Abstract
Indomethacin (IND) is a non-steroid anti-inflammatory agent that is known to induce severe gastric mucosal lesions. In this study, we investigated the protective effect of selenium (SEL), grape seed extract (GSE), and both on IND-induced gastric mucosal ulcers in rats. Sprague–Dawley rats (200–250 g) were given SEL, GSE, and both by oral gavage for 28 days, and then gastric ulcers were induced by oral administration of 25 mg/kg IND. Malondialdehyde (MDA), non-enzymatic (reduced glutathione, GSH) and enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) antioxidants, prostaglandin E2 (PGE2) in gastric mucosa, and serum tumor necrosis factor alpha (TNF-α) were measured. Moreover, gastric ulcer index and preventive index were determined. Indomethacin increased the gastric ulcer index, MDA, TNF-α, and decreased PGE2 and non-enzymatic (GSH) and enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) antioxidants. Pretreatment with SEL, GSE, and both significantly decreased the gastric ulcer index, MDA, and TNF and increased antioxidants and PGE2. Histopathological observations confirm the gastric ulcer index and biochemical parameters. Selenium and GSE have a protective effect against IND-induced gastric ulcers through prevention of lipid peroxidation, increase of GSH, activation of radical scavenging enzymes, PGE2 generation, and anti-inflammatory activity. Co-administration of GSE and SEL is more effective than GSE or SEL alone.
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References
- 1.
Abdallah IZA, Khattab HAH, Heeba GH (2011) Gastroprotective effect of Cordia myxa L. fruit extract against indomethacin-induced gastric ulceration in rats. Life Sci J 8(3):433–445
- 2.
Adhikary B, Yadav SK, Roy K, Bandyopadhyay SK, Chattopadhyay S (2011) Black tea and theaflavins assist healing of indomethacin-induced gastric ulceration in mice by antioxidative action. Evidence-Based Complementary and Alternative Medicine. Article ID 546560, 11 pp. doi:10.1155/2011/546560
- 3.
Avila JR, de la Lastra CA, Martín MJ et al (1996) Role of endogenous sulphydryls and neutrophil infiltration in the pathogenesis of gastric mucosal injury induced by piroxicam in rats. Inflamm Res 45(2):83–88
- 4.
Barnes PJ, Karin M (1997) Nuclear factor-κB—a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336(15):1066–1071
- 5.
Bertrand V, Guessous F, Le Roy AL et al (1999) Copper-indomethacinate associated with zwitterionic phospholipids prevents enteropathy in rats: effect on inducible no synthase. Dig Dis Sci 44(5):991–999
- 6.
Borrelli F, Izzo AA (2000) The plant kingdom as source of anti ulcer remedies. Phytother Res 14(8):581–591
- 7.
Brzozowski T, Konturek PC, Konturek SJ, Brzozowska I, Pawlik T (2005) Role of prostaglandins in gastroprotection and gastric adaptation. J Physiol Pharmacol 56:33–55
- 8.
Cho ML, Heo YJ, Park MK, Oh HJ, Park JS, Woo YJ, Ju JH, Park SH, Kim HY, Min JK (2009) Grape seed proanthocyanidin extract (GSPE) attenuates collagen-induced arthritis. Immunol Lett 124(2):102–110
- 9.
Cuevas VM, Calzado YR, Guerra YP, Year AO, Despaigne SJ, Ferreiro RM, Quintana DC (2011) Effects of grape seed extract, vitamin C, and vitamin E on ethanol- and aspirin-induced ulcers. Advances in Pharmacological Sciences. doi:10.1155/2011/740687
- 10.
Demir S, Yilmaz M, Koseoglu M, Akalin N, Aslan D, Aydin A (2003) Role of free radicals in peptic ulcer and gastritis. Turk J Gastroenterol 14(1):39–43
- 11.
Devi A, Jolitha AB, Ishii N (2006) Grape seed proanthocyanidin extract (GSPE) and antioxidant defense in the brain of adult rats. Med Sci Monit 12(4):124–129
- 12.
Fairweather-Tait SJ, Bao Y, Broadley MR, Collings R, Ford D, Hesketh JE, Hurst R (2011) Selenium in human health and disease. Antioxid Redox Signal 14:1337–1383
- 13.
Fesharaki M, Nasimi A, Mokhtari S, Mokhtari R, Moradian R, Amirpoor N (2006) Reactive oxygen metabolites and anti-oxidative defenses in aspirin-induced gastric damage in rats: gastroprotection by vitamin E. Pathophysiology 13(4):237–243
- 14.
