Buspirone Ameliorates Colon Inflammation in TNBS-Induced Rat Acute Colitis: The Involvement of TLR4/NF-kB Pathway

Abstract

Inflammatory bowel disease (IBD) is an inflammatory situation involving the whole digestive system. This illness includes ulcerative colitis and Crohn’s disease. According to scientific research, the immune system plays an essential part in developing this disease. Recently, buspirone has been discovered to have anti-inflammatory properties. As a result, this research aims to see if buspirone provides anti-inflammatory effects in a rat model of TNBS-induced colitis. Control, TNBS, dexamethasone (2 mg/kg), and buspirone (5, 10, and 20 mg/kg) were randomly given to six groups of 36 male Wistar rats. Colitis was induced by intrarectal instillation of TNBS in all research groups except the control group, and rats were meliorated with dexamethasone and buspirone. Macroscopic and microscopic lesions appeared after colitis induction, while therapy with dexamethasone and buspirone significantly improved the lesions. TLR4 and pNF-κB expression were also enhanced during colitis induction. On the other hand, the administration of dexamethasone or buspirone resulted in a considerable reduction in their expression. Tissue TNF-α and MPO activity were enhanced after induction of colitis in terms of biochemical variables; however, administration of dexamethasone or buspirone reduced TNF-α and MPO activity. Eventually, in an animal model of severe colitis, buspirone displayed anti-inflammatory characteristics via lowering the TLR4/NF-ĸB signaling pathway’s activity in an animal model of acute colitis.

Key words

Inflammatory bowel disease (IBD) - Buspirone - TLR4 - NF-ĸB - TNBS-induced colitis - Rats

