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Different Mechanisms in Formation and Prevention of Indomethacin-induced Gastric Ulcers

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Abstract

Indomethacin is an indol derivative, non-steroidal, anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. Indomethacin became the first-choice drug to produce an experimental ulcer model as a result of having a higher ulcerogenic potential than other non-steroidal anti-inflammatory drugs (NSAIDs). There have been several conflicting reports about the ulcerogenic mechanism of indomethacin; the mechanism is still unclear. It has been suggested that indomethacin induces gastric damage via inhibiting the release of protective factors like cyclooxygenase-1 (COX-1), prostaglandin E2 (PGE2), bicarbonate, and mucus; increasing aggressive factors like acid; and increasing oxidant parameters while decreasing antioxidant parameters. Classic antiulcer drugs are known to produce antiulcer effects by activating against indomethacin (increasing PGE2, mucus, and bicarbonate production; inhibiting acid secretion; decreasing oxidant parameters; and increasing antioxidants). However, some antiulcer drugs have been shown to inhibit indomethacin-induced ulcers without affecting acid and mucus secretion or oxidant parameters, as well as to inhibit the production of protective factors like COX-1, PGE2, and bicarbonate, and to reduce antioxidant parameters. In order to resolve the contradictions in the abovementioned data, this review hypothesized a relationship between indomethacin-induced ulcers and α 2 adrenergic receptors. It is suggested that blockage of α 2 adrenergic receptors may be responsible for the increase in the aggressive factors induced by indomethacin, and stimulation of α 2 adrenergic receptors may be responsible for the increase of protective factors induced by antiulcer drugs.

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References

  1. Botting, R.M. 2006. Inhibitors of cyclooxygenases: mechanisms, selectivity and uses. Journal of Physiology and Pharmacology 57(Suppl 5): 113–124.

    PubMed  Google Scholar 

  2. Amadio Jr., P., D.M. Cummings, and P. Amadio. 1993. Nonsteroidal anti-inflammatory drugs. Tailoring therapy to achieve results and avoid toxicity. Postgraduate Medicine 93: 73–76. 79–81, 85–8 passim.

    PubMed  Google Scholar 

  3. Brandman, S., M.J. Vandenburg, R. Jenkins, and W.J. Currie. 1985. The effect of non-steroidal anti-inflammatory therapy on plasma neuropeptide concentrations in patients with osteoarthritis. British Journal of Rheumatology 24: 46–52.

    PubMed  CAS  Google Scholar 

  4. Mitchell, J.A., and T.D. Warner. 1999. Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID therapy. British Journal of Pharmacology 128: 1121–1132.

    PubMed  CAS  Google Scholar 

  5. Simon, L.S. 1999. Role and regulation of cyclooxygenase-2 during inflammation. American Journal of Medicine 106: 37S–42S.

    PubMed  CAS  Google Scholar 

  6. Suleyman, H., Z. Halici, E. Cadirci, A. Hacimuftuoglu, and H. Bilen. 2008. Indirect role of beta2-adrenergic receptors in the mechanism of anti-inflammatory action of NSAIDS. Journal of Physiology and Pharmacology 59: 661–672.

    PubMed  CAS  Google Scholar 

  7. Wright, J.M. 2002. The double-edged sword of COX-2 selective NSAIDs. CMAJ 167: 1131–1137.

    PubMed  Google Scholar 

  8. Patrignani, P. 2000. Nonsteroidal anti-inflammatory drugs, COX-2 and colorectal cancer. Toxicology Letters 112–113: 493–498.

    PubMed  Google Scholar 

  9. Peskar, B.M., N. Maricic, B. Gretzera, R. Schuligoi, and A. Schmassmann. 2001. Role of cyclooxygenase-2 in gastric mucosal defense. Life Sciences 69: 2993–3003.

    PubMed  CAS  Google Scholar 

  10. Delaney, J.A., L. Opatrny, J.M. Brophy, and S. Suissa. 2007. Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. Canadian Medical Association Journal 177: 347–351.

    PubMed  Google Scholar 

  11. Rainsford, K.D. 2007. Anti-inflammatory drugs in the 21st century. Sub-Cellular Biochemistry 42: 3–27.

    PubMed  CAS  Google Scholar 

  12. Sigthorsson, G., R. Crane, T. Simon, M. Hoover, H. Quan, J. Bolognese, et al. 2000. COX-2 inhibition with rofecoxib does not increase intestinal permeability in healthy subjects: a double blind crossover study comparing rofecoxib with placebo and indomethacin. Gut 47: 527–532.

    PubMed  CAS  Google Scholar 

  13. Suleyman, H., F. Akcay, and K. Altinkaynak. 2002. The effect of nimesulide on the indomethacin- and ethanol-induced gastric ulcer in rats. Pharmacological Research 45: 155–158.

