on gastric mucosa in various models of mucosal injury. J Physiol Pharmacol 53:39–50
Laneuville O, Breuer DK, Dewitt DL, Hla T, Funk CD, Smith WL (1994) Differential inhibition of human prostaglandin endoperoxidase H synthases-1 and -2 by nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther 271:927–934
Lapenna D, De Gioia S, Cofani G, Festi D, Cuccurullo F (1996) Antioxidant properties of omeprazole. FEBS Lett 382:189–192
Loguercio C, Di Pierro M (1999) The role of glutathione in the gastrointestinal tract: a review. Ital J Gastroenterol Hepatol 31:401–407
Lowry OH, Rosebrough MJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Mahmud T, Rafi SS, Scott DL, Wrigglesworth JM, Bjarnason I (1996) Non-steroidal anti-inflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation. Arthritis Rheum 39:1998–2003
Martensson J, Lai JCK, Meister A (1990) High-affinity transport of glutathione is part of a multicomponent system essential for mitochondrial function. Proc Natl Acad Sci USA 87:7185–7189
Martins de Oliveira R, Antunes E, Pedrazzoli J Jr, Gambero A (2007) The inhibitory effects of H+K+ ATPase inhibitors on human neutrophils in vitro: restoration by a K+ ionophore. Inflamm Res 56:105–111
Meister A (1983) Functions of glutathione. In: Larrson A, Orrenius S, Halmgren A, Mannervick B (eds) Functions of glutathione: biochemical, physiological, toxicological and clinical aspects. Raven Press, New York, pp 457–472
Meister A (1991) Glutathione deficiency produced by inhibition of its synthesis, and its reversal; applications in research and therapy. Pharmacol Ther 51:155–194
Naesdal J, Brown K (2006) NSAID-associated adverse effects and acid control aids to prevent them. Drug Saf 29:119–132
Natale G, Lazzeri G, Blandizzi C, Gherardi G, Lenzi P, Pellegrini A, Del Tacca M (2001) Seriate histomorphometry of whole rat stomach: an accurate and reliable method for quantitative analysis of mucosal damage. Toxicol Appl Pharmacol 174:17–26
Natale G, Lazzeri G, Lubrano V, Colucci R, Vassalle C, Fornai M, Blandizzi C, Del Tacca M (2004) Mechanisms of gastroprotection by lansoprazole pretreatment against experimentally induced injury in rats: role of mucosal oxidative damage and sulfhydryl compounds. Toxicol Appl Pharmacol 195:62–72
Pastoris O, Dossena M, Vercesi L, Bruseghini M, Pagnin A, Ceriana P (1991) Biochemical changes induced in the myocardial cell during cardioplegic arrest supplemented with creatine phosphate. J Cardiothorac Vasc Anesth 5:475–480
Richardson P, Hawkey CJ, Stack WA (1998) Proton pump inhibitors. Pharmacology and rationale for use in gastrointestinal disorders. Drugs 56:307–335
Robert A, Eberle D, Kaplowitz N (1987) Role of glutathione in gastric mucosal cytoprotection. J Clin Gastroenterol 9:8–13
Sachs G, Shin JM, Briving C, Wallmark B, Hersey S (1995) The pharmacology of the gastric acid pump: the H+,K+ ATPase. Annu Rev Pharmacol Toxicol 35:277–305
Savoye G, Miralles-Barrachina O, Déchelotte P, Belmonte-Zalar L, Brung-Lefebvre M, Zalar A, Hochain P, Hervé S, Colin R, Lerebours E, Ducrotté P (2001) Low levels of gastric mucosal glutathione during upper gastric bleeding associated with the use of nonsteroidal anti-inflammatory drugs. Eur J Gastroenterol Hepatol 13:1309–1313
Simon WA, Sturm E, Hartmann HJ, Weser U (2006) Hydroxyl radical scavenging reactivity of proton pump inhibitors. Biochem Pharmacol 71:1337–1341
Somasundaram S, Rafi S, Hayllar J, Sigthorsson G, Jacob M, Price AB, Macpherson A, Mahmod T, Scott D, Wrigglesworth JM, Bjarnason I (1997) Mitochondrial damage: a possible mechanism of the “topical” phase of NSAID induced injury to the rat intestine. Gut 41:344–353
Somasundaram S, Sigthorsson G, Simpson RJ, Watts J, Jacob M, Tavares IA, Rafi S, Roseth A, Foster R, Price AB, Wrigglesworth JM, Bjarnason I (2000) Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat. Aliment Pharmacol Ther 14:639–650
Suzuki M, Nakamura M, Mori M, Miura S, Tsuchiya M, Ishii H (1995) Lansoprazole inhibits oxygen-derived free radical production from neutrophils activated by Helicobacter pylori. J Clin Gastroenterol 20:S93–S96
Suzuki M, Mori M, Fukumura D, Suzuki H, Miura S, Ishii H (1999) Omeprazole attenuates neutrophil-endothelial cell adhesive interaction induced by extracts of Helicobacter pylori. J Gastroenterol Hepatol 14:27–31
Takeuchi K, Mizoguchi H, Araki H, Komoike Y, Suzuki K (2001) Lack of gastric toxicity of nitric oxide-releasing indomethacin, NCX-530, in experimental animals. Dig Dis Sci 46:1805–1818
Tsuji S, Sun WH, Tsuji M, Kawai N, Kimura A, Kakiuchi Y, Yasumaru S, Komori M, Murata H, Sasaki Y, Kawano S, Hori M (2002) Lansoprazole induces mucosal protection through gastrin receptor-dependent up-regulation of cyclooxygenase-2 in rats. J Pharmacol Exp Ther 303:1301–1308
Wallace JL (2001) Pathogenesis of NSAID-induced gastroduodenal mucosal injury. Best Pract Res Clin Gastroenterol 15:691–703
Wallace JL, McKnight W, Reuter BK, Vergnolle N (2000) NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology 119:706–714
Wandall JH (1992) Effects of omeprazole on neutrophil chemotaxis, superoxide production, degranulation, and translocation of cytochrome b-245. Gut 33:617–621
Whittle BJ (2003) Gastrointestinal effects of non-steroidal anti-inflammatory drugs. Fundam Clin Pharmacol 17:301–313
Yoshikawa T, Naito Y, Kishi A, Tomii T, Kaneko T, Iinuma S, Ichikawa H, Yasuda M, Takahashi S, Kondo M (1993) Role of active oxygen, lipid peroxidation, and antioxidants in the pathogenesis of gastric mucosal injury induced by indomethacin in rats. Gut 34:732–737
Zedtwitz-Liebenstein K, Wenisch C, Patruta S, Parschalk B, Daxbock F, Graninger W (2002) Omeprazole treatment diminishes intra- and extracellular neutrophil reactive oxygen production and bactericidal activity. Crit Care Med 30:1118–1122
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We thank Dr. Elena Pigoli for reading the manuscript and for her helpful comments. This study was funded in full by a research grant from AstraZeneca.
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Pastoris, O., Verri, M., Boschi, F. et al. Effects of esomeprazole on glutathione levels and mitochondrial oxidative phosphorylation in the gastric mucosa of rats treated with indomethacin. Naunyn-Schmied Arch Pharmacol 378, 421–429 (2008). https://doi.org/10.1007/s00210-008-0314-7
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DOI: https://doi.org/10.1007/s00210-008-0314-7