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Protective Effects of Simvastatin Against Alendronate-Induced Gastric Mucosal Injury in Rats

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Abstract

Background

It has been reported that simvastatin, a statin commonly prescribed for its anti-inflammatory and antioxidant effects, has gastroprotective effects in indomethacin and ethanol-induced gastric ulcers. However, the effects of simvastatin on alendronate-induced gastric mucosal injury remain unexplored.

Aim

This study investigated the use of simvastatin for the treatment of alendronate-induced gastric ulcers in rats.

Methods

Female rats were pretreated with vehicle or simvastatin (20 and 60 mg/kg p.o.). After 1 h, the rats received alendronate (50 mg/kg p.o.). Simvastatin was administered once daily for 7 days, and from the fourth day of simvastatin treatment, alendronate was administered once daily for 4 days. On the final day of treatment, 4 h after alendronate administration, animals were euthanized, their stomachs were removed, and gastric damage was measured. Samples of the stomach were fixed in 10 % formalin immediately after their removal for subsequent histopathological assessment. Unfixed samples were weighed, frozen at −80 °C until assayed for glutathione (GSH), malondialdehyde (MDA), and cytokine levels and myeloperoxidase (MPO) activity. A third group was used to measure mucus and gastric secretion.

Results

Pretreatment with simvastatin prevented alendronate-induced macroscopic gastric damage and reduced the levels of MDA and GSH, TNF-α and IL-1β, MPO activity, and mucus levels, in the stomach.

Conclusions

This study demonstrates the protective effects of simvastatin against alendronate-induced gastric ulceration. Maintenance of mucosal integrity, inhibition of neutrophil activity, and reduced oxidative stress associated with decreased gastric acidity may explain the gastroprotective effects of simvastatin.

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Abbreviations

ALD:

Alendronate

DMSO:

Dimethyl sulfoxide

ELISA:

Enzyme-linked immunosorbent assay

GSH:

Glutathione

IL:

Interleukin

MDA:

Malondialdehyde

MPO:

Myeloperoxidase

NO:

Nitric oxide

SIM:

Simvastatin

TNF:

Tumor necrosis factor

References

  1. Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest. 2005;15:3318–3325.

    Article  Google Scholar 

  2. Fleisch H. Bisphosphonates in Bone Disease: From the Laboratory to the Patient. New York: The Parthenon Group; 1997:32–163.

    Google Scholar 

  3. Chestnut CH, McClung MR, Ensrud KE, et al. Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling. Am J Med. 1995;29:144–152.

    Article  Google Scholar 

  4. Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med. 1996;335:1016–1021.

    Article  PubMed  Google Scholar 

  5. Stein EA. Management of dyslipidemia in the high-risk patient. Am Heart J. 2002;144:43–50.

    Article  Google Scholar 

  6. Beek E, Lowik C, Pluijm G, et al. The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: a clue to the mechanism of action of nitrogen-containing bisphosphonates. J Bone Miner Res. 1999;14:722–729.

    Article  Google Scholar 

  7. Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins. Science. 1999;286:1946–1949.

    Article  CAS  PubMed  Google Scholar 

  8. Meier CR, Schlienger RG, Kraenzlin ME, et al. HMG CoA reductase inhibitors and the risk of fractures. JAMA. 2000;283:3205–3210.

    Article  CAS  PubMed  Google Scholar 

  9. Wang PS, Solomon DH, Mogun H, et al. HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients. JAMA. 2000;283:3211–3216.

    Article  CAS  PubMed  Google Scholar 

  10. Scalia R, Gooszen ME, Jones SP, et al. Simvastatin exerts both anti-inflammatory and cardioprotective effects in apoliprotein E-deficient mice. Circulation. 2001;103:2598–2603.

    Article  CAS  PubMed  Google Scholar 

  11. Pruefer D, Scalia R, Lefer AM. Simvastatin inhibits leukocytes–endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats. Arterioscler Thromb Vasc Biol. 1999;19:2894–2900.