    PubMed  Google Scholar 

  14. Suleyman, H., E. Salamci, E. Cadirci, and Z. Halici. 2007. Beneficial interaction of nimesulide with NSAIDs. Medicinal Chemistry Research 16: 78–87.

    CAS  Google Scholar 

  15. Suleyman, H., L.O. Demirezer, and A. Kuruuzum-Uz. 2004. Effects of Rumex patientia root extract on indomethacine and ethanol induced gastric damage in rats. Pharmazie 59: 147–149.

    PubMed  CAS  Google Scholar 

  16. Thuresson, E.D., K.M. Lakkides, C.J. Rieke, Y. Sun, B.A. Wingerd, R. Micielli, et al. 2001. Prostaglandin endoperoxide H synthase-1: the functions of cyclooxygenase active site residues in the binding, positioning, and oxygenation of arachidonic acid. Journal of Biological Chemistry 276: 10347–10357.

    PubMed  CAS  Google Scholar 

  17. Xie, W.L., J.G. Chipman, D.L. Robertson, R.L. Erikson, and D.L. Simmons. 1991. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proceedings of the National Academy of Sciences of the United States of America 88: 2692–2696.

    PubMed  CAS  Google Scholar 

  18. Chandrasekharan, N.V., H. Dai, K.L. Roos, N.K. Evanson, J. Tomsik, T.S. Elton, et al. 2002. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proceedings of the National Academy of Sciences of the United States of America 99: 13926–13931.

    PubMed  CAS  Google Scholar 

  19. Kujubu, D.A., B.S. Fletcher, B.C. Varnum, R.W. Lim, and H.R. Herschman. 1991. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. Journal of Biological Chemistry 266: 12866–12872.

    PubMed  CAS  Google Scholar 

  20. Meade, E.A., W.L. Smith, and D.L. DeWitt. 1993. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. Journal of Biological Chemistry 268: 6610–6614.

    PubMed  CAS  Google Scholar 

  21. Schuschke, D.A., A.S. Adeagbo, P.K. Patibandla, U. Egbuhuzo, R. Fernandez-Botran, and W.T. Johnson. 2009. Cyclooxygenase-2 is upregulated in copper-deficient rats. Inflammation 32: 333–339.

    PubMed  CAS  Google Scholar 

  22. Willoughby, D.A., A.R. Moore, and P.R. Colville-Nash. 2000. COX-1, COX-2, and COX-3 and the future treatment of chronic inflammatory disease. Lancet 355: 646–648.

    PubMed  CAS  Google Scholar 

  23. Kataoka, H., Y. Horie, R. Koyama, S. Nakatsugi, and M. Furukawa. 2000. Interaction between NSAIDs and steroid in rat stomach: safety of nimesulide as a preferential COX-2 inhibitor in the stomach. Digestive Diseases and Sciences 45: 1366–1375.

    PubMed  CAS  Google Scholar 

  24. Ding, S.Z., S.K. Lam, S.T. Yuen, B.C. Wong, W.M. Hui, J. Ho, et al. 1998. Prostaglandin, tumor necrosis factor alpha and neutrophils: causative relationship in indomethacin-induced stomach injuries. European Journal of Pharmacology 348: 257–263.

    PubMed  CAS  Google Scholar 

  25. Appleyard, C.B., D.M. McCafferty, A.W. Tigley, M.G. Swain, and J.L. Wallace. 1996. Tumor necrosis factor mediation of NSAID-induced gastric damage: role of leukocyte adherence. American Journal of Physiology 270: G42–G48.

    PubMed  CAS  Google Scholar 

  26. Buttgereit, F., G.R. Burmester, and L.S. Simon. 2001. Gastrointestinal toxic side effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2-specific inhibitors. American Journal of Medicine 110(Suppl 3A): 13S–19S.

    PubMed  CAS  Google Scholar 

  27. Komoike, Y., M. Takeeda, A. Tanaka, S. Kato, and K. Takeuchi. 2002. Prevention by parenteral aspirin of indomethacin-induced gastric lesions in rats: mediation by salicylic acid. Digestive Diseases and Sciences 47: 1538–1545.

    PubMed  CAS  Google Scholar 

  28. Serhan, C.N. 1994. Lipoxin biosynthesis and its impact in inflammatory and vascular events. Biochimica et Biophysica Acta 1212: 1–25.

    PubMed  CAS  Google Scholar 

  29. Mancini, J.A., G.P. O’Neill, C. Bayly, and P.J. Vickers. 1994. Mutation of serine-516 in human prostaglandin G/H synthase-2 to methionine or aspirin acetylation of this residue stimulates 15-R-HETE synthesis. FEBS Letters 342: 33–37.

    PubMed  CAS  Google Scholar 

  30. Claria, J., and C.N. Serhan. 1995. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proceedings of the National Academy of Sciences of the United States of America 92: 9475–9479.

