Official Journal of the College of Pharmacy, University of Mosul

Document Type : Review Paper

Authors

1 Sinjar General Hospital, Nineveh Health Department, Nineveh, Iraq

2 Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Iraq

Abstract

Background: Statins have demonstrated various beneficial clinical outcomes, not only in patients with elevated cholesterol levels but also in those with normal levels, a collective phenomenon known as pleiotropic effects. In the cardiovascular system, statins exhibit numerous pleiotropic effects, including the improvement of endothelial function by enhancing nitric oxide synthesis, anti-inflammatory actions, and antioxidant properties. Similarly, within the gastrointestinal tract, statins confer advantageous pleiotropic effects. Aim: This review delves into the potential mechanisms underpinning the gastroprotective impact of statins against indomethacin-induced gastric ulcers. In particular, the administration of statins resulted in a notable elevation in the levels of NO and PGE2 in the mucosa of the stomach. These results substantiate the gastroprotective role of statin is attributed to scavenging of free radicals, elevation of nitric oxide levels, and enhancement of prostaglandin E2 levels. Conclusion: To sum up, the results indicate that statins could be a preferable therapeutic choice for individuals who are susceptible to developing gastric ulcers as a result of NSAIDs usage.


Keywords

Main Subjects

  1. Schaefer EJ, McNamara JR, Tayler T, Daly JA, Gleason JL, Seman LJ, et al. Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial lipoproteins in patients with coronary heart disease versus control subjects. American Journal of Cardiology 2004;93(1):31-9.
  2. Schillinger M, Exner M, Mlekusch W, Amighi J, Sabeti S, Muellner M, et al. Statin therapy improves cardiovascular outcome of patients with peripheral artery disease. European Heart Journal 2004;25(9):742-8.
  3. Nohria A, Prsic A, Liu PY, Okamoto R, Creager MA, Selwyn A, et al. Statins inhibit Rho kinase activity in patients with atherosclerosis. Atherosclerosis 2009;205(2):517-21.
  4. Mraiche F, Cena J, Das D, Vollrath B. Effects of statins on vascular function of endothelin-1. British Journal of Pharmacology 2005;144(5):715-26.
  5. McTaggart SJ. Isoprenylated proteins. Cellular and Molecular Life Sciences 2006;63(3):255-67.
  6. Corpataux JM, Naik J, Porter KE, London NJ. The effect of six different statins on the proliferation, migration, and invasion of human smooth muscle cells. Journal of Surgical Research 2005;129(1):52-6.
  7. Rikitake Y, Liao JK. Rho GTPases, statins, and nitric oxide. Circulation Research 2005;97(12):1232-5.
  8. Rossoni LV, Wareing M, Wenceslau CF, Al-Abri M, Cobb C, Austin C. Acute simvastatin increases endothelial nitric oxide synthase phosphorylation via AMP-activated protein kinase and reduces contractility of isolated rat mesenteric resistance arteries. Clinical Science (Lond). 2011;121(10):449-58.
  9. Franzoni F, Quinones-Galvan A, Regoli F, Ferrannini E, Galetta F. A comparative study of the in vitro antioxidant activity of statins. International Journal of Cardiology 2003;90(2-3):317-21.
  10. Wijarnpreecha K, Panjawatanan P, Leelasinjaroen P, Ungprasert P. Statins and risk of peptic ulcer disease: A systematic review and meta-analysis. Arab Journal of Gastroenterology  2020;21(3):135-8.
  11. Heeba GH, Hassan MK, Amin RS. Gastroprotective effect of simvastatin against indomethacin-induced gastric ulcer in rats: role of nitric oxide and prostaglandins. European Journal of Pharmacology 2009;607(1-3):188-93.
  12. Holstein SA, Wohlford-Lenane CL, Wiemer DF, Hohl RJ. Isoprenoid pyrophosphate analogues regulate expression of Ras-related proteins. Biochemistry 2003;42(15):4384-91.
