Skip to main content
Top
Published in: Digestive Diseases and Sciences 8/2022

21-10-2021 | Chronic Inflammatory Bowel Disease | Original Article

Anti-inflammatory Effects of Ivermectin in the Treatment of Acetic Acid-Induced Colitis in Rats: Involvement of GABAB Receptors

Authors: Armin Aryannejad, Mohammadreza Tabary, Nafise Noroozi, Baharnaz Mashinchi, Setare Iranshahi, Seyed Mohammad Tavangar, Razieh Mohammad Jafari, Amir Rashidian, Ahmad Reza Dehpour

Published in: Digestive Diseases and Sciences | Issue 8/2022

Login to get access

Abstract

Background

Recent investigations have proposed the potential role of gamma-aminobutyric acid (GABA) in regulating motility and immunity of the gastrointestinal system.

Aims

We aimed to investigate the anti-inflammatory effects of ivermectin (IVM) through GABAB receptors following acetic acid-induced colitis in rats.

Methods

In a controlled experimental study, we enrolled 78 male Wistar rats (13 groups; 6 rats/group). After colitis induction using acetic acid (4%), IVM, baclofen (a standard GABAB agonist) or the combination of both agents was delivered to rats orally (by gavage), with the same dosage continued for 5 days. The control group received the vehicle, and prednisolone (a standard anti-inflammatory agent) was administered in a separate group as the positive control. Colon samples were collected on the sixth day for histopathological evaluations and measurement of myeloperoxidase (MPO) activity, TNF-α levels, and p-NF-ĸB p65, COX-2 and iNOS expression levels.

Results

The greatest recovery was found after administering IVM 0.5, baclofen 0.5, or IVM 0.2 + baclofen 0.2 mg/kg/day (ulcer index [UI] = 1.4 ± 0.4, 1.7 ± 0.6, and 1.4 ± 0.3, respectively; p  < 0.001 vs. the control [UI = 6.5 ± 0.7]). Histopathological evaluations revealed a significant decrease in the inflammation severity in the three above-mentioned groups. P-NF-ĸB p65, COX-2, and iNOS expression, MPO activity, and TNF-α levels also decreased dramatically following treatment with IVM 0.5, baclofen 0.5, or the combination therapy (p < 0.001 vs. the control).

