Skip to main content

Advertisement

Log in

Potential Anti-Inflammatory Effect of Escitalopram in Iodoacetamide-Induced Colitis in Depressed Ovariectomized Rats: Role of α7-nAChR

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Escitalopram, a drug of choice in the treatment of depression, was recently shown to possess an anti-inflammatory activity. The aim of the present study was to elucidate the effect of escitalopram on peripheral inflammatory cascades in iodoacetamide-induced colitis associated with depressive behavior in ovariectomized rats. Moreover, the role of α-7 nicotinic acetylcholine receptor in mediating the anti-colitic effect of escitalopram was examined using a nicotinic receptor antagonist methyllycaconitine citrate. Colitis was induced by intracolonic injection of 4% iodoacetamide in ovariectomized rats. Escitalopram (10 mg/kg/day, i.p.) was then injected for 1 week and several parameters including macroscopic (colon mass index and ulcerative area), microscopic (histopathology and scoring), and biochemical (myeloperoxidase and tumor necrosis factor-α) were determined. Colitis induction in ovariectomized rats resulted in a marked increase in colon mass index, ulcerative area, histopathological scoring, myeloperoxidase activity and tumor necrosis factor-α levels. These effects were ameliorated by escitalopram, even in the presence of methyllycaconitine indicating that α-7 nicotinic acetylcholine receptor does not mediate the anti-inflammatory effect of escitalopram. The present study revealed the beneficial effect of escitalopram in iodoacetamide induced colitis in ovariectomized rats and suggests that it may represent a new therapeutic agent for the treatment of inflammatory bowel disease, especially in patients with or at high risk of depressive behavior.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Keethy, D., C. Mrakotsky, and E. Szigethy. 2014. Pediatric IBD and depression: Treatment implications. Current Opinion in Pediatrics 26 (5): 561–567.

    Article  Google Scholar 

  2. Macer, B.J., S.L. Prady, and A. Mikocka-Walus. 2017. Antidepressants in inflammatory bowel disease: A systematic review. Inflammatory Bowel Diseases 23 (4): 534–550.

    Article  Google Scholar 

  3. Kristensen, M.S., et al. 2018. The influence of antidepressants on the disease course among patients with Crohn’s disease and ulcerative colitis—A Danish Nationwide register–based cohort study. Inflammatory Bowel Diseases 25 (5): 886–893.

    Article  Google Scholar 

  4. Filipovic, B.R., and B.F. Filipovic. 2014. Psychiatric comorbidity in the treatment of patients with inflammatory bowel disease. World journal of gastroenterology: WJG 20 (13): 3552.

    Article  CAS  Google Scholar 

  5. Mikocka-Walus, A.A., A.L. Gordon, B.J. Stewart, and J.M. Andrews. 2012. The role of antidepressants in the management of inflammatory bowel disease (IBD): A short report on a clinical case-note audit. Journal of Psychosomatic Research 72 (2): 165–167.

    Article  Google Scholar 

  6. Itatsu, T., A. Nagahara, M. Hojo, A. Miyazaki, T. Murai, M. Nakajima, and S. Watanabe. 2011. Use of selective serotonin reuptake inhibitors and upper gastrointestinal disease. Internal Medicine 50 (7): 713–717.

    Article  CAS  Google Scholar 

  7. Dong, C., J.C. Zhang, W. Yao, Q. Ren, C. Yang, M. Ma, M. Han, R. Saito, and K. Hashimoto. 2016. Effects of escitalopram, R-citalopram, and reboxetine on serum levels of tumor necrosis factor-α, interleukin-10, and depression-like behavior in mice after lipopolysaccharide administration. Pharmacology Biochemistry and Behavior 144: 7–12.

    Article  CAS  Google Scholar 

  8. Ghia, J.E., P. Blennerhassett, H. Kumar–Ondiveeran, E.F. Verdu, and S.M. Collins. 2006. The vagus nerve: A tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 131 (4): 1122–1130.

    Article  Google Scholar 

  9. Ghia, J.-E., P. Blennerhassett, and S.M. Collins. 2008. Impaired parasympathetic function increases susceptibility to inflammatory bowel disease in a mouse model of depression. The Journal of Clinical Investigation 118 (6): 2209–2218.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Borovikova, L.V., S. Ivanova, M. Zhang, H. Yang, G.I. Botchkina, L.R. Watkins, H. Wang, N. Abumrad, J.W. Eaton, and K.J. Tracey. 2000. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405 (6785): 458–462.