    Article  CAS  PubMed  Google Scholar 

  12. Ungureanu D, Filip C, Artenie A, Artenie R. Evaluation of simvastatin antioxidant effects. Rev Med Chir Soc Med Nat. 2003;107:66–71.

    Google Scholar 

  13. Tariq M, Khan HA, Elfaki I, et al. Gastric antisecretory and antiulcer effects of simvastatin in rats. J Gastroenterol Hepatol. 2007;22:2316–2323.

    Article  CAS  PubMed  Google Scholar 

  14. Heeba GH, Hassan MKA, Amin RS. Gastroprotective effect of simvastatin against indomethacin-induced gastric ulcer in rats: role of nitric oxide and prostaglandins. Eur J Pharmacol. 2009;607:188–193.

    Article  CAS  PubMed  Google Scholar 

  15. Silva RO, Lucetti LT, Wong DVT, et al. Alendronate induces gastric damage by reducing nitric oxide synthase expression and NO/cGMP/KATP signaling pathway. Nitric Oxide. 2014;40:22–30.

    Article  CAS  PubMed  Google Scholar 

  16. Costa NRD, Silva RO, Nicolau LA, et al. Role of soluble guanylate cyclase activation in the gastro protective effect of the HO-1/CO pathway against alendronate-induced gastric damage in rats. Eur J Pharmacol. 2013;700:51–59.

    Article  CAS  PubMed  Google Scholar 

  17. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem. 1968;25:192–205.

    Article  CAS  PubMed  Google Scholar 

  18. Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem. 1978;86:271–278.

    Article  CAS  PubMed  Google Scholar 

  19. Bradley PP, Christensen RD, Rothstein G. Cellular and extracellular myeloperoxidase in pyogenic inflammation. Blood. 1982;60:618–622.

    CAS  PubMed  Google Scholar 

  20. Cunha FQ, Boukili MA, Motta JI, Vargaftig BB, Ferreira SH. Blockade by fenspiride of endotoxin-induced neutrophil migration in the rat. Eur J Pharmacol. 1993;238:47–52.

    Article  CAS  PubMed  Google Scholar 

  21. Laine L, Weinstein WM. Histology of alcoholic hemorrhagic “gastritis”: a prospective evaluation. Gastroenterology. 1988;94:1254–1262.

    CAS  PubMed  Google Scholar 

  22. Corne SJ, Morrissey SM, Woods RJ. Proceedings: a method for the quantitative estimation of gastric barrier mucus. J Physiol. 1974;242:116–117.

    Google Scholar 

  23. Shay H. A simple method for the uniform production of gastric ulceration in the rat. Gastroenterology. 1945;5:43–61.

    Google Scholar 

  24. Jadhav SB, Jain GK. Statins and osteoporosis: new role for old drugs. J Pharm Pharmacol. 2006;58:3–18.

    Article  CAS  PubMed  Google Scholar 

  25. Uzzan B, Cohen R, Nicolas P, et al. Effects of statins on bone mineral density: a meta-analysis of clinical studies. Bone. 2007;40:1581–1587.

    Article  CAS  PubMed  Google Scholar 

  26. Nicolau LAD, Silva RO, Damasceno SRB, et al. The hydrogen sulfide donor, Lawesson’s reagent, prevents alendronate-induced gastric damage in rats. Braz J Med Biol Res. 2013;46:708–714.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Wallace JL, Dicay M, Mcknight W, et al. N-bisphosphonates cause gastric epithelial injury independent of effects on the microcirculation. Aliment Pharmacol Ther. 1999;13:1675–1682.

    Article  CAS  PubMed  Google Scholar 

  28. Ohashi Y, Aihara E, Takasuka H, Takahashi K, Takeuchi K. Antral ulcers induced by alendronate, a nitrogen-containing bisphosphonate, in rat stomachs—prophylactic effect of rebamipide. J Physiol Pharmacol. 2009;60:85–93.

    CAS  PubMed  Google Scholar 

  29. Wallace JL, Ma L. Inflammatory mediators in gastrointestinal defense and injury. Exp Biol Med. 2001;226:1003–1015.

    CAS  Google Scholar 

  30. Kanatsu K, Aihara E, Okayama M, Kato S, Takeuchi K. Mucosal irritative and healing impairment action of risedronate in rat stomachs: comparison with alendronate. J Gastroenterol Hepatol. 2004;19:512–520.