Conclusions

IVM exerted promising anti-inflammatory effects in treating acetic acid-induced colitis in rats. Its synergistic effect with baclofen also signified the possible involvement of GABAB receptors in this process.
Appendix
Available only for authorised users
Literature
1.
go back to reference Molodecky NA, Soon S, Rabi DM, Ghali WA, Ferris M, Chernoff G, Benchimol EI, Panaccione R, Ghosh S, Barkema HW. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142:46-54.e42.CrossRef Molodecky NA, Soon S, Rabi DM, Ghali WA, Ferris M, Chernoff G, Benchimol EI, Panaccione R, Ghosh S, Barkema HW. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142:46-54.e42.CrossRef
2.
go back to reference Tasdemir S, Parlakpinar H, Vardi N, Kaya E, Acet A. Effect of endogen-exogenous melatonin and erythropoietin on dinitrobenzene sulfonic acid–induced colitis. Fundam Clin Pharmacol 2013;27:299–307.CrossRef Tasdemir S, Parlakpinar H, Vardi N, Kaya E, Acet A. Effect of endogen-exogenous melatonin and erythropoietin on dinitrobenzene sulfonic acid–induced colitis. Fundam Clin Pharmacol 2013;27:299–307.CrossRef
3.
go back to reference Xavier R, Podolsky D. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007;448:427–434.CrossRef Xavier R, Podolsky D. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007;448:427–434.CrossRef
4.
5.
go back to reference Monteleone G, Pallone F, MacDonald TT. Emerging immunological targets in inflammatory bowel disease. Curr Opin Pharmacol 2011;11:640–645.CrossRef Monteleone G, Pallone F, MacDonald TT. Emerging immunological targets in inflammatory bowel disease. Curr Opin Pharmacol 2011;11:640–645.CrossRef
6.
go back to reference Braus NA, Elliott DE. Advances in the pathogenesis and treatment of IBD. Clin Immunol 2009;132:1–9.CrossRef Braus NA, Elliott DE. Advances in the pathogenesis and treatment of IBD. Clin Immunol 2009;132:1–9.CrossRef
7.
go back to reference Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. The Lancet 2007;369:1641–1657.CrossRef Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. The Lancet 2007;369:1641–1657.CrossRef
8.
go back to reference Dejban P, Sahraei M, Chamanara M, Dehpour A, Rashidian A. Anti-inflammatory effect of amitriptyline in a rat model of acetic acid-induced colitis: the involvement of the TLR4/NF-kB signaling pathway. Fundam Clin Pharmacol. 2020. Dejban P, Sahraei M, Chamanara M, Dehpour A, Rashidian A. Anti-inflammatory effect of amitriptyline in a rat model of acetic acid-induced colitis: the involvement of the TLR4/NF-kB signaling pathway. Fundam Clin Pharmacol. 2020.
10.
go back to reference Tabary M, Aryannejad A, Noroozi N, Tavangar SM, Jafari RM, Araghi F, Dadkhahfar S, Dehpour AR. Ivermectin increases random-pattern skin flap survival in rats: the novel role of GABAergic system. J Surg Res 2021;259:431–441.CrossRef Tabary M, Aryannejad A, Noroozi N, Tavangar SM, Jafari RM, Araghi F, Dadkhahfar S, Dehpour AR. Ivermectin increases random-pattern skin flap survival in rats: the novel role of GABAergic system. J Surg Res 2021;259:431–441.CrossRef
12.
go back to reference Yan S, Ci X, Chen N, Chen C, Li X, Chu X, Li J, Deng X. Anti-inflammatory effects of ivermectin in mouse model of allergic asthma. Inflam Res 2011;60:589–596.CrossRef Yan S, Ci X, Chen N, Chen C, Li X, Chu X, Li J, Deng X. Anti-inflammatory effects of ivermectin in mouse model of allergic asthma. Inflam Res 2011;60:589–596.CrossRef
13.
go back to reference Risks NIoHOfPfR, Association AREN. Institutional Animal Care and Use Committee Guidebook. vol 92. US Department of Health and Human Services, Public Health Service, National. 1992. Risks NIoHOfPfR, Association AREN. Institutional Animal Care and Use Committee Guidebook. vol 92. US Department of Health and Human Services, Public Health Service, National. 1992.
