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Montelukast suppresses the development of irritable bowel syndrome phenotype possibly through modulating NF-κB signaling in an experimental model

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Abstract

Irritable bowel syndrome (IBS) is a functional gut disorder with multi-factorial pathophysiology that causes recurring pain or discomfort in the abdomen, as well as altered bowel habits. Montelukast, a well-known cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is widely used for the anti-inflammatory management of asthma. The present study aimed to evaluate the effects of pharmacological inhibition of CysLT1R on acetic acid-induced diarrhea-predominant IBS (D-IBS) in rats. Behavioral pain responses to noxious mechanical stimulation were decreased in the montelukast-treated rats as compared to the model animals following colorectal distension (CRD)-induced visceral hypersensitivity. Stool frequency decreased dose-dependently by montelukast in IBS rats exposed to restraint stress. A significantly shorter immobility time was also observed in IBS rats who received montelukast vs IBS group in the forced swimming test (depression-like behavior). Furthermore, there were significant decreases in the NF-κB protein expression, inflammatory cytokine (TNF-α, and IL-1ß) levels, and histopathological inflammatory injuries concomitant with increased anti-inflammatory cytokine, IL-10, in montelukast-treated rats compared with the IBS group. Cysteinyl leukotriene production and CysLT1R mRNA expression showed no remarkable differences among the experimental groups. The present results suggest the possible beneficial effects of montelukast in the management of D-IBS symptoms. The molecular mechanism underlying such effects, at least to some extent, might be through modulating CysLT1R-mediated NF-κB signaling. Yet, more studies are required to demonstrate the clinical potential of this drug for IBS therapy.

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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This study is a part of the Master’s thesis (Registration number: 67). All who assisted at the Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran, are gratefully acknowledged. The authors did not receive support from any organization for the submitted work.

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PK: investigation, acquisition, analysis and interpretation of data, and writing—original draft. NK: investigation, acquisition, and analysis of data. A-RD: conceptualization and supervision. MG–K: conceptualization and supervision. HS: conceptualization, methodology, supervision, and funding acquisition. All authors revised and approved the final version of the manuscript.

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Correspondence to Hamed Shafaroodi.

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All procedures in the present study were carried out in accordance with the NIH guide for the care and use of laboratory animals (National Institutes of Health Publication #85-23) and the institutional guidelines for animal care and use (Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences (TUMS) (ethics approval code: IR.TUMS.MEDICINE.REC.1399.183).

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Khodabakhsh, P., Khoie, N., Dehpour, AR. et al. Montelukast suppresses the development of irritable bowel syndrome phenotype possibly through modulating NF-κB signaling in an experimental model. Inflammopharmacol 30, 313–325 (2022). https://doi.org/10.1007/s10787-021-00907-7

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