Taming the cytokine storm: repurposing montelukast for the attenuation and prophylaxis of severe COVID-19 symptoms

Nitesh Sanghai, Geoffrey K Tranmer, Nitesh Sanghai, Geoffrey K Tranmer

Abstract

As a result of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, a clinical complication can arise that is characterized by a hyperinflammatory cytokine profile, often termed a 'cytokine storm'. A protein complex (nuclear factor kappa-light-chain-enhancer of activated B cells; NF-κB) is intricately involved in regulating inflammation and the immune response following viral infections, with a reduction in cytokine production often observed following a decrease in NF-κB activity. An approved asthma drug, montelukast, has been found to modulate the activity of NF-κB, and result in a corresponding decrease in proinflammatory mediators. Herein, we hypothesize that repurposing montelukast to suppress NF-κB activation will result in an attenuation of proinflammatory mediators and a decrease in cytokine production, thereby leading to a reduction in symptom severity and to improved clinical outcomes in patients with Coronavirus 2019 (COVID-19).

Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Antagonism of cysteinyl leukotriene receptor 1 by montelukast attenuates the activation of nuclear factor (NF)-κB transcription factor p50-p65, decreasing downstream gene expression and production of proinflammatory mediators, and mitigating cytokine storm syndrome. Abbreviations: 5-LOX, 5-lipoxygenase; Cys-LTs, cysteinyl leukotrienes; LTA4, leukotriene A4; LTB4, leukotriene B4; PLA2, phospholipase A2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

References

    1. Wisastra R.D., Dekker F.J. Inflammation, cancer and oxidative lipoxygenase activity are intimately linked. Cancers. 2014;6:1500–1521.
    1. Huang C. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.
    1. Zhou Y. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients. Natl. Sci. Rev. 2020;7:998–1002. doi: 10.1093/nsr/nwaa041.
    1. Giuliani C. The role of the transcription factor Nuclear Factor-kappa B in thyroid autoimmunity and cancer. Front. Endocrinol. 2018;9:471.
    1. Santoro M.G. NF‐κB and virus infection: who controls whom. EMBO J. 2003;22:2552–2560.
    1. Hiscott J. Hostile takeovers: viral appropriation of the NF-kB pathway. J. Clin. Invest. 2001;107:143–151.
    1. Ludwig S., Planz O. Influenza viruses and the NF-κB signaling pathway–towards a novel concept of antiviral therapy. Biol. Chem. 2008;389:1307–1312.
    1. Guo Y.-R. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak–an update on the status. Mil. Med. Res. 2020;7:1–10.
    1. Walter L.A., McGregor A.J. Sex- and gender-specific observations and implications for COVID-19. West. J. Emerg. Med. 2020;21:507–509.
    1. Richardson S. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323:2052–2059.
    1. Nachman S. 2020. Estrogen Patch for COVID-19 Symptoms. .
    1. Xing D. Estrogen modulates NFκB signaling by enhancing IκBα levels and blocking p65 binding at the promoters of inflammatory genes via estrogen receptor-β. PLoS One. 2012;7
    1. Ghisletti S. 17β-estradiol inhibits inflammatory gene expression by controlling NF-κB intracellular localization. Mol. Cell. Biol. 2005;25:2957–2968.
    1. Tilstra J.S. NF-κB in aging and disease. Aging Dis. 2011;2:449–465.
    1. Salminen A. Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Res. Rev. 2008;7:83–105.
    1. Hajifathalian K. Obesity is associated with worse outcomes in COVID-19: analysis of early data from New York city. Obesity. 2020;28:1606–1612.
    1. Klang E. Morbid obesity as an independent risk factor for COVID-19 mortality in hospitalized patients younger than 50. Obesity. 2020;28:1595–1599.
    1. Kalligeros M. Association of obesity with disease severity among patients with Coronavirus Disease 2019. Obesity. 2020;28:1200–1204.
    1. Zhang F. Obesity predisposes to the risk of higher mortality in young COVID-19 patients. J. Med. Virol. 2020:1–7. doi: 10.1002/jmv.26039.
    1. Catrysse L., van Loo G. Inflammation and the metabolic syndrome: the tissue-specific functions of NF-kB. Trends Cell Biol. 2017;27:417–429.
    1. Tornatore L. The nuclear factor kappa B signaling pathway: integrating metabolism with inflammation. Trends Cell Biol. 2012;22:557–566.
    1. Hoffmann M. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–280.
    1. Henry B. COVID-19 induced Renin-Angiotensin System (RAS) imbalance may drive acute lung injury: the evidence and therapeutic options. BMJ. 2020;368:m406.
    1. Ruiz-Ortega M. Angiotensin II activates nuclear transcription factor κB through AT1 and AT2 in vascular smooth muscle cells: molecular mechanisms. Circ. Res. 2000;86:1266–1272.
    1. Wolf G. Angiotensin II activates nuclear transcription factor-κB through AT1 and AT2 receptors. Kidney Int. 2002;61:1986–1995.
    1. Anon . Merck; 2019. Product Monograph: Singulair.
    1. Hung C.-H. Effects of leukotriene receptor antagonists on monocyte chemotaxis, p38 and cytoplasmic calcium. Pediatr. Allergy Immunol. 2006;17:250–258.
    1. Maeba S. Effect of montelukast on nuclear factor κB activation and proinflammatory molecules. Ann. Allergy Asthma Immunol. 2005;94:670–674.
    1. Tahan F. Montelukast inhibits tumour necrosis factor‐α‐mediated interleukin‐8 expression through inhibition of nuclear factor‐κB p65‐associated histone acetyltransferase activity. Clin. Exp. Allergy. 2008;38:805–811.
    1. Wu Y. Montelukast prevents the decrease of interleukin-10 and inhibits NF-κB activation in inflammatory airway of asthmatic guinea pigs. Can. J. Physiol. Pharmacol. 2006;84:531–537.
    1. May, B.C. Inflammatory Response Research Inc. Levocetirizine and montelukast in the treatment of inflammation mediated conditions. US20170173001A1.

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