    Article  CAS  Google Scholar 

  11. Grandi, A., I. Zini, L. Flammini, A.M. Cantoni, V. Vivo, V. Ballabeni, E. Barocelli, and S. Bertoni. 2017. alpha7 nicotinic agonist AR-R17779 protects mice against 2,4,6-Trinitrobenzene sulfonic acid-induced colitis in a spleen-dependent way. Frontiers in Pharmacology 8: 809.

    Article  Google Scholar 

  12. Salem, H.A., and W. Wadie. 2017. Effect of niacin on inflammation and angiogenesis in a murine model of ulcerative colitis. Scientific Reports 7 (1): 7139.

    Article  Google Scholar 

  13. Ibrahim, W.W., M.M. Safar, M.M. Khattab, and A.M. Agha. 2016. 17beta-estradiol augments antidepressant efficacy of escitalopram in ovariectomized rats: Neuroprotective and serotonin reuptake transporter modulatory effects. Psychoneuroendocrinology 74: 240–250.

    Article  CAS  Google Scholar 

  14. Wazea, S.A., W. Wadie, A.K. Bahgat, and H.S. el-Abhar. 2018. Galantamine anti-colitic effect: Role of alpha-7 nicotinic acetylcholine receptor in modulating Jak/STAT3, NF-kappaB/HMGB1/RAGE and p-AKT/Bcl-2 pathways. Scientific Reports 8 (1): 5110.

    Article  Google Scholar 

  15. Rocha, B.A., R. Fleischer, J.M. Schaeffer, S.P. Rohrer, and G.J. Hickey. 2005. 17β-estradiol-induced antidepressant-like effect in the forced swim test is absent in estrogen receptor-β knockout (BERKO) mice. Psychopharmacology 179 (3): 637–643.

    Article  CAS  Google Scholar 

  16. Estrada-Camarena, E., A. Fernández-Guasti, and C. López-Rubalcava. 2003. Antidepressant-like effect of different estrogenic compounds in the forced swimming test. Neuropsychopharmacology 28 (5): 830–838.

    Article  CAS  Google Scholar 

  17. Wang, W.P., et al. 2001. Protective role of heme oxygenase-1 on trinitrobenzene sulfonic acid-induced colitis in rats. American Journal of Physiology. Gastrointestinal and Liver Physiology 281 (2): G586–G594.

    Article  CAS  Google Scholar 

  18. Bradley, P.P., D.A. Priebat, R.D. Christensen, and G. Rothstein. 1982. Measurement of cutaneous inflammation: Estimation of neutrophil content with an enzyme marker. The Journal of Investigative Dermatology 78 (3): 206–209.

    Article  CAS  Google Scholar 

  19. Abreu, M.T. 2002. The pathogenesis of inflammatory bowel disease: Translational implications for clinicians. Current Gastroenterology Reports 4 (6): 481–489.

    Article  Google Scholar 

  20. Cryan, J.F., R.J. Valentino, and I. Lucki. 2005. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neuroscience and Biobehavioral Reviews 29 (4–5): 547–569.

    Article  CAS  Google Scholar 

  21. Rygula, R., N. Abumaria, G. Flügge, E. Fuchs, E. Rüther, and U. Havemann-Reinecke. 2005. Anhedonia and motivational deficits in rats: Impact of chronic social stress. Behavioural Brain Research 162 (1): 127–134.

    Article  Google Scholar 

  22. Bogdanova, O.V., S. Kanekar, K.E. D'Anci, and P.F. Renshaw. 2013. Factors influencing behavior in the forced swim test. Physiology & Behavior 118: 227–239.

    Article  CAS  Google Scholar 

  23. Minaiyan, M., V. Hajhashemi, M. Rabbani, E. Fattahian, and P. Mahzouni. 2015. Effect of venlafaxine on experimental colitis in normal and reserpinised depressed rats. Research in Pharmaceutical Sciences 10 (4): 295–306.

    PubMed  PubMed Central  Google Scholar 

  24. Toms, C., and F. Powrie. 2001. Control of intestinal inflammation by regulatory T cells. Microbes and Infection 3 (11): 929–935.