14.
go back to reference Rashidian A, Muhammadnejad A, Dehpour A-R, Mehr SE, Akhavan MM, Shirkoohi R, Chamanara M, Mousavi S-E, Rezayat S-M. Atorvastatin attenuates TNBS-induced rat colitis: the involvement of the TLR4/NF-kB signaling pathway. Inflammopharmacology 2016;24:109–118.CrossRef Rashidian A, Muhammadnejad A, Dehpour A-R, Mehr SE, Akhavan MM, Shirkoohi R, Chamanara M, Mousavi S-E, Rezayat S-M. Atorvastatin attenuates TNBS-induced rat colitis: the involvement of the TLR4/NF-kB signaling pathway. Inflammopharmacology 2016;24:109–118.CrossRef
15.
go back to reference Underwood W, Anthony R. AVMA guidelines for the euthanasia of animals. Retrieved March 2020;2013:2020–2021. Underwood W, Anthony R. AVMA guidelines for the euthanasia of animals. Retrieved March 2020;2013:2020–2021.
16.
go back to reference Franek M, Vaculin S, Rokyta R. GABA~ B receptor agonist baclofen has non-specific antinociceptive effect in the model of peripheral neuropathy in rat. Physiol Res 2004;53:351–355.PubMed Franek M, Vaculin S, Rokyta R. GABA~ B receptor agonist baclofen has non-specific antinociceptive effect in the model of peripheral neuropathy in rat. Physiol Res 2004;53:351–355.PubMed
17.
go back to reference Witaicenis A, Luchini AC, Hiruma-Lima CA, Felisbino SL, Garrido-Mesa N, Utrilla P, Gálvez J, di Stasi LC. Suppression of TNBS-induced colitis in rats by 4-methylesculetin, a natural coumarin: comparison with prednisolone and sulphasalazine. Chemico Biol Interact 2012;195:76–85.CrossRef Witaicenis A, Luchini AC, Hiruma-Lima CA, Felisbino SL, Garrido-Mesa N, Utrilla P, Gálvez J, di Stasi LC. Suppression of TNBS-induced colitis in rats by 4-methylesculetin, a natural coumarin: comparison with prednisolone and sulphasalazine. Chemico Biol Interact 2012;195:76–85.CrossRef
18.
go back to reference Yousefi-Ahmadipour A, Rashidian A, Mirzaei MR, Farsinejad A, PourMohammadi-Nejad F, Ghazi-Khansari M, Ai J, Shirian S, Allahverdi A, Saremi J. Combination therapy of mesenchymal stromal cells and sulfasalazine attenuates trinitrobenzene sulfonic acid induced colitis in the rat: The S1P pathway. J Cell Physiol 2019;234:11078–11091.CrossRef Yousefi-Ahmadipour A, Rashidian A, Mirzaei MR, Farsinejad A, PourMohammadi-Nejad F, Ghazi-Khansari M, Ai J, Shirian S, Allahverdi A, Saremi J. Combination therapy of mesenchymal stromal cells and sulfasalazine attenuates trinitrobenzene sulfonic acid induced colitis in the rat: The S1P pathway. J Cell Physiol 2019;234:11078–11091.CrossRef
19.
go back to reference El-Salhy M, Umezawa K. Anti-inflammatory effects of novel AP-1 and NF-κB inhibitors in dextran-sulfate-sodium-induced colitis in rats. Int J Mol Med 2016;37:1457–1464.CrossRef El-Salhy M, Umezawa K. Anti-inflammatory effects of novel AP-1 and NF-κB inhibitors in dextran-sulfate-sodium-induced colitis in rats. Int J Mol Med 2016;37:1457–1464.CrossRef
20.
go back to reference Deshmukh C, Veeresh B, Pawar A. Protective effect of Emblica officinalis fruit extract on acetic acid induced colitis in rats. J Herbal Med Toxicol 2010;4:83–87. Deshmukh C, Veeresh B, Pawar A. Protective effect of Emblica officinalis fruit extract on acetic acid induced colitis in rats. J Herbal Med Toxicol 2010;4:83–87.
21.
go back to reference Rashidian A, Mehrzadi S, Ghannadi AR, Mahzooni P, Sadr S, Minaiyan M. Protective effect of ginger volatile oil against acetic acid-induced colitis in rats: a light microscopic evaluation. J Integr Med 2014;12:115–120.CrossRef Rashidian A, Mehrzadi S, Ghannadi AR, Mahzooni P, Sadr S, Minaiyan M. Protective effect of ginger volatile oil against acetic acid-induced colitis in rats: a light microscopic evaluation. J Integr Med 2014;12:115–120.CrossRef
22.
