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.
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References
Keethy, D., C. Mrakotsky, and E. Szigethy. 2014. Pediatric IBD and depression: Treatment implications. Current Opinion in Pediatrics 26 (5): 561–567.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Abreu, M.T. 2002. The pathogenesis of inflammatory bowel disease: Translational implications for clinicians. Current Gastroenterology Reports 4 (6): 481–489.
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.
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.
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.
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.
Toms, C., and F. Powrie. 2001. Control of intestinal inflammation by regulatory T cells. Microbes and Infection 3 (11): 929–935.
Polverini, P. 1997. Role of the macrophage in angiogenesis-dependent diseases, in Regulation of angiogenesis, 11–28. Berlin: Springer.
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.
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.
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.
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.
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.
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.
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.
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.
Wang, H., et al. 2003. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421 (6921): 384.
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.
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.
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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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
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DOI: https://doi.org/10.1007/s10753-019-01068-0