    Article  CAS  PubMed  Google Scholar 

  31. Thieabaud D, Sauty A, Burckhard A, et al. An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates. Calcif Tissue Int. 1997;61:386–392.

    Article  Google Scholar 

  32. Yamaguchi K, Motegi M, Iwakura Y, Endo Y. Involvement of interleukin-1 in the inflammatory actions of aminobisphosphonates in mice. Br J Pharmacol. 2000;130:1646–1654.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Weitz-Schmidt G. Statins as anti-inflammatory agents. Trends Pharmacol Sci. 2002;23:482–487.

    Article  CAS  PubMed  Google Scholar 

  34. Schönbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation. 2004;109:II18–II26.

    Article  PubMed  Google Scholar 

  35. Sager PT, Melani L, Lipka J, et al. Effect of coadministration of ezetimibe and simvastatin on high-sensitivity C-reactive protein. Am J Cardiol. 2003;15:1414–1418.

    Article  Google Scholar 

  36. Bracht L, Barbosa CP, Caparroz-Assef SM, et al. Effects of simvastatin, atorvastatin, ezetimibe, and ezetimibe+ simvastatin combination on the inflammatory process and on the liver metabolic changes of arthritic rats. Basic Clin Pharmacol. 2012;26:722–734.

    CAS  Google Scholar 

  37. Vaananenn PM, Medding JB, Wallace JL. Rol of oxygen derived free radicals in indomethacin-induced gastric injury. Am J Physiol. 1991;261:G470–G475.

    Google Scholar 

  38. Yoshikawa T, Naito Y, Kishi A, et al. Role of active oxygen, lipid peroxidation and antioxidants in the pathogenesis of gastric mucosal injury induced by indomethacin in rats. Gut. 1993;34:732–737.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Chattopadhyay I, Bandyopadhyay U, Biswas K, Maity P, Banerjee RK. Indomethacin inactivates gastric peroxidase to induced reactive-oxygen-mediated gastric mucosal injury and curcumin protects it by preventing peroxidase inactivation and scavenging reactive oxygen. Free Radic Biol Med. 2006;40:1397–1408.

    Article  CAS  PubMed  Google Scholar 

  40. Sener G, Paskaloglu K, Kapucu C, Cetinel S, Contuk G, Ayanoglu-Dulger G. Octreotide ameliorates alendronate-induced gastric injury. Peptides. 2004;25:115–121.

    Article  CAS  PubMed  Google Scholar 

  41. Sener G, Kapucu C, Cetinel S, Cikler E, Ayanoglu-Dulge RG. Gastroprotective effect of leukotriene receptor blocker montelukast in alendronate-induced lesions of the rat gastric mucosa. Prostaglandins Leukot Essent Fatty Acids. 2005;72:1–11.

    Article  CAS  PubMed  Google Scholar 

  42. Wallace JL, Keenan CM, Granger DN. Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophil dependent process. Am J Physiol. 1990;259:G462–G467.

    CAS  PubMed  Google Scholar 

  43. Ohashi Y, Aihara E, Amagase K, Takeuchi K. Induction of antral ulcers by alendronate, a nitrogen-containing bisphosphonate, in rat stomachs (abstract). Gastroenterology. 2008;134:A-237.

    Article  Google Scholar 

  44. Szabo S, Trier JS, Frankel PW. Sulfhydryl compounds may mediate gastric cytoprotection. Science. 1981;214:200–202.

    Article  CAS  PubMed  Google Scholar 

  45. Szabo S, Nagy L, Plebani M. Glutathione, protein sulfhydryls and cysteine proteases in gastric mucosal injury and protection. Clin Chim Acta. 1992;206:95–105.

    Article  CAS  PubMed  Google Scholar 

  46. Lichtenberger LM, Romero JJ, Gibson GW, Blank MA. Effect of bisphosphonates on surface hydrophobicity and phosphatidylcholine concentration of rodent gastric mucosa. Dig Dis Sci. 2000;45:1792–1801.