  13. Seshiah PN, Weber DS, Rocic P, Valppu L, Taniyama Y, Griendling KK. Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. Circulation Research 2002;91(5):406-13.
  14. Habib S, Ali A. Biochemistry of nitric oxide. Indian Journal of Clinical Biochemistry 2011;26(1):3-17.
  15. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. New Engl Journal of Medecine 1993;329(27):2002-12.
  16. Bir SC, Xiong Y, Kevil CG, Luo J. Emerging role of PKA/eNOS pathway in therapeutic angiogenesis for ischaemic tissue diseases. Cardiovascular Research 2012;95(1):7-18.
  17. Brown JF, Hanson PJ, Whittle BJ. Nitric oxide donors increase mucus gel thickness in rat stomach. European Journal of Pharmacology 1992;223(1):103-4.
  18. Schairer DO, Chouake JS, Nosanchuk JD, Friedman AJ. The potential of nitric oxide releasing therapies as antimicrobial agents. Virulence 2012;3(3):271-9.
  19. Stanek A, Gadowska-Cicha A, Gawron K, Wielkoszynski T, Adamek B, Cieslar G, et al. Role of nitric oxide in physiology and pathology of the gastrointestinal tract. Mini-Reviews in Medicinal Chemistry 2008;8(14):1549-60.
  20. Wallace JL, Miller MJ. Nitric oxide in mucosal defense: a little goes a long way. Gastroenterology. 2000;119(2):512-20.
  21. Calatayud S, Sanz MJ, Canet A, Bello R, de Rojas FD, Esplugues JV. Mechanisms of gastroprotection by transdermal nitroglycerin in the rat. British Journal of Pharmacology 1999;127(5):1111-8.
  22. Takeuchi K, Satoh H. NSAID-induced small intestinal damage--roles of various pathogenic factors. Digestion 2015;91(3):218-32.
  23. Han T, Tang Y, Li J, Xue B, Gong L, Li J, et al. Nitric oxide donor protects against acetic acid-induced gastric ulcer in rats via S-nitrosylation of TRPV1 on vagus nerve. Scientific Reports 2017;7(1):2063.
  24. Bodi N, Szalai Z, Bagyanszki M. Nitrergic Enteric Neurons in Health and Disease-Focus on Animal Models. International Journal of Molecular Sciences 2019;20(8).
  25. Engevik AC, Kaji I, Goldenring JR. The Physiology of the Gastric Parietal Cell. Physiological Reviews 2020;100(2):573-602.
  26. Goswami S. Interplay of potassium channel, gastric parietal cell and proton pump in gastrointestinal physiology, pathology and pharmacology. Minerva Gastroenterology 2022;68(3):289-305.
  27. Yao X, Smolka AJ. Gastric Parietal Cell Physiology and Helicobacter pylori-Induced Disease. Gastroenterology 2019;156(8):2158-73.
  28. Brown JF, Hanson PJ, Whittle BJ. The nitric oxide donor, S-nitroso-N-acetyl-penicillamine, inhibits secretory activity in rat isolated parietal cells. Biochemical and Biophysical Research Communications 1993;195(3):1354-9.
  29. Iwata M, Inoue T, Asai Y, Hori K, Fujiwara M, Matsuo S, et al. The protective role of localized nitric oxide production during inflammation may be mediated by the heme oxygenase-1/carbon monoxide pathway. Biochemistry and Biophysics Reports 2020; 23:1007-90.
  30. Abu-Soud HM, Hazen SL. Nitric oxide modulates the catalytic activity of myeloperoxidase. Journal of Biological Chemistry 2000;275(8):5425-30.
  31. Liang TY, Deng RM, Li X, Xu X, Chen G. The role of nitric oxide in peptic ulcer: a narrative review. Medical Gas Research 2021;11(1):42-5.
  32. Lamarque D, Moran AP, Szepes Z, Delchier JC, Whittle BJ. Cytotoxicity associated with induction of nitric oxide synthase in rat duodenal epithelial cells in vivo by lipopolysaccharide of Helicobacter pylori: inhibition by superoxide dismutase. British Journal of Pharmacology 2000;130(7):1531-8.
  33. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiological Reviews 2007;87(1):315-424.
  34. Drini M. Peptic ulcer disease and non-steroidal anti-inflammatory drugs. Australian Prescriber 2017;40(3):91-3.