go back to reference Rezayat SM, Dehpour A-R, Motamed SM, Yazdanparast M, Chamanara M, Sahebgharani M, Rashidian A. Foeniculum vulgare essential oil ameliorates acetic acid-induced colitis in rats through the inhibition of NF-kB pathway. Inflammopharmacology 2018;26:851–859.CrossRef Rezayat SM, Dehpour A-R, Motamed SM, Yazdanparast M, Chamanara M, Sahebgharani M, Rashidian A. Foeniculum vulgare essential oil ameliorates acetic acid-induced colitis in rats through the inhibition of NF-kB pathway. Inflammopharmacology 2018;26:851–859.CrossRef
23.
go back to reference Jurjus AR, Khoury NN, Reimund J-M. Animal models of inflammatory bowel disease. J Pharmacol Toxicol Methods 2004;50:81–92.CrossRef Jurjus AR, Khoury NN, Reimund J-M. Animal models of inflammatory bowel disease. J Pharmacol Toxicol Methods 2004;50:81–92.CrossRef
24.
go back to reference Rashidian A, Keshavarz-Bahaghighat H, Abdollahi A, Chamanara M, Faghir-Ghanesefat H, Hoseini-Ahmadabadi M, Dehpour AR. Agmatine ameliorates acetic acid-induced colitis in rats: involvement of nitrergic system. Immunopharmacol Immunotoxicol 2019;41:242–249.CrossRef Rashidian A, Keshavarz-Bahaghighat H, Abdollahi A, Chamanara M, Faghir-Ghanesefat H, Hoseini-Ahmadabadi M, Dehpour AR. Agmatine ameliorates acetic acid-induced colitis in rats: involvement of nitrergic system. Immunopharmacol Immunotoxicol 2019;41:242–249.CrossRef
25.
go back to reference Rashidian A, Rashki A, Abdollahi A, Haddadi N-S, Chamanara M, Mumtaz F, Dehpour AR. Dapsone reduced acetic acid-induced inflammatory response in rat colon tissue through inhibition of NF-kB signaling pathway. Immunopharmacol Immunotoxicol 2019;41:607–613.CrossRef Rashidian A, Rashki A, Abdollahi A, Haddadi N-S, Chamanara M, Mumtaz F, Dehpour AR. Dapsone reduced acetic acid-induced inflammatory response in rat colon tissue through inhibition of NF-kB signaling pathway. Immunopharmacol Immunotoxicol 2019;41:607–613.CrossRef
26.
go back to reference Roberts E, Frankel S. γ-Aminobutyric acid in brain: its formation from glutamic acid. J Biol Chem 1950;187:55–63.CrossRef Roberts E, Frankel S. γ-Aminobutyric acid in brain: its formation from glutamic acid. J Biol Chem 1950;187:55–63.CrossRef
27.
go back to reference Olsen RW, Sieghart W. International Union of Pharmacology. LXX. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit composition, pharmacology, and function. Pharmacol Rev 2008;60:243–260.CrossRef Olsen RW, Sieghart W. International Union of Pharmacology. LXX. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit composition, pharmacology, and function. Pharmacol Rev 2008;60:243–260.CrossRef
28.
go back to reference Ma X, Sun Q, Sun X, Chen D, Wei C, Yu X, Liu C, Li Y, Li J. Activation of GABAA receptors in colon epithelium exacerbates acute colitis. Front Immunol 2018;9:987.CrossRef Ma X, Sun Q, Sun X, Chen D, Wei C, Yu X, Liu C, Li Y, Li J. Activation of GABAA receptors in colon epithelium exacerbates acute colitis. Front Immunol 2018;9:987.CrossRef
29.
go back to reference Uezono Y, Kaibara M, Hayashi H, Kawakami S, Enjoji A, Kanematsu T, Taniyama K. Characterization of GABAB receptor in the human colon. J Pharmacol Sci 2004;94:211–213.CrossRef Uezono Y, Kaibara M, Hayashi H, Kawakami S, Enjoji A, Kanematsu T, Taniyama K. Characterization of GABAB receptor in the human colon. J Pharmacol Sci 2004;94:211–213.CrossRef
30.
go back to reference Jin Z, Mendu SK, Birnir B. GABA is an effective immunomodulatory molecule. Amino Acids 2013;45:87–94.CrossRef Jin Z, Mendu SK, Birnir B. GABA is an effective immunomodulatory molecule. Amino Acids 2013;45:87–94.CrossRef
31.
go back to reference Piechota-Polanczyk A, Fichna J. The role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases. Naunyn-Schmiedeberg’s Archiv Pharmacol 2014;387:605–620.CrossRef Piechota-Polanczyk A, Fichna J. The role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases. Naunyn-Schmiedeberg’s Archiv Pharmacol 2014;387:605–620.CrossRef
