Abstract
Mucosal inflammation in colitis is associated with changes in the intestinal serotonin (5-HT) level. Sumatriptan, a 5‐HT1B/1D receptor agonist, has demonstrated anti-inflammatory characteristics. The purpose of this study was to determine the effects of sumatriptan in a rat model of acute experimental colitis and to elucidate the probable participation of presynaptic 5-HT1B/1D receptors. To induce colitis, acetic acid (4%) was injected intrarectally. Treatments were given intraperitoneally (IP) once daily over 3 consecutive days starting 1-h post-induction. Sumatriptan was given at 0.5, 1, 2, and 5 mg/kg. GR-127935, a 5-HT1B/1D receptor antagonist, was injected (0.1 and 0.3 mg/kg) 30 min prior to the most effective dose of sumatriptan (1 mg/kg). On day 4, the colon samples were isolated. Significant enhancements of the tissue tumor necrosis factor-alpha (TNF-α), myeloperoxidase (MPO), microscopic and macroscopic damages, body weight losses, and also reductions in tissue superoxide dismutase (SOD) and 5-HT were observed in colitis rats. On the other hand, sumatriptan at doses 0.5, 1, and 2 mg/kg could diminish pathologic changes in the measured biomarkers, histopathologic damages, and body weight losses. Although GR-127935 at dose 0.3 mg/kg could markedly improve the pathologic indexes, its sub-effective dose (0.1 mg/kg) reversed the protective effect of sumatriptan (1 mg/kg). Moreover, sumatriptan (1 and 5 mg/kg) and GR-127935 (0.3 mg/kg) increased the serotonin level. Post-treatment with low-dose sumatriptan demonstrated a protective impact on this peripheral inflammatory condition. Notably, this protective effect may be mediated, at least in part, through 5-HT1B/1D receptors, as well as anti-inflammatory and anti-oxidative characteristics.
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References
Ahonen A, Kyösola K, Penttilä O (1976) Enterochromaffin cells in macrophages in ulcerative colitis and irritable colon. Ann Clin Res 8(1):1–7
Ala M, Ghasemi M, Mohammad Jafari R, Dehpour AR (2021) Beyond its anti-migraine properties, sumatriptan is an anti-inflammatory agent: A systematic review. Drug Dev Res 82(7):896–906
Anstead GM (1998) Steroids, retinoids, and wound healing. Adv Wound Care: J Prev Healing 11(6):277–285
Araldi D, Ferrari LF, Levine JD (2016) Gi-protein coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming. Pain 157(8):1773
Ardizzone S, Porro GB (2002) Inflammatory bowel disease: new insights into pathogenesis and treatment. J Intern Med 252(6):475–496
Arzt E, Costas M, Finkielman S, Nahmod VE (1991) Serotonin inhibition of tumor necrosis factor-α synthesis by human monocytes. Life Sci 48(26):2557–2562
Bearcroft C, Perrett D, Farthing M (1998) Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study. Gut 42(1):42–46
Bertrand PP, Barajas-Espinosa A, Neshat S, Bertrand RL, Lomax AE (2010) Analysis of real-time serotonin (5-HT) availability during experimental colitis in mouse. Am J Physiol-Gastrointest Liver Physiol 298(3):G446–G455
Bischoff SC, Mailer R, Pabst O, Weier G, Sedlik W, Li Z, Chen JJ, Murphy DL, Gershon MD (2009) Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2, 4, 6-trinitrobenzene sulfonic acid colitis in mice. Am J Physiol-Gastrointest Liver Physiol 296(3):G685–G695
Bishop A, Pietroletti R, Taat C, Brummelkamp W, Polak J (1987) Increased populations of endocrine cells in Crohn’s ileitis. Virchows Archiv A 410(5):391–396
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72(1–2):248–254
Brahadeesh M, Suresha RN, Satish AM (2013) Screening of the drug sumatriptan for its antiinflammatory potential in albino rats. Int J Recent Trends Sci Technol 9(1):76–80
Budarf ML, Labbé C, David G, Rioux JD (2009) GWA studies: rewriting the story of IBD. Trends Genet 25(3):137–146
Carmichael NM, Charlton MP, Dostrovsky JO (2008) Activation of the 5-HT1B/D receptor reduces hindlimb neurogenic inflammation caused by sensory nerve stimulation and capsaicin. Pain 134(1–2):97–105
Coates MD, Mahoney CR, Linden DR, Sampson JE, Chen J, Blaszyk H, Crowell MD, Sharkey KA, Gershon MD, Mawe GM (2004) Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterol 126(7):1657–1664