 

 

  1. Kamar SS, Latif NSA, Elrefai MFM, Amin SN. Gastroprotective effects of nebivolol and simvastatin against cold restraint stress-induced gastric ulcer in rats. Anatomy & Cell Biology 2020;53(3):301-12.
  2. Gorabi AM, Kiaie N, Hajighasemi S, Banach M, Penson PE, Jamialahmadi T, et al. Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications. Journal of Clinical Medicine 2019;8(12).
  3. Marnett LJ, Wright TL, Crews BC, Tannenbaum SR, Morrow JD. Regulation of prostaglandin biosynthesis by nitric oxide is revealed by targeted deletion of inducible nitric-oxide synthase. Journal of Biological Chemistry 2000;275(18):13427-30.
  4. Gonzalez JD, Llinas MT, Nava E, Ghiadoni L, Salazar FJ. Role of nitric oxide and prostaglandins in the long-term control of renal function. Hypertension 1998;32(1):33-8.
  5. Cohen MM. Role of endogenous prostaglandins in gastric secretion and mucosal defense. Clinical and Investigative Medicine 1987;10(3):226-31.
  6. Duggan KC, Walters MJ, Musee J, Harp JM, Kiefer JR, Oates JA, et al. Molecular basis for cyclooxygenase inhibition by the non-steroidal anti-inflammatory drug naproxen. Journal of Biological Chemistry 2010;285(45):34950-9.
  7. Font-Nieves M, Sans-Fons MG, Gorina R, Bonfill-Teixidor E, Salas-Perdomo A, Marquez-Kisinousky L, et al. Induction of COX-2 enzyme and down-regulation of COX-1 expression by lipopolysaccharide (LPS) control prostaglandin E2 production in astrocytes. Journal of Biological Chemistry 2012;287(9):6454-68.
  8. Wallace JL, Devchand PR. Emerging roles for cyclooxygenase-2 in gastrointestinal mucosal defense. British Journal of Pharmacology 2005;145(3):275-82.
  9. Tanaka A, Araki H, Komoike Y, Hase S, Takeuchi K. Inhibition of both COX-1 and COX-2 is required for development of gastric damage in response to nonsteroidal anti-inflammatory drugs. Journal of Physiology-Paris 2001;95(1-6):21-7.
  10. Cordle A, Koenigsknecht-Talboo J, Wilkinson B, Limpert A, Landreth G. Mechanisms of statin-mediated inhibition of small G-protein function. Journal of Biological Chemistry 2005;280(40):34202-9.
  11. Xiao H, Qin X, Ping D, Zuo K. Inhibition of Rho and Rac geranylgeranylation by atorvastatin is critical for preservation of endothelial junction integrity. PLoS One 2013;8(3):e59233.
  12. Margaritis M, Channon KM, Antoniades C. Statins as regulators of redox state in the vascular endothelium: beyond lipid lowering. Antioxidant and Redox Signaling 2014;20(8):1198-215.
  13. Pantea M, Negovan A, Voidazan S, Macarie M, Mocan S, Bataga S. Statins and gastroduodenal endoscopic lesions: A case-control study. Medicine (Baltimore). 2018;97(50):e13579.
  14. Lin CJ, Liao WC, Chen YA, Lin HJ, Feng CL, Lin CL, et al. Statin Therapy Is Associated with Reduced Risk of Peptic Ulcer Disease in the Taiwanese Population. Frontiers in Pharmacology 2017;8: 210.
  15. Kwiecien S, Brzozowski T, Konturek SJ. Effects of reactive oxygen species action on gastric mucosa in various models of mucosal injury Journal of Physiology and Pharmacology 2002;53(1):39-50.
  16. Maity P, Bindu S, Dey S, Goyal M, Alam A, Pal C, et al. Indomethacin, a non-steroidal anti-inflammatory drug, develops gastropathy by inducing reactive oxygen species-mediated mitochondrial pathology and associated apoptosis in gastric mucosa: a novel role of mitochondrial aconitase oxidation. Journal of Biological Chemistry 2009;284(5):3058-68.
  17. Kunikata T, Tanaka A, Miyazawa T, Kato S, Takeuchi K. 16,16-Dimethyl prostaglandin E2 inhibits indomethacin-induced small intestinal lesions through EP3 and EP4 receptors. Digestive Diseases and Sciences 2002;47(4):894-904.
  18. Takeuchi K, Miyazawa T, Tanaka A, Kato S, Kunikata T. Pathogenic importance of intestinal hypermotility in NSAID-induced small intestinal damage in rats. Digestion 2002;66(1):30-41.
  19. Takeuchi K, Ueki S, Okabe S. Importance of gastric motility in the pathogenesis of indomethacin-induced gastric lesions in rats. Digestive Diseases and Sciences 1986;31(10):1114-22.
  20. Satoh H. Role of dietary fiber in formation and prevention of small intestinal ulcers induced by nonsteroidal anti-inflammatory drug. Current Pharmaceutical Design 2010;16(10):1209-13.
  21. Nagano Y, Matsui H, Tamura M, Shimokawa O, Nakamura Y, Kaneko T, et al. NSAIDs and acidic environment induce gastric mucosal cellular mitochondrial dysfunction. Digestion 2012;85(2):131-5.
  22. Tomita T, Sadakata H, Tamura M, Matsui H. Indomethacin-induced generation of reactive oxygen species leads to epithelial cell injury before the formation of intestinal lesions in mice. Journal of Physiology and Pharmacology 2014;65(3):435-40.
  23. Satoh H, Shiotani S, Otsuka N, Hatao K, Nishimura S. Role of dietary fibres, intestinal hypermotility and leukotrienes in the pathogenesis of NSAID-induced small intestinal ulcers in cats. Gut 2009;58(12):1590-6.
  24. Tanaka A, Araki H, Hase S, Komoike Y, Takeuchi K. Up-regulation of COX-2 by inhibition of COX-1 in the rat: a key to NSAID-induced gastric injury. Alimentary Pharmacology & Therapeutics 2002;16 Suppl 2:90-101.
  25. Komoike Y, Takeeda M, Tanaka A, Kato S, Takeuchi K. Prevention by parenteral aspirin of indomethacin-induced gastric lesions in rats: mediation by salicylic acid. Digestive Diseases and Sciences 2002;47(7):1538-45.