    Article  CAS  PubMed  Google Scholar 

  47. Sener G, Goren FO, Ulosoy NB, Ersoy Y, Arbak S, Dulger GA. Protective effect of melatonin and omeprazole against alendronat-induced gastric damage. Dig Dis Sci. 2005;50:1506–1512.

    Article  CAS  PubMed  Google Scholar 

  48. Peter CP, Handt LK, Smith SM. Esophageal irritation due to alendronate sodium tablets. Dig Dis Sci. 2002;43:1998–2002.

    Article  Google Scholar 

  49. Dobrucki LE, Kalinowski L, Dobrucki IT, Malinski T. Statin-stimulated nitric oxide release from endothelium. Med Sci Monit. 2001;7:622–627.

    CAS  PubMed  Google Scholar 

  50. Jiang JL, Jiang DJ, Tang YH, Li NS, Deng HW, Li YJ. Effect of simvastatin on endothelium-dependent vaso-relaxation and endogenous nitric oxide synthase inhibitor. Acta Pharmacol Sin. 2004;25:893–901.

    CAS  PubMed  Google Scholar 

  51. Kim H, Kim KH. Effects of a nitric oxide donor and nitric oxide synthase inhibitors on acid secretion of isolated rabbit gastric glands. Pharmacology. 1996;53:331–339.

    Article  CAS  PubMed  Google Scholar 

  52. Kato S, Kitamura M, Korolkiewicz RP, Takeuchi K. Role of nitric oxide in regulation of gastric acid secretion in rats: effects of NO donors and NO synthase inhibitor. Br J Pharmacol. 1998;123:839–846.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Berg A, Redeen S, Ericson AC, Sjöstrand SE. Nitric oxide—an endogenous inhibitor of gastric acid secretion in isolated human gastric glands. BMC Gastroenterol. 2004;4:1–9.

    Article  Google Scholar 

  54. Silva RO, Bingana RD, Soares PMG, Souza MHLP, Medeiros JVR. The role of nitric oxide in alendronate-mediated acceleration of gastric emptying and gastrointestinal transit in rats. Afr J Pharm Pharmacol. 2015;9:307–312.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge the financial support from National Counsel of Technological and Scientific Development—CNPq (Brazil) and Research Foundation for the State of Piauí—FAPEPI.

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Authors and Affiliations

  1. Post Graduation Program in Pharmacology, Medicinal Plant Research Center (NPPM), Federal University of Piauí, Teresina, PI, Brazil

    Nathalia S. Carvalho, Douglas S. Costa & Jand Venes R. Medeiros

  2. Post Graduation Program in Biotechnology, Biotechnology and Biodiversity Center Research (BIOTEC), Federal University of Piauí, Parnaíba, PI, Brazil

    Mônica M. Silva, Thiago S. L. Araújo, Nayara A. Sousa, Luan K. M. Souza & Jand Venes R. Medeiros

  3. Laboratory of Pharmacology of Inflammation and Cancer (LAFICA), Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil

    Renan O. Silva, Lucas A. D. Nicolau & Pedro M. G. Soares

  4. BIOTEC/LAFFEX/UFPI, Av. São Sebastião, no. 2819, Parnaíba, PI, CEP 64202-020, Brazil

    Jand Venes R. Medeiros

Authors
  1. Nathalia S. Carvalho
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  2. Mônica M. Silva
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  3. Renan O. Silva
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  4. Lucas A. D. Nicolau
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  6. Douglas S. Costa
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  7. Nayara A. Sousa
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  8. Luan K. M. Souza
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Correspondence to Jand Venes R. Medeiros.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Carvalho, N.S., Silva, M.M., Silva, R.O. et al. Protective Effects of Simvastatin Against Alendronate-Induced Gastric Mucosal Injury in Rats. Dig Dis Sci 61, 400–409 (2016). https://doi.org/10.1007/s10620-015-3890-7

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  • DOI: https://doi.org/10.1007/s10620-015-3890-7

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