Dehdashtian A, Afshari K, Jazaeri SZ, Haddadi N-S, Sheikhi M, Abbaszadeh-Kasbi A, Tavangar SM, Jazaeri F, Amirlak B, Dehpour AR (2019) Sumatriptan increases skin flap survival through activation of 5-hydroxytryptamine 1b/1d receptors in rats: the mediating role of the nitric oxide pathway. Plast Reconstr Surg 144(1):70e–77e
Dejban P, Rahimi N, Takzare N, Jahansouz M, Dehpour AR (2019) Protective effects of sumatriptan on ischaemia/reperfusion injury following torsion/detorsion in ipsilateral and contralateral testes of rat. Andrologia 51(9):e13358
Dhalla NS, Temsah RM, Netticadan T (2000) Role of oxidative stress in cardiovascular diseases. J Hypertens 18(6):655–673
Ellwood AJ, Curtis MJ (1997) Involvement of 5-HT1B/1D and 5-HT2A receptors in 5-HT-induced contraction of endothelium-denuded rabbit epicardial coronary arteries. Br J Pharmacol 122(5):875–884
El-Merahbi R, Löffler M, Mayer A, Sumara G (2015) The roles of peripheral serotonin in metabolic homeostasis. FEBS Lett 589(15):1728–1734
El-Salhy M, Danielsson Å, Stenling R, Grimelius L (1997) Colonic endocrine cells in inflammatory bowel disease. J Intern Med 242(5):413–419
Elson CO, Sartor RB, Tennyson GS, Riddell RH (1995) Experimental models of inflammatory bowel disease. Gastroenterology 109(4):1344–1367
Eslami F, Rahimi N, Ostovaneh A, Ghasemi M, Dejban P, Abbasi A, Dehpour AR (2021) Sumatriptan reduces severity of status epilepticus induced by lithium–pilocarpine through nitrergic transmission and 5-HT1B/D receptors in rats: a pharmacological-based evidence. Fundam Clin Pharmacol 35(1):131–140
Fakhraei N, Abdolghaffari AH, Delfan B, Abbasi A, Rahimi N, Khansari A, Rahimian R, Dehpour AR (2014) Protective effect of hydroalcoholic olive leaf extract on experimental model of colitis in rat: involvement of nitrergic and opioidergic systems. Phytother Res 28(9):1367–1373
Fakhraei N, Javadian N, Rahimian R, Nili F, Rahimi N, Hashemizadeh S, Dehpour AR (2018) Involvement of central opioid receptors in protective effects of methadone on experimental colitis in rats. Inflammopharmacology 26(6):1399–1413
Farmer SG, Laniyonu AA (1984) Effects of p-chlorophenylalanine on the sensitivity of rat intestine to agonists and on intestinal 5-hydroxytryptamine levels during Nippostrongylus brasiliensis infection. Br J Pharmacol 82(4):883
Fitzpatrick PF (1999) Tetrahydropterin-dependent amino acid hydroxylases. Annu Rev Biochem 68(1):355–381
Gershon MD (2003) Serotonin and its implication for the management of irritable bowel syndrome. Rev Gastroenterol Disord 3:S25–S34
Gershon MD, Drakontides AB, Ross LL (1965) Serotonin: synthesis and release from the myenteric plexus of the mouse intestine. Science 149(3680):197–199
Gharishvandi F, Abdollahi A, Shafaroodi H, Jafari RM, Pasalar P, Dehpour AR (2020) Involvement of 5-HT1B/1D receptors in the inflammatory response and oxidative stress in intestinal ischemia/reperfusion in rats. Eur j pharmacol 882:173265
Ghia JE, Li N, Wang H, Collins M, Deng Y, El–Sharkawy RT, Côté F, Mallet J, Khan WI (2009) Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterol 137(5):1649–1660
Haddadi N-S, Foroutan A, Shakiba S, Afshari K, Ostadhadi S, Daneshpazhooh M, Dehpour A-R (2018) Attenuation of serotonin-induced itch by sumatriptan: possible involvement of endogenous opioids. Arch Dermatol Res 310(2):165–172
Hagar HH, El Medany A, El Eter E, Arafa M (2007) Ameliorative effect of pyrrolidinedithiocarbamate on acetic acid-induced colitis in rats. Eur J Pharmacol 554(1):69–77
Ham TS (2002) Regional distribution and relative frequency of gastrointestinal endocrine cells in large intestines of C57BL/6 mice. J Vet Sci 3(3):233–238
Haub S, Ritze Y, Bergheim I, Pabst O, Gershon M, Bischoff S (2010) Enhancement of intestinal inflammation in mice lacking interleukin 10 by deletion of the serotonin reuptake transporter. Neurogastroenterol Motil 22(7):826-e229
Hendrickson BA, Gokhale R, Cho JH (2002) Clinical aspects and pathophysiology of inflammatory bowel disease. Clin Microbiol Rev 15(1):79–94