    PubMed  CAS  Google Scholar 

  31. Serhan, C.N., and E. Oliw. 2001. Unorthodox routes to prostanoid formation: new twists in cyclooxygenase-initiated pathways. Journal of Clinical Investigation 107: 1481–1489.

    PubMed  CAS  Google Scholar 

  32. Wallace, J.L., O.M. De Lima Jr., and S. Fiorucci. 2005. Lipoxins in gastric mucosal health and disease. Prostaglandins Leukotrienes and Essential Fatty Acids 73: 251–255.

    CAS  Google Scholar 

  33. Fiorucci, S., O.M. De Lima Jr., A. Mencarelli, B. Palazzetti, E. Distrutti, W. McKnight, et al. 2002. Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin-induced damage. Gastroenterology 123: 1598–1606.

    PubMed  CAS  Google Scholar 

  34. Wallace, J.L., W. McKnight, B.K. Reuter, and N. Vergnolle. 2000. NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology 119: 706–714.

    PubMed  CAS  Google Scholar 

  35. Gretzer, B., N. Maricic, M. Respondek, R. Schuligoi, and B.M. Peskar. 2001. Effects of specific inhibition of cyclo-oxygenase-1 and cyclo-oxygenase-2 in the rat stomach with normal mucosa and after acid challenge. British Journal of Pharmacology 132: 1565–1573.

    PubMed  CAS  Google Scholar 

  36. Tanaka, A., H. Araki, Y. Komoike, S. Hase, and K. Takeuchi. 2001. Inhibition of both COX-1 and COX-2 is required for development of gastric damage in response to nonsteroidal antiinflammatory drugs. Journal of Physiology Paris 95: 21–27.

    CAS  Google Scholar 

  37. Yuan, C., R.S. Sidhu, D.V. Kuklev, Y. Kado, M. Wada, I. Song, et al. 2009. Cyclooxygenase Allosterism, Fatty Acid-mediated Cross-talk between Monomers of Cyclooxygenase Homodimers. Journal of Biological Chemistry 284: 10046–10055.

    PubMed  CAS  Google Scholar 

  38. Waisman, Y., G. Dinari, H. Marcus, M. Ligumsky, Y. Rosenbach, I. Zahavi, et al. 1985. Naloxone is protective against indomethacin-induced intestinal ulceration in the rat. Gastroenterology 89: 86–91.

    PubMed  CAS  Google Scholar 

  39. Tazi-Saad, K., J. Chariot, J. Vatier, M. Del Tacca, and C. Roze. 1991. Antisecretory and anti-ulcer effects of morphine in rats after gastric mucosal aggression. European Journal of Pharmacology 192: 271–277.

    PubMed  CAS  Google Scholar 

  40. Gyires, K., S. Furst, E. Farczadi, and A. Marton. 1985. Morphine potentiates the gastroulcerogenic effect of indometacin in rats. Pharmacology 30: 25–31.

    PubMed  CAS  Google Scholar 

  41. Zahavi, I., T. Weizen, H. Marcus, F. Karmeli, and G. Dinari. 1996. Ketotifen is protective against indomethacin-induced intestinal ulceration in the rat. Israel Journal of Medical Sciences 32: 312–315.

    PubMed  CAS  Google Scholar 

  42. Fukuda, T., T. Arakawa, Y. Shimizu, K. Ohtani, K. Higuchi, and K. Kobayashi. 1995. Effects of lansoprazole on ethanol-induced injury and PG synthetic activity in rat gastric mucosa. Journal of Clinical Gastroenterology 20(Suppl 2): S5–S7.

    PubMed  Google Scholar 

  43. Brzozowski, T., P.C. Konturek, S.J. Konturek, I. Brzozowska, and T. Pawlik. 2005. Role of prostaglandins in gastroprotection and gastric adaptation. Journal of Physiology and Pharmacology 56(Suppl 5): 33–55.

    PubMed  Google Scholar 

  44. Dennis, E.A. 2000. Phospholipase A2 in eicosanoid generation. American Journal of Respiratory and Critical Care Medicine 161: S32–S35.

    PubMed  CAS  Google Scholar 

  45. Schimmer, B.P., and K.L. Parker. 1996. Adrenocorticotropin hormone. In Goodman & Gilman’s the pharmacological basis of therapeutics. Vol. 9, ed. L.S. Goodman, L.E. Limbird, P.B. Milinoff, and R.W. Ruddon, 1458–1485. New York: Mc Graw-Hill.

    Google Scholar 

  46. Bailey, J.M. 1991. New mechanisms for effects of anti-inflammatory glucocorticoids. Biofactors 3: 97–102.

    PubMed  CAS  Google Scholar 

  47. Suleyman, H., Z. Halici, E. Cadirci, A. Hacimuftuoglu, S. Keles, and F. Gocer. 2007. Indirect role of alpha2-adrenoreceptors in anti-ulcer effect mechanism of nimesulide in rats. Naunyn-Schmiedebergs Archives of Pharmacology 375: 189–198.