Gong G, Méplan C, Gautrey H, Hall J, Hesketh JE (2012) Differential effects of selenium and knock-down of glutathione peroxidases on TNFα and flagellin inflammatory responses in gut epithelial cells. Genes Nutr 7:167–178
- 15.
Gryglewski RJ, Szczeklik A, Wandzilak M (1987) The effect of six prostaglandins, prostacyclin and iloprost on generation of superoxide anions by human polymorphonuclear leukocytes stimulated by zymosan or formyl-methionyl-leucylphenylalanine. Biochem Pharmacol 36(24):4209–4213
- 16.
Halliwell B, Gutteridge JM (1992) Biologically relevant metal ion-dependent hydroxyl radical generation: an update. FEBS Lett 307:108–112
- 17.
Halter F, Tarnawski AS, Schmassmann A, Peskar BM (2001) Cyclooxygenase 2—implications on maintenance of gastric mucosal integrity and ulcer healing: controversial issues and perspectives. Gut 49(3):443–453
- 18.
Hamaguchi M, Watanabe T, Higuchi K, Tominaga K, Fujiwara Y, Arkawa T (2001) Mechanisms and roles of neutrophil infiltration in stress-induced gastric injury in rats. Dig Dis Sci 46(12):2708–2715
- 19.
Hano J, Bugajski J, Danek L (1976) Effect ofadrenergic blockade on gastric secretion altered by catecholamines in rats. Arch Immunol Ther Exp (Warsz) 24(4):507–524
- 20.
Hogaboam CM, Bissonnete EY, Chin BC, Befus AD, Wallace J (1993) Prostaglandins inhibit inflammatory mediator release from rat mast cells. Gastroenterol 104(1):122–129
- 21.
Imam SZ, Newport GD, Islam F, Slikker WJ, Ali SF (1999) Selenium, an antioxidant, protects against methamphetamine induced dopaminergic neurotoxicity. Brain Res 818:575–578
- 22.
Jainu M, Mohan V, Devi S (2006) Protective effect of Cissus quadrangularis on neutrophil mediated tissue injury induced by aspirin in rats. J Ethnopharmacol 104(3):302–305
- 23.
Kim JH, Kim BW, Kwon HJ, Nam S-W (2011) Curative effect of selenium against indomethacin-induced gastric ulcers in rats. J Microbiol Biotechnol 21(4):400–404
- 24.
Kim JH, Park SH, Nam SW, Choi YH (2012) Gastroprotective effect of selenium on ethanol-induced gastric damage in rats. Int J Mol Sci 13:5740–5750
- 25.
Kunkel SL, Wiggins R, Chensue SW, Larrick J (1986) Regulation of macrophage tumor necrosis factor production by prostaglandin E2. Biochem Biophys Res Commun 137(1):404–410
- 26.
Kwiecien S, Brzozowski T, Konturek SJ (2002) Effects of reactive oxygen species on gastric mucosa in various models of mucosal injury. J Physiol Pharmacol 53(1):39–50
- 27.
Laine L, Takeuchi K, Tarnawski A (2008) Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology 135:41–60
- 28.
Miyoshi N, Oubrahim H, Chock PB, Stadtman ER (2006) Age-dependent cell death and the role of ATP in hydrogen peroxide-induced apoptosis and necrosis. Proc Natl Acad Sci USA 103:1727–31
- 29.
Nwafor PA, Effraim KD, Jacks TW (1996) Gastroprotective effects of aqueous extracts of Khaya senegalensis bark on indomethacin-induced ulceration in rats. West Afr J Pharmacol Drug Res 12:46–50
- 30.
Peskar BM, Ehrlich K, Peskar BA (2002) Role of ATP-sensitive potassium channels in prostaglandin-mediated gastroprotection in the rat. J Pharmacol Exp Ther 301(3):969–974
- 31.
Polat B, Albayrak Y, Suleyman B, Dursun H, Odabasoglu F, Yigiter M, Halici Z, Suleyman H (2011) Antiulcerative effect of dexmedetomidine on indomethacin-induced gastric ulcer in rats. Pharmacol Rep 63:518–526
- 32.
Prasad SV, Srinivas A, Ambareesh K (2012) Protective role oxitard on drug induced ulcers in rats. Int J Biol Med Res 3(3):1948–1951
- 33.
Rodríguez I, Illnait J, Molina V et al (2010) Comparison of the antioxidant effects of D-002 (beeswax alcohols) and grape seed extract (GSE) on plasma oxidative variables in healthy subjects. Lat Am J Pharm 29:255–562
- 34.