Inoue S, Matsumoto T, Iida M, Mizuno M, Kuroki F, Hoshika K, Shimizu M (1999) Characterization of cytokine expression in the rectal mucosa of ulcerative colitis: correlation with disease activity. Am J Gastroenterol 94(9):2441–2446
Khalilzadeh M, Panahi G, Rashidian A, Hadian MR, Abdollahi A, Afshari K, Shakiba S, Norouzi-Javidan A, Rahimi N, Momeny M (2018) The protective effects of sumatriptan on vincristine-induced peripheral neuropathy in a rat model. Neurotoxicol 67:279–286
Khan WI, Motomura Y, Wang H, El-Sharkawy RT, Verdu EF, Verma-Gandhu M, Rollins BJ, Collins SM (2006) Critical role of MCP-1 in the pathogenesis of experimental colitis in the context of immune and enterochromaffin cells. Am J Physiol-Gastrointest Liver Physiol 291(5):G803–G811
Kim D-Y, Camilleri M (2000) Serotonin: a mediator of the brain-gut connection. Am J Gastroenterol 95(10):2698
Kordasti S, Sjövall H, Lundgren O, Svensson L (2004) Serotonin and vasoactive intestinal peptide antagonists attenuate rotavirus diarrhoea. Gut 53(7):952–957
Ku S, Lee H, Lee J (2004) An immunohistochemical study of gastrointestinal endocrine cells in the Balb/c mouse. Anat Histol Embryol 33(1):42–48
Kubera M, Maes M, Kenis G, Kim Y-K, Lasoń W (2005) Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor α and interleukin-6. Psychiatry Res 134(3):251–258
Li N, Ghia J-E, Wang H, McClemens J, Cote F, Suehiro Y, Mallet J, Khan WI (2011) Serotonin activates dendritic cell function in the context of gut inflammation. Am J Pathol 178(2):662–671
Linde M (2006) Migraine: a review and future directions for treatment. Acta Neurol Scand 114(2):71–83
Linden DR, Chen J-X, Gershon MD, Sharkey KA, Mawe GM (2003) Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis. Am J Physiol-Gastrointest Liver Physiol 285(1):G207–G216
Magro F, Vieira-Coelho M, Fraga S, Serräo M, Veloso FT, Ribeiro T, Soares-da-Silva P (2002) Impaired synthesis or cellular storage of norepinephrine, dopamine, and 5-hydroxytryptamine in human inflammatory bowel disease. Dig Dis Sci 47(1):216–224
Mauras N (2001) Growth hormone therapy in the glucocorticosteroid-dependent child: metabolic and linear growth effects. Horm Res Paediatr 56(Suppl. 1):13–18
Minderhoud IM, Oldenburg B, Schipper ME, Ter Linde JJ, Samsom M (2007) Serotonin synthesis and uptake in symptomatic patients with Crohn’s disease in remission. Clin Gastroenterol Hepatol 5(6):714–720
Moore BA, Sharkey KA, Mantle M (1996) Role of 5-HT in cholera toxin-induced mucin secretion in the rat small intestine. Am J Physiol-Gastrointest Liver Physiol 270(6):G1001–G1009
Mullane KM, Kraemer R, Smith B (1985) Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemie myocardium. J Pharmacol Methods 14(3):157–167
Nagata K, Fujimiya M, Sugiura H, Uehara M (2001) Intracellular localization of serotonin in mast cells of the colon in normal and colitis rats. Histochem J 33(9–10):559–568
Nitzan-Luques A, Minert A, Devor M, Tal M (2013) Dynamic genotype-selective phenotypic switching of CGRP expression contributes to differential neuropathic pain phenotype. Exp Neurol 250:194–204
Ogata H, Hibi T (2003) Cytokine and anti-cytokine therapies for inflammatory bowel disease. Curr Pharm Des 9(14):1107–1113
Oshima S-I, Fujimura M, Fukimiya M (1999) Changes in number of serotonin-containing cells and serotonin levels in the intestinal mucosa of rats with colitis induced by dextran sodium sulfate. Histochem Cell Biol 112(4):257–263
Regmi SC, Park S-Y, Ku SK, Kim J-A (2014) Serotonin regulates innate immune responses of colon epithelial cells through Nox2-derived reactive oxygen species. Free Radical Biol Med 69:377–389
Reinecker HC, Steffen M, Witthoeft T, Pflueger I, Schreiber S, MacDermott R, Raedler A (1993) Enhand secretion of tumour necrosis factor-alpha, IL-6, and IL-1β by isolated lamina ropria monouclear cells from patients with ulcretive cilitis and Crohn’s disease. Clin Exp Immunol 94(1):174–181
Roberts C, Price GW, Middlemiss DN (2001) Ligands for the investigation of 5-HT autoreceptor function. Brain Res Bull 56(5):463–469