    CAS  Google Scholar 

  48. Hirai, H., K. Tanaka, S. Takano, M. Ichimasa, M. Nakamura, and K. Nagata. 2002. Cutting edge: agonistic effect of indomethacin on a prostaglandin D2 receptor, CRTH2. Journal of Immunology 168: 981–985.

    CAS  Google Scholar 

  49. Stubbs, V.E., P. Schratl, A. Hartnell, T.J. Williams, B.A. Peskar, A. Heinemann, et al. 2002. Indomethacin causes prostaglandin D(2)-like and eotaxin-like selective responses in eosinophils and basophils. Journal of Biological Chemistry 277: 26012–26020.

    PubMed  CAS  Google Scholar 

  50. Hirai, H., K. Tanaka, O. Yoshie, K. Ogawa, K. Kenmotsu, Y. Takamori, et al. 2001. Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. Journal of Experimental Medicine 193: 255–261.

    PubMed  CAS  Google Scholar 

  51. Monneret, G., S. Gravel, M. Diamond, J. Rokach, and W.S. Powell. 2001. Prostaglandin D2 is a potent chemoattractant for human eosinophils that acts via a novel DP receptor. Blood 98: 1942–1948.

    PubMed  CAS  Google Scholar 

  52. Gervais, F.G., R.P. Cruz, A. Chateauneuf, S. Gale, N. Sawyer, F. Nantel, et al. 2001. Selective modulation of chemokinesis, degranulation, and apoptosis in eosinophils through the PGD2 receptors CRTH2 and DP. Journal of Allergy and Clinical Immunology 108: 982–988.

    PubMed  CAS  Google Scholar 

  53. Tanaka, K., H. Hirai, S. Takano, M. Nakamura, and K. Nagata. 2004. Effects of prostaglandin D2 on helper T cell functions. Biochemical and Biophysical Research Communications 316: 1009–1014.

    PubMed  CAS  Google Scholar 

  54. Goto, H., S. Nakazawa, K. Segawa, Y. Tsukamoto, S. Hase, T. Arisawa, et al. 1989. The role of prostaglandin D2 in the genesis of indomethacin-induced gastric lesions in rats. Scandinavian Journal of Gastroenterology Supplement 162: 91–94.

    PubMed  CAS  Google Scholar 

  55. Filaretova, L., A. Tanaka, T. Miyazawa, S. Kato, and K. Takeuchi. 2002. Mechanisms by which endogenous glucocorticoid protects against indomethacin-induced gastric injury in rats. American Journal of Physiology Gastrointestinal and Liver Physiology 283: G1082–G1089.

    PubMed  CAS  Google Scholar 

  56. Isakson, P. C., K. M. Verburg, T. J. Maziasz, G. S. Geis. 1999. Selective inhibitors of COX-2. Gastroenterology, 12.

  57. Zanatta, F., R.B. Gandolfi, M. Lemos, J.C. Ticona, A. Gimenez, B.K. Clasen, et al. 2009. Gastroprotective activity of alkaloid extract and 2-phenylquinoline obtained from the bark of Galipea longiflora Krause (Rutaceae). Chemico-Biological Interactions 180: 312–317.

    PubMed  CAS  Google Scholar 

  58. Yong, D.G., B.Q. Geng, G.G. Gu, F.M. Zhong, and W.H. Yu. 1991. Anti-ulcer effect of anisodamine in rats. Zhongguo Yao Li Xue Bao 12: 522–525.

    PubMed  CAS  Google Scholar 

  59. Yong, D.G., B.Q. Geng, Y. Li, and S. Bi. 1995. Antiulcer effect of diltiazem in rats. Zhongguo Yao Li Xue Bao 16: 517–520.

    PubMed  CAS  Google Scholar 

  60. Welage, L.S. 2003. Pharmacologic properties of proton pump inhibitors. Pharmacotherapy 23: 74S–80S.

    PubMed  CAS  Google Scholar 

  61. Karadi, O., Z. Nagy, B. Bodis, and G. Mozsik. 2001. Atropine-induced gastrointestinal cytoprotection dependences to the intact of vagal nerve against indomethacin-induced gastrointestinal mucosal and microvascular damage in rats. Journsl of Physiol Paris 95: 29–33.

    CAS  Google Scholar 

  62. Kaan, S.K., and C.H. Cho. 1997. Effects of selective beta-adrenoceptor antagonists on gastric ulceration in the rat. Journal of Pharmacy and Pharmacology 49: 200–205.

    PubMed  CAS  Google Scholar 

  63. Ruppin, H., B. Person, A. Robert, and W. Domschke. 1981. Gastric cytoprotection in man by prostaglandin E2. Scandinavian Journal of Gastroenterology 16: 647–652.