Publication History

Received: 30 April 2022

Accepted: 16 May 2022

Article published online:
12 July 2022

• References

• 1 Zhao Q, Duck LW, Huang F. et al. CD4+T cell activation and concomitant mTOR metabolic inhibition can ablate microbiota-specific memory cells and prevent colitis. Science Immunology 2020; 5 eabc6373
• 2 Rezayat SM, Dehpour AR, Motamed SM. et al. Foeniculum vulgare essential oil ameliorates acetic acid-induced colitis in rats through the inhibition of NF-kB pathway. Inflammopharmacology 2018; 26: 851-859
• 3 Tasaka Y, Yasunaga D, Kiyoi T. et al. Involvement of stimulation of α7 nicotinic acetylcholine receptors in the suppressive effect of tropisetron on dextran sulfate sodium-induced colitis in mice. J Pharmacol Sci 2015; 127: 275-283
• 4 Goyal N, Rana A, Ahlawat A. et al. Animal models of inflammatory bowel disease: a review. Inflammopharmacology 2014; 22: 219-233
• 5 Yousefi-Ahmadipour A, Rashidian A, Mirzaei MR. et al. 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
• 6 Zhang Y, Zha Z, Shen W. et al. Anemoside B4 ameliorates TNBS-induced colitis through S100A9/MAPK/NF-κB signaling pathway. Chinese Medicine 2021; 16: 11
• 7 Lu Y, Li X, Liu S. et al. Toll-like Receptors and Inflammatory Bowel Disease. Front Immunol 2018; 9: 72
• 8 Luo X, Yue B, Yu Z. et al. Obacunone Protects Against Ulcerative Colitis in Mice by Modulating Gut Microbiota, Attenuating TLR4/NF-κB Signaling Cascades, and Improving Disrupted Epithelial Barriers. Front Microbiol 2020; 11: 497
• 9 Hu LH, Liu JY, Yin JB. Eriodictyol attenuates TNBS-induced ulcerative colitis through repressing TLR4/NF-kB signaling pathway in rats. Kaohsiung J Med Sci 2021;
• 10 Jann MW. Buspirone: an update on a unique anxiolytic agent. Pharmacotherapy 1988; 8: 100-116
• 11 Knap B, Kwiatkowski S, Kolasińska K. et al. Azapirones for the treatment of anxiety – an overview. World Scientific News 2018; 109: 14-25
• 12 Eison AS, Temple DL. Buspirone: review of its pharmacology and current perspectives on its mechanism of action. The American journal of medicine 1986; 80: 1-9
• 13 Thomas Broome S, Fisher T, Faiz A. et al. Assessing the Anti-Inflammatory Activity of the Anxiolytic Drug Buspirone Using CRISPR-Cas9 Gene Editing in LPS-Stimulated BV-2 Microglial Cells. Cells 2021; 10
• 14 Kim J-K, Han S-K, Joo M-K. et al. Buspirone alleviates anxiety, depression, and colitis; and modulates gut microbiota in mice. Scientific Reports 2021; 11: 6094
• 15 Mohammad Jafari R, Shayesteh S, Ala M. et al. Dapsone Ameliorates Colitis through TLR4/NF-kB Pathway in TNBS Induced Colitis Model in Rat. Archives of medical research 2021; 52: 595-602
• 16 Bertoni S, Arcaro V, Vivo V. et al. Suppression of inflammatory events associated to intestinal ischemia-reperfusion by 5-HT1A blockade in mice. Pharmacological research 2014; 81: 17-25
• 17 Abdel-Salam OM, Shaffie NM, Mohammed NA. et al. The 5-HT1A Agonist Buspirone Decreases Liver Oxidative Stress and Exerts Protective Effect Against CCl4–Toxicity. Journal of Experimental and Clinical Toxicology 2017; 1: 13-26
• 18 Jadhav N, Deshpande A, Baradol R. Effect of buspirone on blood glucose levels in rats. National Journal of Physiology, Pharmacy and Pharmacology 2019; 9: 996-1000
• 19 Yousefi-Manesh H, Dejban P, Mumtaz F. et al. Risperidone attenuates acetic acid-induced colitis in rats through inhibition of TLR4/NF-kB signaling pathway. Immunopharmacol Immunotoxicol 2020; 42: 464-472
• 20 Molodecky NA, Soon IS, Rabi DM. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142: 46-54.e42 quiz e30
• 21 Daneshmand A, Mohammadi H, Rahimian R. et al. Chronic lithium administration ameliorates 2,4,6-trinitrobenzene sulfonic acid-induced colitis in rats; potential role for adenosine triphosphate sensitive potassium channels. J Gastroenterol Hepatol 2011; 26: 1174-1181
• 22 Fakhraei N, Javadian N, Rahimian R. et al. Involvement of central opioid receptors in protective effects of methadone on experimental colitis in rats. Inflammopharmacology 2018; 26: 1399-1413
• 23 Minaiyan M, Hajhashemi V, Rabbani M. et al. Evaluation of anti-colitic effect of fluvoxamine against acetic acid-induced colitis in normal and reserpinized depressed rats. Eur J Pharmacol 2015; 746: 293-300
• 24 Das S, Kanodia L, Mukherjee A. et al. Effect of ethanolic extract of leaves of Paederia foetida Linn. on acetic acid induced colitis in albino rats. Indian J Pharmacol 2013; 45: 453-457