32.
go back to reference Duthey B, Hübner A, Diehl S, Boehncke S, Pfeffer J, Boehncke WH. Anti-inflammatory effects of the GABAB receptor agonist baclofen in allergic contact dermatitis. Exp Dermatol 2010;19:661–666.CrossRef Duthey B, Hübner A, Diehl S, Boehncke S, Pfeffer J, Boehncke WH. Anti-inflammatory effects of the GABAB receptor agonist baclofen in allergic contact dermatitis. Exp Dermatol 2010;19:661–666.CrossRef
33.
go back to reference Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 2003;3:521–533.CrossRef Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 2003;3:521–533.CrossRef
35.
go back to reference Ordás I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther 2012;91:635–646.CrossRef Ordás I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther 2012;91:635–646.CrossRef
36.
go back to reference Neurath MF, Pettersson S, Zum Büschenfelde K-HM, Strober W. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF–κB abrogates established experimental colitis in mice. Nat Med 1996;2:998–1004.CrossRef Neurath MF, Pettersson S, Zum Büschenfelde K-HM, Strober W. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF–κB abrogates established experimental colitis in mice. Nat Med 1996;2:998–1004.CrossRef
37.
go back to reference Liu F, Zhang Y-Y, Song N, Lin J, Liu M-k, Huang C-L, Zhou C, Wang H, Wang M, Shen J-F. GABAB receptor activation attenuates inflammatory orofacial pain by modulating interleukin-1β in satellite glial cells: Role of NF-κB and MAPK signaling pathways. Brain Res Bull 2019;149:240–250.CrossRef Liu F, Zhang Y-Y, Song N, Lin J, Liu M-k, Huang C-L, Zhou C, Wang H, Wang M, Shen J-F. GABAB receptor activation attenuates inflammatory orofacial pain by modulating interleukin-1β in satellite glial cells: Role of NF-κB and MAPK signaling pathways. Brain Res Bull 2019;149:240–250.CrossRef
38.
go back to reference Ardite E, Panes J, Miranda M, Salas A, Elizalde J, Sans M, Arce Y, Bordas J, Fernández-Checa J, Pique J. Effects of steroid treatment on activation of nuclear factor κB in patients with inflammatory bowel disease. Br J Pharmacol 1998;124:431–433.CrossRef Ardite E, Panes J, Miranda M, Salas A, Elizalde J, Sans M, Arce Y, Bordas J, Fernández-Checa J, Pique J. Effects of steroid treatment on activation of nuclear factor κB in patients with inflammatory bowel disease. Br J Pharmacol 1998;124:431–433.CrossRef
42.
go back to reference Antoniou E, Margonis GA, Angelou A, Pikouli A, Argiri P, Karavokyros I, Papalois A, Pikoulis E. The TNBS-induced colitis animal model: an overview. Ann Med Surg 2016;11:9–15.CrossRef Antoniou E, Margonis GA, Angelou A, Pikouli A, Argiri P, Karavokyros I, Papalois A, Pikoulis E. The TNBS-induced colitis animal model: an overview. Ann Med Surg 2016;11:9–15.CrossRef
43.
go back to reference Yamada T, Marshall S, Specian RD, Grisham MB. A comparative analysis of two models of colitis in rats. Gastroenterology 1992;102:1524–1534.CrossRef Yamada T, Marshall S, Specian RD, Grisham MB. A comparative analysis of two models of colitis in rats. Gastroenterology 1992;102:1524–1534.CrossRef
Metadata
Title
Anti-inflammatory Effects of Ivermectin in the Treatment of Acetic Acid-Induced Colitis in Rats: Involvement of GABAB Receptors
Authors
Armin Aryannejad
Mohammadreza Tabary
Nafise Noroozi
Baharnaz Mashinchi
Setare Iranshahi
Seyed Mohammad Tavangar
Razieh Mohammad Jafari
Amir Rashidian
Ahmad Reza Dehpour
Publication date
21-10-2021
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 8/2022
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-021-07258-x

Other articles of this Issue 8/2022

Digestive Diseases and Sciences 8/2022 Go to the issue