    Article  PubMed  CAS  Google Scholar 

  64. Gu, G.G., D.G. Yong, and B.Q. Geng. 1990. Anti-gastric ulcer activity of zinc sulfadiazine in rats. Zhongguo Yao Li Xue Bao 11: 460–462.

    PubMed  CAS  Google Scholar 

  65. Luo, G.Y., Y. He, and L.B. Tu. 1990. Effects of clonidine on experimental stomach ulcer in rats. Zhongguo Yao Li Xue Bao 11: 457–459.

    PubMed  CAS  Google Scholar 

  66. Kapui, Z., K. Boer, I. Rozsa, G. Blasko, and I. Hermecz. 1993. Investigations of indomethacin-induced gastric ulcer in rats. Arzneimittel-Forschung 43: 767–771.

    PubMed  CAS  Google Scholar 

  67. Guzel, C., G. Ulak, A. Sermet, R. Cicek, and M. Ulak. 1995. Effect of fish oil on indometacin-induced gastric lesions in rats. Arzneimittel-Forschung 45: 1172–1173.

    PubMed  CAS  Google Scholar 

  68. Kaan, S.K., and C.H. Cho. 1996. A study of the antiulcer mechanisms of propranolol in rats. Inflammation Research 45: 370–375.

    PubMed  CAS  Google Scholar 

  69. Kleine, A., S. Kluge, and B.M. Peskar. 1993. Stimulation of prostaglandin biosynthesis mediates gastroprotective effect of rebamipide in rats. Digestive Diseases and Sciences 38: 1441–1449.

    PubMed  CAS  Google Scholar 

  70. Kobayashi, T., Y. Ohta, K. Inui, J. Yoshino, and S. Nakazawa. 2002. Protective effect of omeprazole against acute gastric mucosal lesions induced by compound 48/80, a mast cell degranulator, in rats. Pharmacological Research 46: 75–84.

    PubMed  CAS  Google Scholar 

  71. Li, B., H.R. Liu, Y.Q. Pan, Q.S. Jiang, J.C. Shang, X.H. Wan, et al. 2006. Protective effects of total alkaloids from rhizoma Coptis chinensis on alcohol-induced gastric lesion in rats. Zhongguo Zhong Yao Za Zhi 31: 51–54.

    PubMed  CAS  Google Scholar 

  72. Takeuchi, K., E. Aihara, Y. Sasaki, Y. Nomura, and F. Ise. 2006. Involvement of cyclooxygenase-1, prostaglandin E2 and EP1 receptors in acid-induced HCO3- secretion in stomach. Journal of Physiology and Pharmacology 57: 661–676.

    PubMed  CAS  Google Scholar 

  73. Waisman, Y., I. Zahavi, H. Marcus, M. Ligumsky, Y. Rosenbach, and G. Dinari. 1988. Sucralfate is protective against indomethacin-induced intestinal ulceration in the rat. Digestion 41: 78–82.

    PubMed  CAS  Google Scholar 

  74. Ueki, S., K. Takeuchi, and S. Okabe. 1988. Gastric motility is an important factor in the pathogenesis of indomethacin-induced gastric mucosal lesions in rats. Digestive Diseases and Sciences 33: 209–216.

    PubMed  CAS  Google Scholar 

  75. Mimaki, H., S. Kawauchi, S. Kagawa, S. Ueki, and K. Takeuchi. 2001. Bicarbonate stimulatory action of nizatidine, a histamine H(2)-receptor antagonist, in rat duodenums. Journal of Physiology Paris 95: 165–171.

    CAS  Google Scholar 

  76. Naito, Y., T. Yoshikawa, N. Yoshida, and M. Kondo. 1998. Role of oxygen radical and lipid peroxidation in indomethacin-induced gastric mucosal injury. Digestive Diseases and Sciences 43: 30S–34S.

    PubMed  CAS  Google Scholar 

  77. Dengiz, G.O., F. Odabasoglu, Z. Halici, E. Cadirci, and H. Suleyman. 2007. Gastroprotective and antioxidant effects of montelukast on indomethacin-induced gastric ulcer in rats. Journal of Pharmacological Sciences 105: 94–102.

    PubMed  CAS  Google Scholar 

  78. Dengiz, G.O., F. Odabasoglu, Z. Halici, H. Suleyman, E. Cadirci, and Y. Bayir. 2007. Gastroprotective and antioxidant effects of amiodarone on indomethacin-induced gastric ulcers in rats. Archives of Pharmacal Research 30: 1426–1434.

    PubMed  CAS  Google Scholar 

  79. El-Missiry, M.A., I.H. El-Sayed, and A.I. Othman. 2001. Protection by metal complexes with SOD-mimetic activity against oxidative gastric injury induced by indomethacin and ethanol in rats. Annals of Clinical Biochemistry 38: 694–700.