Rutz S, Riegert C, Rothmaier AK, Buhot M-C, Cassel J-C, Jackisch R (2006) Presynaptic serotonergic modulation of 5-HT and acetylcholine release in the hippocampus and the cortex of 5-HT1B-receptor knockout mice. Brain Res Bull 70(1):81–93
Shajib MS, Wang H, Kim JJ, Sunjic I, Ghia J-E, Denou E, Collins M, Denburg JA, Khan WI (2013) Interleukin 13 and serotonin: linking the immune and endocrine systems in murine models of intestinal inflammation. PloS one 8(8):e72774
Shanahan F (2001) Inflammatory bowel disease: immunodiagnostics, immunotherapeutics, and ecotherapeutics. Gastroenterol 120(3):622–635
Sheibani M, Faghir-Ghanesefat H, Dehpour S, Keshavarz-Bahaghighat H, Sepand MR, Ghahremani MH, Azizi Y, Rahimi N, Dehpour AR (2019) Sumatriptan protects against myocardial ischaemia–reperfusion injury by inhibition of inflammation in rat model. Inflammopharmacol 27(5):1071–1080
Sikander A, Sinha SK, Prasad KK, Rana SV (2015) Association of serotonin transporter promoter polymorphism (5-HTTLPR) with microscopic colitis and ulcerative colitis. Dig Dis Sci 60(4):887–894
Skingle M, Beattie D, Scopes D, Starkey S, Connor H, Feniuk W, Tyers M (1995) GR127935: a potent and selective 5-HT1D receptor antagonist. Behav Brain Res 73(1–2):157–161
Spiller R (2008) Serotonin and GI clinical disorders. Neuropharmacol 55(6):1072–1080
Spiller R, Jenkins D, Thornley J, Hebden J, Wright T, Skinner M, Neal K (2000) Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 47(6):804–811
Verheggen R, Werner I, Lücker A, Brüss M, Göthert M, Kaumann AJ (2006) 5-Hydroxytryptamine-induced contraction of human temporal arteries coexpressing 5-HT2A receptors and wild-type or variant (Phe124Cys) 5-HT1B receptors: increased contribution of 5-HT1B receptors to the total contractile amplitude in arteries from Phe124Cys heterozygous individuals. Pharmacogenet Genomics 16(8):601–607
Wang H, Steeds J, Motomura Y, Deng Y, Verma-Gandhu M, El-Sharkawy RT, McLaughlin JT, Grencis RK, Khan WI (2007) CD4+ T cell-mediated immunological control of enterochromaffin cell hyperplasia and 5-hydroxytryptamine production in enteric infection. Gut 56(7):949–957
Watson JM, Burton MJ, Price GW, Jones BJ, Middlemiss DN (1996) GR127935 acts as a partial agonist at recombinant human 5-HT1Dα and 5-HT1Dβ receptors. Eur J Pharmacol 314(3):365–372
Woodruff TM, Arumugam TV, Shiels IA, Reid RC, Fairlie DP, Taylor SM (2003) A potent human C5a receptor antagonist protects against disease pathology in a rat model of inflammatory bowel disease. J Immunol 171(10):5514–5520
Yang G-B, Lackner AA (2004) Proximity between 5-HT secreting enteroendocrine cells and lymphocytes in the gut mucosa of rhesus macaques (Macaca mulatta) is suggestive of a role for enterochromaffin cell 5-HT in mucosal immunity. J Neuroimmunol 146(1–2):46–49
Funding
The study was supported by two grants, one from the Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran (No. 29643–139-02–94), and the other one from the Iran National Science Foundation (INSF) under the grant no. 96002757.
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Prof. ARD and NF conceived and designed the study; RH, NF, HM, DM, and FN conducted experiments; RH, NF, FN, and MF performed analysis and interpretation of data; RH, NF, and HM wrote the manuscript; Prof. ARD supervised the study. All authors read and approved the manuscript and all data were generated in-house.
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All the experimental procedures were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8023, revised 1978). Moreover, the Research and Medical Ethics Committees of Tehran University of Medical Science approved the study under the ethical code IR.TUMS.REC.1394.1872.
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Hosseini, R., Fakhraei, N., Malekisarvar, H. et al. Effect of sumatriptan on acetic acid-induced experimental colitis in rats: a possible role for the 5‐HT1B/1D receptors. Naunyn-Schmiedeberg's Arch Pharmacol 395, 563–577 (2022). https://doi.org/10.1007/s00210-022-02215-5
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DOI: https://doi.org/10.1007/s00210-022-02215-5