• 25 Niu X, Fan T, Li W. et al. Protective effect of sanguinarine against acetic acid-induced ulcerative colitis in mice. Toxicol Appl Pharmacol 2013; 267: 256-265
• 26 Gupta RA, Motiwala MN, Dumore NG. et al. Effect of piperine on inhibition of FFA induced TLR4 mediated inflammation and amelioration of acetic acid induced ulcerative colitis in mice. J Ethnopharmacol 2015; 164: 239-246
• 27 Zeng Z, Zhan L, Liao H. et al. Curcumin improves TNBS-induced colitis in rats by inhibiting IL-27 expression via the TLR4/NF-κB signaling pathway. Planta Med 2013; 79: 102-109
• 28 Lashgari N-A, Roudsari NM, Zandi N. et al. Current overview of opioids in progression of inflammatory bowel disease; pharmacological and clinical considerations. Molecular Biology Reports 2021; 48: 855-874
• 29 Johnson DE, Rollema H, Schmidt AW. et al. Serotonergic effects and extracellular brain levels of eletriptan, zolmitriptan and sumatriptan in rat brain. Eur J Pharmacol 2001; 425: 203-210
• 30 Cho JH, Nicolae DL, Gold LH. et al. Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1. Proc Natl Acad Sci U S A 1998; 95: 7502-7507
• 31 Torchinsky MB, Garaude J, Martin AP. et al. Innate immune recognition of infected apoptotic cells directs T(H)17 cell differentiation. Nature 2009; 458: 78-82
• 32 Kamada N, Hisamatsu T, Okamoto S. et al. Unique CD14+intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis. The Journal of clinical investigation 2008; 118: 2269-2280
• 33 Cheng J, Shah YM, Ma X. et al. Therapeutic role of rifaximin in inflammatory bowel disease: clinical implication of human pregnane X receptor activation. J Pharmacol Exp Ther 2010; 335: 32-41
• 34 Lashgari N-A, Momeni Roudsari N, Khayatan D. et al. Ginger and its constituents: Role in treatment of inflammatory bowel disease. BioFactors 2022; 48: 7-21
• 35 Ke X, Zhou F, Gao Y. et al. Qing Hua Chang Yin exerts therapeutic effects against ulcerative colitis through the inhibition of the TLR4/NF‑κB pathway. International journal of molecular medicine 2013; 32: 926-930
• 36 Wang K, Wan Y. Nuclear Receptors and Inflammatory Diseases. Experimental Biology and Medicine 2008; 233: 496-506
• 37 Rashidian A, Muhammadnejad A, Dehpour AR. et al. Atorvastatin attenuates TNBS-induced rat colitis: the involvement of the TLR4/NF-kB signaling pathway. Inflammopharmacology 2016; 24: 109-118
• 38 Kast RE, Altschuler EL. Tumor necrosis factor-alpha in hepatitis B: potential role for bupropion. J Hepatol 2003; 39: 131-133
• 39 Reinecker HC, Steffen M, Witthoeft T. et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol 1993; 94: 174-181
• 40 Chamanara M, Rashidian A, Mehr SE. et al. Melatonin ameliorates TNBS-induced colitis in rats through the melatonin receptors: involvement of TLR4/MyD88/NF-κB signalling pathway. Inflammopharmacology 2019; 27: 361-371
• 41 Dejban P, Rahimi N, Takzare N. et al. Biochemical and histopathological evidence for the beneficial effects of modafinil on the rat model of inflammatory bowel disease: involvement of nitric oxide pathway. Pharmacol Rep 2020; 72: 135-146
• 42 Masoodi I, Kochhar R, Dutta U. et al. Evaluation of Fecal Myeloperoxidase as a Biomarker of Disease Activity and Severity in Ulcerative Colitis. Digestive Diseases and Sciences 2012; 57: 1336-1340
• 43 Khandale M, Magadum SB, Limaye R. The Study of anti-inflammatory activity of Buspirone in rats. International J of Healthcare and Biomedical Research 2015; 4: 51-59
• 44 Rashidian A, Dejban P, Karami Fard K. et al. Bupropion Ameliorates Acetic Acid–Induced Colitis in Rat: the Involvement of the TLR4/NF-kB Signaling Pathway. Inflammation 2020; 43: 1999-2009
• 45 Gammans R, Stringfellow J, Hvizdos AJ. et al. Use of buspirone in patients with generalized anxiety disorder and coexisting depressive symptoms. Neuropsychobiology 1992; 25: 193-201
• 46 Kim J-K, Han S-K, Joo M-K. et al. Buspirone alleviates anxiety, depression, and colitis; and modulates gut microbiota in mice. Scientific reports 2021; 11: 1-12
• 47 Gao X, Tang Y, Lei N. et al. Symptoms of anxiety/depression is associated with more aggressive inflammatory bowel disease. Scientific Reports 2021; 11: 1-7
• 48 Hu S, Chen Y, Chen Y. et al. Depression and Anxiety Disorders in Patients With Inflammatory Bowel Disease. Front Psychiatry 2021; 12: 714057