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The 5-HT4 receptor agonist mosapride attenuates NSAID-induced gastric mucosal damage

  • Original Article—Alimentary Tract
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Abstract

Background

The cholinergic anti-inflammatory pathway is a novel physiological mechanism found at various locations in the body where the nicotinic regulation of inflammatory cells through the autonomic nervous system is involved. In this study, we tested the hypothesis that cholinergic nerve stimulation by a 5-HT4 agonist may modulate the progression of gastric mucosal ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs).

Methods

Acute gastric ulcers were induced in rats by the oral administration of indomethacin.

Results

Gastric damage analysis indicated that pretreatment with mosapride, a selective 5-HT4 agonist, at 0.25, 0.5, and 0.75 mg/kg, inhibited the mucosal damage induced by indomethacin. In gastric emptying analysis, an evacuation effect was observed in the 3.0 mg/kg mosapride pretreatment group, but this effect was not observed in the lower dose (0.5 mg/kg) group. The antiulcerogenic activity of mosapride treatment (at 0.5 mg/kg) was blocked by a 5-HT4-specific antagonist, GR113808 (1 mg/kg, i.v.). Additionally, we demonstrated that methyllycaconitine (0.29 and 0.87 mg/kg i.p.), a selective inhibitor of α7 nicotinic acetylcholine (ACh) receptors (α7nAChRs), ablated the antiulcerogenic action of mosapride.

Conclusions

These results suggest that the mucosal protective action of mosapride may be mediated by an action on immune cells through the acceleration of ACh release from parasympathetic nerves via the activation of 5-HT4 receptors, followed by activation of the nicotinic anti-inflammatory system. It appears that the α7nAChR may be involved in the antiulcerogenic action of mosapride.

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References

  1. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132(1):397–414.

    Article  CAS  PubMed  Google Scholar 

  2. Schuurkes JA, Van Nueten JM. Control of gastroduodenal coordination: dopaminergic and cholinergic pathways. Scand J Gastroenterol Suppl. 1984;92:8–12.

    CAS  PubMed  Google Scholar 

  3. Olsson S, Edwards IR. Tachycardia during cisapride treatment. Br Med J. 1992;305(6856):748–9.

    Article  CAS  Google Scholar 

  4. Wysowski DK, Bacsanyi J. Cisapride and fatal arrhythmia. N Engl J Med. 1996;335(4):290–1.

    Article  CAS  PubMed  Google Scholar 

  5. Mizuta Y, Shikuwa S, Isomoto H, Mishima R, Akazawa Y, Masuda J, et al. Recent insights into digestive motility in functional dyspepsia. J Gastroenterol. 2006;41(11):1025–40.

    Article  PubMed  Google Scholar 

  6. Camilleri M, Vazquez-Roque MI, Burton D, Ford T, McKinzie S, Zinsmeister AR, et al. Pharmacodynamic effects of a novel prokinetic 5-HT receptor agonist, ATI-7505, in humans. Neurogastroenterol Motil. 2007;19(1):30–8.

    Article  CAS  PubMed  Google Scholar 

  7. Mikami T, Ochi Y, Suzuki K, Saito T, Sugie Y, Sakakibara M. 5-Amino-6-chloro-N-[(1-isobutylpiperidin-4-yl)methyl]-2-methylimidazo[1, 2- alpha]pyridine-8-carboxamide (CJ-033, 466), a novel and selective 5-hydroxytryptamine4 receptor partial agonist: pharmacological profile in vitro and gastroprokinetic effect in conscious dogs. J Pharmacol Exp Ther. 2008;325(1):190–9.

    Article  CAS  PubMed  Google Scholar 

  8. Beattie DT, Armstrong SR, Shaw JP, Marquess D, Sandlund C, Smith JA, et al. The in vivo gastrointestinal activity of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity. Naunyn Schmiedebergs Arch Pharmacol. 2008;378(1):139–47.

    Article  CAS  PubMed  Google Scholar 

  9. de Jonge WJ, Ulloa L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol. 2007;151(7):915–29.

    Article  PubMed  Google Scholar 

  10. Bonaz B. The cholinergic anti-inflammatory pathway and the gastrointestinal tract. Gastroenterology. 2007;133(4):1370–3.

    Article  CAS  PubMed  Google Scholar 

  11. Tracey KJ. The inflammatory reflex. Nature. 2002;420(6917):853–9.

    Article  CAS  PubMed  Google Scholar 

  12. Ulloa L. The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov. 2005;4(8):673–84.

    Article  CAS  PubMed  Google Scholar 

  13. Gwilt CR, Donnelly LE, Rogers DF. The non-neuronal cholinergic system in the airways: an unappreciated regulatory role in pulmonary inflammation? Pharmacol Ther. 2007;115(2):208–22.

    Article  CAS  PubMed  Google Scholar 

  14. Kawashima K, Fujii T. Basic and clinical aspects of non-neuronal acetylcholine: overview of non-neuronal cholinergic systems and their biological significance. J Pharmacol Sci. 2008;106(2):167–73.

    Article  CAS  PubMed  Google Scholar 

  15. Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology. 2006;131(4):1122–30.

    Article  PubMed  Google Scholar 

  16. Ghia JE, Blennerhassett P, Collins SM. Impaired parasympathetic function increases susceptibility to inflammatory bowel disease in a mouse model of depression. J Clin Invest. 2008;118(6):2209–18.