    PubMed  CAS  Google Scholar 

  80. Suleyman, H., E. Cadirci, A. Albayrak, B. Polat, Z. Halici, F. Koc, et al. 2009. Comparative study on the gastroprotective potential of some antidepressants in indomethacin-induced ulcer in rats. Chemico-Biological Interactions 180: 318–324.

    PubMed  CAS  Google Scholar 

  81. Pozzoli, C., A. Menozzi, D. Grandi, E. Solenghi, M.C. Ossiprandi, C. Zullian, et al. 2007. Protective effects of proton pump inhibitors against indomethacin-induced lesions in the rat small intestine. Naunyn-Schmiedebergs Archives of Pharmacology 374: 283–291.

    CAS  Google Scholar 

  82. Hassan, A., E. Martin, and P. Puig-Parellada. 1998. Role of antioxidants in gastric mucosal damage induced by indomethacin in rats. Methods and Findings in Experimental and Clinical Pharmacology 20: 849–854.

    PubMed  CAS  Google Scholar 

  83. Hiraishi, H., A. Terano, S. Ota, H. Mutoh, T. Sugimoto, T. Harada, et al. 1994. Protection of cultured rat gastric cells against oxidant-induced damage by exogenous glutathione. Gastroenterology 106: 1199–1207.

    PubMed  CAS  Google Scholar 

  84. Suzuki, M., M. Mori, S. Miura, M. Suematsu, D. Fukumura, H. Kimura, et al. 1996. Omeprazole attenuates oxygen-derived free radical production from human neutrophils. Free Radical Biology and Medicine 21: 727–731.

    PubMed  CAS  Google Scholar 

  85. Peralta, C., R. Rull, A. Rimola, R. Deulofeu, J. Rosello-Catafau, E. Gelpi, et al. 2001. Endogenous nitric oxide and exogenous nitric oxide supplementation in hepatic ischemia-reperfusion injury in the rat. Transplantation 71: 529–536.

    PubMed  CAS  Google Scholar 

  86. Nielsen, F., B.B. Mikkelsen, J.B. Nielsen, H.R. Andersen, and P. Grandjean. 1997. Plasma malondialdehyde as biomarker for oxidative stress: reference interval and effects of life-style factors. Clinical Chemistry 43: 1209–1214.

    PubMed  CAS  Google Scholar 

  87. Son, M., H.K. Kim, W.B. Kim, J. Yang, and B.K. Kim. 1996. Protective effect of taurine on indomethacin-induced gastric mucosal injury. Advances in Experimental Medicine and Biology 403: 147–155.

    PubMed  CAS  Google Scholar 

  88. Vaananen, P.M., J.B. Meddings, and J.L. Wallace. 1991. Role of oxygen-derived free radicals in indomethacin-induced gastric injury. American Journal of Physiology 261: G470–G475.

    PubMed  CAS  Google Scholar 

  89. Agastya, G., B.C. West, and J.M. Callahan. 2000. Omeprazole inhibits phagocytosis and acidification of phagolysosomes of normal human neutrophils in vitro. Immunopharmacology and Immunotoxicology 22: 357–372.

    PubMed  CAS  Google Scholar 

  90. Suzuki, M., M. Mori, D. Fukumura, H. Suzuki, S. Miura, and H. Ishii. 1999. Omeprazole attenuates neutrophil-endothelial cell adhesive interaction induced by extracts of Helicobacter pylori. Journal of Gastroenterology and Hepatology 14: 27–31.

    PubMed  CAS  Google Scholar 

  91. Wandall, J.H. 1992. Effects of omeprazole on neutrophil chemotaxis, super oxide production, degranulation, and translocation of cytochrome b-245. Gut 33: 617–621.

    PubMed  CAS  Google Scholar 

  92. Murakami, K., K. Okajima, M. Uchiba, N. Harada, M. Johno, H. Okabe, et al. 1997. Rebamipide attenuates indomethacin-induced gastric mucosal lesion formation by inhibiting activation of leukocytes in rats. Digestive Diseases and Sciences 42: 319–325.

    PubMed  CAS  Google Scholar 

  93. Takeuchi, K., K. Takehara, and T. Ohuchi. 1996. Diethyldithiocarbamate, a superoxide dismutase inhibitor, reduces indomethacin-induced gastric lesions in rats. Digestion 57: 201–209.

    PubMed  CAS  Google Scholar 

  94. Blandizzi, C., M. Fornai, R. Colucci, G. Natale, V. Lubrano, C. Vassalle, et al. 2005. Lansoprazole prevents experimental gastric injury induced by non-steroidal anti-inflammatory drugs through a reduction of mucosal oxidative damage. World Journal of Gastroenterology 11: 4052–4060.