Sabina EP, Rasool M (2007) Therapeutic efficacy of Indian ayurvedic herbal formulation triphala on lipid peroxidation, antioxidant status and inflammatory mediator TNF-a in adjuvant-induced arthritic mice. Int J Biol Chern 1:149–155
- 35.
Santucci L, Fiorucci S, Di Matteo FM, Morelli A (1995) Role of tumor necrosis factor alpha release and leukocyte margination in indomethacin-induced gastric injury in rats. Gastroenterology 108(2):393–401
- 36.
Saud B, Nandi J, Ong G, Finocchiaro S, Levine RA (2005) Inhibition of TNF-α improves indomethacin-induced enteropathy in rats by modulating iNOS expression. Dig Dis Sci 50(9):1677–1683
- 37.
Sehirli O, Tatlidede EM, Yuksel C, Erzik S, Cetinel BC, Sener G (2008) Antioxidant effect of alpha-lipoic acid against ethanol-induced gastric mucosal erosion in rats. Pharmacology 81:173–180
- 38.
Selling JA, Hogan DL, Aly A, Koss MA, Insberg JI (1987) Indomethacin inhibits duodenal mucosal bicarbonate secretion and endogenous prostaglandin E2 output in human subjects. Ann Intern Med 106(3):368–371
- 39.
Shen F, Hu Z, Goswami J, Gaffen SL (2006) Identification of common transcriptional regulatory elements in interleukin-17 target genes. J Biol Chem 281:24138–24148
- 40.
Spatafora M, Chiappara G, D'Amico D, Volpes D, Melis M, Pace E, Merendino A (1991) Effect of indomethacin on the kinetics of tumor necrosis factor alpha release and tumor necrosis factor alpha gene expression by human blood monocytes. Pharmacal Res 23:247–57
- 41.
Suleyman H, Cadirci E, Albayrak A, Polat B, Halici Z, Koc F, Hacimuftuoglu A, Bayir Y (2009) Comparative study on the gastroprotective potential of some antidepressants in indomethacin-induced ulcer in rats. Chem Biol Interact 180:318–324
- 42.
Suleyman B, Halici Z, Odabasoglu F, Gocer F (2012) The effect of lacidipine on indomethacin induced ulcers in rats. Int J Pharmacol 8(2):115–121
- 43.
Swarnakar S, Ganguly K, Kundu P, Banerjee A, Maity P, Sharma AV (2005) Curcumin regulates expression and activity of matrix metalloproteinase 9 and 2 during prevention and healing of indomethacin-induced gastric ulcer. The J Biol Chem 280(10):9409–9415
- 44.
Vunta H, Belda BJ, Arner RJ, Channa Reddy C, Vanden Heuvel JP, Sandeep Prabhu K (2008) Selenium attenuates pro-inflammatory gene expression in macrophages. Mol Nutr Food Res 52:1316–1323
- 45.
Vunta H, Davis F, Palempalli UD, Bhat D, Arner RJ, Thompson JT, Peterson DG, Reddy CC, Prabhu KS (2007) The anti-inflammatory effects of selenium are mediated through 15-deoxy-Δ12,14-prostaglandin J2 in macrophages. J Biol Chem 282(25):17964–17973
- 46.
Wallace JL (2008) Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn’t the stomach digest itself? Physiol Rev 88:1547–1565
- 47.
Wei XM, Heywood GJ, Di Girolamo N, Thomas PS (2003) Nicorandil inhibits the release of TNF alpha from a lymphocyte cell line and peripheral blood lymphocytes. Int Immunopharmacol 3(12):1581–1588
- 48.
Yamaguchi F, Yoshimura Y, Nakazawa H, Ariga T (1999) Free radical scavenging activity of grape seed extract and antioxidants by electron spin resonance spectrometry in an H2O2/NaOH/DMSO system. J Agric Food Chem 47:2544–8
- 49.
Zhang F, Yu W, Hargrove JL et al (2002) Inhibition of TNF-α induced ICAM-1, VCAM-1 and E-selectin expression by selenium. Atherosclerosis 161(2):381–386
Acknowledgment
We thank doctor Asem Shalaby, Lecturer of Pathology, Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt, for his assistance in histopathological studies.
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The authors have no conflict of interest to declare.
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Abbas, A.M., Sakr, H.F. Effect of selenium and grape seed extract on indomethacin-induced gastric ulcers in rats. J Physiol Biochem 69, 527–537 (2013). https://doi.org/10.1007/s13105-013-0241-z
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Keywords
- Indomethacin
- Selenium
- Grape seed extract
- Gastric ulcer