    Article  CAS  Google Scholar 

  25. Polverini, P. 1997. Role of the macrophage in angiogenesis-dependent diseases, in Regulation of angiogenesis, 11–28. Berlin: Springer.

    Google Scholar 

  26. Mawdsley, J.E., M.G. Macey, R.M. Feakins, L. Langmead, and D.S. Rampton. 2006. The effect of acute psychologic stress on systemic and rectal mucosal measures of inflammation in ulcerative colitis. Gastroenterology 131 (2): 410–419.

    Article  CAS  Google Scholar 

  27. Mittermaier, C., C. Dejaco, T. Waldhoer, A. Oefferlbauer-Ernst, W. Miehsler, M. Beier, W. Tillinger, A. Gangl, and G. Moser. 2004. Impact of depressive mood on relapse in patients with inflammatory bowel disease: A prospective 18-month follow-up study. Psychosomatic Medicine 66 (1): 79–84.

    Article  Google Scholar 

  28. Diamond, M., J.P. Kelly, and T.J. Connor. 2006. Antidepressants suppress production of the Th1 cytokine interferon-γ, independent of monoamine transporter blockade. European Neuropsychopharmacology 16 (7): 481–490.

    Article  CAS  Google Scholar 

  29. Bah, T.M., M. Benderdour, S. Kaloustian, R. Karam, G. Rousseau, and R. Godbout. 2011. Escitalopram reduces circulating pro-inflammatory cytokines and improves depressive behavior without affecting sleep in a rat model of post-cardiac infarct depression. Behavioural Brain Research 225 (1): 243–251.

    Article  CAS  Google Scholar 

  30. Zabihi, M., V. Hajhashemi, A. Talebi, and M. Minaiyan. 2017. Evaluation of central and peripheral effects of doxepin on acetic acid-induced colitis in rat and the involved mechanisms. EXCLI Journal 16: 414–425.

    PubMed  PubMed Central  Google Scholar 

  31. Hashioka, S., P. McGeer, A. Monji, and S. Kanba. 2009. Anti-inflammatory effects of antidepressants: Possibilities for preventives against Alzheimer's disease. Central Nervous System Agents in Medicinal Chemistry 9 (1): 12–19.

    Article  CAS  Google Scholar 

  32. Ghia, J.-E., P. Blennerhassett, R.T. el-Sharkawy, and S.M. Collins. 2007. The protective effect of the vagus nerve in a murine model of chronic relapsing colitis. American Journal of Physiology-Gastrointestinal and Liver Physiology 293 (4): G711–G718.

    Article  CAS  Google Scholar 

  33. Bai, A., Y. Guo, and N. Lu. 2007. The effect of the cholinergic anti-inflammatory pathway on experimental colitis. Scandinavian Journal of Immunology 66 (5): 538–545.

    Article  CAS  Google Scholar 

  34. Wang, H., et al. 2003. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421 (6921): 384.

    Article  CAS  Google Scholar 

  35. Ji, H., M.F. Rabbi, B. Labis, V.A. Pavlov, K.J. Tracey, and J.E. Ghia. 2014. Central cholinergic activation of a vagus nerve-to-spleen circuit alleviates experimental colitis. Mucosal Immunology 7 (2): 335–347.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Prof. Laila A. Rashed (Medical Biochemistry Department, Faculty of Medicine, Cairo University, Egypt), for her valuable assistance in ELIZA and Western blotting procedures. The authors are also thankful to Prof. Nermeen Shaffie (Department of Pathology, National Research Centre, Cairo, Egypt) for her precious efforts in histological examinations.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

Authors

Contributions

All authors contribute equally.

Corresponding author

Correspondence to Salah A. Abdo.

Ethics declarations

Conflict of Interest

The authors declare that there is no conflict of interests regarding the publication of this paper.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abdo, S.A., Wadie, W., Abdelsalam, R.M. et al. Potential Anti-Inflammatory Effect of Escitalopram in Iodoacetamide-Induced Colitis in Depressed Ovariectomized Rats: Role of α7-nAChR. Inflammation 42, 2056–2064 (2019). https://doi.org/10.1007/s10753-019-01068-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-019-01068-0

KEY WORDS

Navigation