    PubMed  CAS  Google Scholar 

  95. Tanaka, J., and Y. Yuda. 1996. Lipid peroxidation in gastric mucosal lesions induced by indomethacin in rat. Biological and Pharmaceutical Bulletin 19: 716–720.

    PubMed  CAS  Google Scholar 

  96. Halici, M., F. Odabasoglu, H. Suleyman, A. Cakir, A. Aslan, and Y. Bayir. 2005. Effects of water extract of Usnea longissima on antioxidant enzyme activity and mucosal damage caused by indomethacin in rats. Phytomedicine 12: 656–662.

    PubMed  CAS  Google Scholar 

  97. Erkin, B., D. Dokmeci, S. Altaner, and F.N. Turan. 2006. Gastroprotective effect of L-carnitine on indomethacin-induced gastric mucosal injury in rats: a preliminary study. Folia Medica (Plovdiv) 48: 86–89.

    Google Scholar 

  98. Fornai, M., G. Natale, R. Colucci, M. Tuccori, G. Carazzina, L. Antonioli, et al. 2005. Mechanisms of protection by pantoprazole against NSAID-induced gastric mucosal damage. Naunyn-Schmiedebergs Archives of Pharmacology 372: 79–87.

    CAS  Google Scholar 

  99. Robert, A., C. Lancaster, J.P. Davis, S.O. Field, A.J. Sinha, and B.A. Thornburgh. 1985. Cytoprotection by prostaglandin occurs in spite of penetration of absolute ethanol into the gastric mucosa. Gastroenterology 88: 328–333.

    PubMed  CAS  Google Scholar 

  100. van der Vliet, A., and A. Bast. 1992. Role of reactive oxygen species in intestinal diseases. Free Radical Biology and Medicine 12: 499–513.

    PubMed  Google Scholar 

  101. Zamora, Z., R. Gonzalez, D. Guanche, N. Merino, S. Menendez, F. Hernandez, et al. 2008. Ozonized sunflower oil reduces oxidative damage induced by indomethacin in rat gastric mucosa. Inflammation Research 57: 39–43.

    PubMed  CAS  Google Scholar 

  102. Bayir, Y., F. Odabasoglu, A. Cakir, A. Aslan, H. Suleyman, M. Halici, et al. 2006. The inhibition of gastric mucosal lesion, oxidative stress and neutrophil-infiltration in rats by the lichen constituent diffractaic acid. Phytomedicine 13: 584–590.

    PubMed  CAS  Google Scholar 

  103. Fields, M., C.G. Lewis, and M.D. Lure. 1996. Antioxidant defense system in lung of male and female rats: interactions with alcohol, copper, and type of dietary carbohydrate. Metabolism 45: 49–56.

    PubMed  CAS  Google Scholar 

  104. Cadirci, E., H. Suleyman, H. Aksoy, Z. Halici, U. Ozgen, A. Koc, et al. 2007. Effects of Onosma armeniacum root extract on ethanol-induced oxidative stress in stomach tissue of rats. Chemico-Biological Interactions 170: 40–48.

    PubMed  CAS  Google Scholar 

  105. Berenguer, B., L.M. Sanchez, A. Quilez, M. Lopez-Barreiro, O. de Haro, J. Galvez, et al. 2006. Protective and antioxidant effects of Rhizophora mangle L. against NSAID-induced gastric ulcers. Journal of Ethnopharmacology 103: 194–200.

    PubMed  CAS  Google Scholar 

  106. Lanas, A., E. Bajador, P. Serrano, J. Fuentes, S. Carreno, J. Guardia, et al. 2000. Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding. New England Journal of Medicine 343: 834–839.

    PubMed  CAS  Google Scholar 

  107. Martin, M.J., M.D. Jimenez, and V. Motilva. 2001. New issues about nitric oxide and its effects on the gastrointestinal tract. Current Pharmceutical Design 7: 881–908.

    CAS  Google Scholar 

  108. Hogg, N., and B. Kalyanaraman. 1999. Nitric oxide and lipid peroxidation. Biochimica et Biophysica Acta 1411: 378–384.

    PubMed  CAS  Google Scholar 

  109. Fan, T.Y., Q.Q. Feng, C.R. Jia, Q. Fan, C.A. Li, and X.L. Bai. 2005. Protective effect of Weikang decoction and partial ingredients on model rat with gastric mucosa ulcer. World Journal of Gastroenterology 11: 1204–1209.

    PubMed  Google Scholar 

  110. Morsy, M.A., and A.A. Fouad. 2008. Mechanisms of gastroprotective effect of eugenol in indomethacin-induced ulcer in rats. Phytotherapy Research 22: 1361–1366.

    PubMed  CAS  Google Scholar 

  111. Toroudi, H.P., M. Rahgozar, A. Bakhtiarian, and B. Djahanguiri. 1999. Potassium channel modulators and indomethacin-induced gastric ulceration in rats. Scandinavian Journal of Gastroenterology 34: 962–966.