    CAS  PubMed  Google Scholar 

  17. Hiramoto T, Chida Y, Sonoda J, Yoshihara K, Sudo N, Kubo C. The hepatic vagus nerve attenuates Fas-induced apoptosis in the mouse liver via alpha7 nicotinic acetylcholine receptor. Gastroenterology. 2008;134(7):2122–31.

    Article  PubMed  Google Scholar 

  18. Villegas I, La Casa C, de la Lastra CA, Motilva V, Herrerias JM, Martin MJ. Mucosal damage induced by preferential COX-1 and COX-2 inhibitors: role of prostaglandins and inflammatory response. Life Sci. 2004;74(7):873–84.

    Article  CAS  PubMed  Google Scholar 

  19. Avila JR, de la Lastra CA, Martin MJ, Motilva V, Luque I, Delgado D, et al. Role of endogenous sulphydryls and neutrophil infiltration in the pathogenesis of gastric mucosal injury induced by piroxicam in rats. Inflamm Res. 1996;45(2):83–8.

    Article  CAS  PubMed  Google Scholar 

  20. Tanigawa T, Pai R, Arakawa T, Higuchi K, Tarnawski AS. TGF-beta signaling pathway: its role in gastrointestinal pathophysiology and modulation of ulcer healing. J Physiol Pharmacol. 2005;56(1):3–13.

    CAS  PubMed  Google Scholar 

  21. Arakawa T, Higuchi K, Fukuda T, Fujiwara Y, Kobayashi K, Kuroki T. Prostaglandins in the stomach: an update. J Clin Gastroenterol. 1998;27(Suppl 1):S1–11.

    Article  PubMed  Google Scholar 

  22. Gudis K, Sakamoto C. The role of cyclooxygenase in gastric mucosal protection. Dig Dis Sci. 2005;50(Suppl 1):S16–23.

    Article  CAS  PubMed  Google Scholar 

  23. Wilson KT, Crabtree JE. Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies. Gastroenterology. 2007;133(1):288–308.

    Article  CAS  PubMed  Google Scholar 

  24. Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn’t the stomach digest itself? Physiol Rev. 2008;88(4):1547–65.

    Article  CAS  PubMed  Google Scholar 

  25. Santos CL, Medeiros BA, Palheta-Junior RC, Macedo GM, Nobre-e-Souza MA, Troncon LE, et al. Cyclooxygenase-2 inhibition increases gastric tone and delays gastric emptying in rats. Neurogastroenterol Motil. 2007;19(3):225–32.

    Article  CAS  PubMed  Google Scholar 

  26. Fu XW, Lindstrom J, Spindel ER. Nicotine activates and up-regulates nicotinic acetylcholine receptors in bronchial epithelial cells. Am J Respir Cell Mol Biol. 2009;41(1):93–9.

    Article  CAS  PubMed  Google Scholar 

  27. Alarcon-de-la-Lastra Romero C, Lopez A, Martin MJ, la Casa C, Motilva V. Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. Pharmacology. 1997;54(4):193–202.

    Article  CAS  PubMed  Google Scholar 

  28. Takeuchi K, Kato S, Hirata T, Nishiwaki H. Gastric motility and mucosal ulcerogenic responses induced by prokinetic drugs in rats under prostaglandin-deficient conditions. Dig Dis Sci. 1997;42(2):251–8.

    Article  CAS  PubMed  Google Scholar 

  29. Wallace JL, Granger DN. Pathogenesis of NSAID gastropathy: are neutrophils the culprits? Trends Pharmacol Sci. 1992;13(4):129–31.

    Article  CAS  PubMed  Google Scholar 

  30. Appleyard CB, McCafferty DM, Tigley AW, Swain MG, Wallace JL. Tumor necrosis factor mediation of NSAID-induced gastric damage: role of leukocyte adherence. Am J Physiol. 1996;270(1 Pt 1):G42–8.

    CAS  PubMed  Google Scholar 

  31. Takeuchi K, Tanaka A, Ohno R, Yokota A. Role of COX inhibition in pathogenesis of NSAID-induced small intestinal damage. J Physiol Pharmacol. 2003;54(Suppl 4):165–82.

    PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Professor A. M. Bari (Department of Pathology, Bangladesh Agricultural University) for critical reading of this manuscript. This work was supported by a Grant-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology (Japan).

Conflict of interest statement

H. Ozaki has received grant support from Dainippon Sumitomo Pharmaceutical Inc. The remaining authors have declared no financial interests.

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Authors and Affiliations

  1. Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo, 113-8657, Japan

    Masahiko Fujisawa, Takahisa Murata, Masatoshi Hori & Hiroshi Ozaki

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  1. Masahiko Fujisawa
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  2. Takahisa Murata
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  3. Masatoshi Hori
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  4. Hiroshi Ozaki
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Correspondence to Hiroshi Ozaki.

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Fujisawa, M., Murata, T., Hori, M. et al. The 5-HT4 receptor agonist mosapride attenuates NSAID-induced gastric mucosal damage. J Gastroenterol 45, 179–186 (2010). https://doi.org/10.1007/s00535-009-0170-3

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  • DOI: https://doi.org/10.1007/s00535-009-0170-3

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