    PubMed  CAS  Google Scholar 

  112. al-Bekairi, A.M., A.M. al-Rajhi, and M. Tariq. 1994. Effect of (+/−)-verapamil and hydralazine on stress- and chemically-induced gastric ulcers in rats. Pharmacological Research 29: 225–236.

    PubMed  CAS  Google Scholar 

  113. Bang, L., J.E. Nielsen-Kudsk, N. Gruhn, S. Trautner, S.A. Theilgaard, S.P. Olesen, et al. 1998. Hydralazine-induced vasodilation involves opening of high conductance Ca2+-activated K+ channels. European Journal of Pharmacology 361: 43–49.

    PubMed  CAS  Google Scholar 

  114. Del Soldato, P. 1986. Gastric lesion-preventing or -potentiating activity of clonidine in rats. Japanese Journal of Pharmacology 41: 257–259.

    PubMed  Google Scholar 

  115. DiJoseph, J.F., J.R. Eash, and G.N. Mir. 1987. Gastric antisecretory and antiulcer effects of WHR1582A, a compound exerting alpha-2 adrenoceptor agonist activity. Journal of Pharmacology and Experimental Therapeutics 241: 97–102.

    PubMed  CAS  Google Scholar 

  116. Kunchandy, J., S. Khanna, and S.K. Kulkarni. 1985. Effect of alpha2 agonists clonidine, guanfacine and B-HT 920 on gastric acid secretion and ulcers in rats. Archives Internationales de Pharmacodynamie et de Therapie 275: 123–138.

    PubMed  CAS  Google Scholar 

  117. Gyires, K., K. Mullner, S. Furst, and A.Z. Ronai. 2000. Alpha-2 adrenergic and opioid receptor-mediated gastroprotection. Journal of Physiology Paris 94: 117–121.

    CAS  Google Scholar 

  118. Fulop, K., Z. Zadori, A.Z. Ronai, and K. Gyires. 2005. Characterisation of alpha2-adrenoceptor subtypes involved in gastric emptying, gastric motility and gastric mucosal defence. European Journal of Pharmacology 528: 150–157.

    PubMed  Google Scholar 

  119. Suleyman, H., B. Demircan, F. Gocer, Z. Halici, and A. Hacimuftuoglu. 2004. Role of adrenal gland hormones in the mechanism of antiulcer action of nimesulide and ranitidine. Polish Journal of Pharmacology 56: 799–804.

    PubMed  Google Scholar 

  120. Filaretova, L., A. Tanaka, Y. Komoike, and K. Takeuchi. 2002. Selective cyclooxygenase-2 inhibitor induces gastric mucosal damage in adrenalectomized rats. Inflammopharmacology 10: 413–422.

    CAS  Google Scholar 

  121. Suleyman, H., E. Cadirci, A. Albayrak, and Z. Halici. 2008. Nimesulide is a selective COX-2 inhibitory, atypical non-steroidal anti-inflammatory drug. Current Medecinal Chemistry 15: 278–283.

    CAS  Google Scholar 

  122. Kiro, A., I. Zahavi, H. Marcus, and G. Dinari. 1992. L-dopa is protective against indomethacin-induced small intestinal ulceration in the rat: possible role of an alpha-2-adrenergic mechanism. Life Sciences 51: 1151–1156.

    PubMed  CAS  Google Scholar 

  123. Hoffman, B.B. 2006. Therapy of hypertension. In Godman and Gilman’s the pharmacological basis of therapeutics, ed. L.L. Brunton, 845–897. New-York: Mc Graw-Hill.

    Google Scholar 

  124. Reams, G.P., and J.H. Bauer. 1999. Atlas of diseases of the kidney, 28–30. Philadelphia: Blackwell Science.

    Google Scholar 

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Acknowledgment

We would like to express our thanks to Research Assistant Mss. Beyzagul Polat for her contribution to this work.

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Authors and Affiliations

  1. Faculty of Medicine, Department of Pharmacology, Ataturk University, Erzurum, Turkey

    Halis Suleyman, Abdulmecit Albayrak & Zekai Halici

  2. Faculty of Medicine, Department of Internal Medicine, Ataturk University, Erzurum, Turkey

    Mehmet Bilici

  3. Faculty of Pharmacy, Department of Pharmacology, Ataturk University, Erzurum, Turkey

    Elif Cadirci

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  1. Halis Suleyman
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  2. Abdulmecit Albayrak
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  3. Mehmet Bilici
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Correspondence to Halis Suleyman.

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Suleyman, H., Albayrak, A., Bilici, M. et al. Different Mechanisms in Formation and Prevention of Indomethacin-induced Gastric Ulcers. Inflammation 33, 224–234 (2010). https://doi.org/10.1007/s10753-009-9176-5

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