Summary recent studies have provided novel evidence regarding the effect of nicotine agonists on the prevention or modulation of cytokines storm and reduction of infection. In this study we tried to attempt to address these issues from a therapeutic perspective of nicotine agonists in this manner and we describe one of the most challenging theories of immunotherapy in coronavirus-19 (COVID-19). The analysis of the proposed mechanism goes beyond the physiological consequences of a way to design new strategies to provide anti-inflammatory drugs. Â© 2020 Elsevier Lt

Allahverdi Khani, M.

Darbeheshti, S.

Motaghinejad, M.

SalehiRad, M.

eprints Iran University of Medical Sciences

Contents lists available at ScienceDirectMedical Hypothesesjournal homepage: www.elsevier.com/locate/mehyLetter to EditorsSurvival of COVID-19 patients requires precise immune regulation: The hypotheticalimmunoprotective role of nicotinic agonistsA R T I C L E I N F OKeywords:COVID-19Nicotinic agonistImmunotherapyA B S T R A C TSummary recent studies have provided novel evidence regarding the effect of nicotine agonists on the preventionor modulation of cytokines storm and reduction of infection. In this study we tried to attempt to address theseissues from a therapeutic perspective of nicotine agonists in this manner and we describe one of the mostchallenging theories of immunotherapy in coronavirus-19 (COVID-19). The analysis of the proposed mechanismgoes beyond the physiological consequences of a way to design new strategies to provide anti-inflammatorydrugs.IntroductionCoronaviruses appear periodically and unpredictably from year2002 with the onset of SARS-COV, and then with MERS-COV and nowwith COVID-19 (SARS-CoV-2). This family of viruses causing infectiousdiseases and they became a constant threat to human health. There isno definitive and approved treatment for cardiorespiratory sequels ofthese COV infections. Although from a pathophysiological point of viewthere is a deep understanding of the immune response to the virus,there is no approved treatment for immunomodulation in these patientsthus it seems that treatment of immune system problems such as sys-temic pulmonary inflammatory responses associated with COV is ne-cessitating. Immunity based treatment can be a good alternative andsavior therapy to some antiviral treatment. As we know cytokine stormsin lung tissue in most deadly events in patients with COV infection.Therefore, in cases of COV induced pneumonia, it is important tocontrol cytokine production and inflammatory response. Although thisstrategy is challenging due to a lack of clear immune response andendangering the host defense, it does not seem impossible. In an at-tempt to address these issues from a therapeutic perspective, we de-scribe our hypothesis about one of the most challenging theories ofimmunotherapy in COV viruses.HypothesisReplication of RNA viruses such as the COV family is accompaniedby excessive production of interferons, neutrophils and macrophageswhich brings about a massive immune response, referred to as “cyto-kine storm”. This overproduction negatively affects the balance of theinflammatory responses and the normal function of cytokines.This immune system disorder can lead to series of symptoms in-cluding fever, edema, and hypotension in mild cases. In severe cases itcan cause systemic inflammation, heart failure, pulmonary failurewhich consequently led acute respiratory syndrome and eventuallydeath. In COVID-19 infection, like other coronavirus infections, a si-milar scenario is expected with varying degrees of immune inter-ference.It is expected that the management of the activity and performanceof the cytokines might lead to the prevention of severe endothelialdysfunctions and pulmonary fibrosis in patients affected by COVID-19.Previous studies have demonstrated the indicated impressive relationbetween the nervous system and immune system. These studies de-monstrated that nervous system has modulatory effects on the pro-duction of multiple inflammatory cytokines in lung tissue [1,2].The cholinergic pathway, via acetylcholine neurotransmitters, caninteract with nicotinic acetylcholine receptors. Further activation ofthese receptors can apply a suppressive effect on the production of pro-inflammatory cytokines [3] (Fig. 1). Among the nicotine receptor sub-types, the subunit 7(α-7) is the most prominent due to its high ex-pression in immune cells (B cells, macrophages, T cells, and target cells)and its association with humoral and intrinsic immunity. Therefore,evaluation of pharmacological approaches to activate α-7nAChR forinhibition of immunologic phenomenon such as cytokine storm can behelpful. Nicotine is a non-selective agonist of this receptor that mimicshttps://doi.org/10.1016/j.mehy.2020.109871Received 18 March 2020; Received in revised form 8 May 2020; Accepted 21 May 2020Medical Hypotheses 143 (2020) 1098710306-9877/ © 2020 Elsevier Ltd. All rights reserved.Tacetylcholine binding to stimulate vagal activity and decrease cytokinefunction and block the inflammatory pathway. The general algorithm ofthis idea was illustrated in Fig. 2. Hence, comprehension of this theorycan provide better therapeutic guidance for the treatment of cor-onavirus infections, especially COVID-19.DiscussionWe describe one of the trends in the decline of the cytokine storm. Itseems that lethality and uncontrolled complications of coronavirusesare due to the lack of control of the cytokine storms. Although thepathogenesis of coronaviruses is complex and requires specific treat-ment, previous studies have shown the efficacy of neutralizing anti-inflammatory cytokines in inflammatory conditions caused by COVID-19 [1]. Dose-dependent anti-inflammatory effects of the 7nAChR-1agonist have been demonstrated, and previous studies have shown thatactivation of this receptor can have an anti-inflammatory role andimmune cells regulating [4]. Nicotine is agonist of mentioned receptorbut cannot be used clinically due to its toxicity, addictive nature, andlack of specificity. Other agonists of 7nAChR-1 receptors in this group,such as GTS-21, produce the same nicotine effects without nicotineproblems. Also some studies have reported limited use of GTS-21 in theclinical phase and have shown that this agent can cause a decrease ofcytokine levels and significantly reduced inflammatory biomarker afterinfection [3,5]. It has been thought that a nicotine agonist compoundlike GTS-21 is able to suppress the production of pro-inflammatoryFig. 1. The hypothetical cellular ‘COVID-19 inflammatory pathway” virus with the influx of neutrophils and monocytes/macrophages results in the hyperproductionof pro-inflammatory cytokines. And “cytokine storm” occurs, weakened by the intensification of the immune system's inflammatory response. But it seems that‘nicotinic anti-inflammatory pathway’ triggered by the α7 nAChR in immune cells during infection, bacterial components, or intracellular mediators trigger pro-inflammatory pathways that converge in the activation of the NF-kB, which will translocate into the nucleus and induce the transcriptional activation of a variety ofinflammatory cytokines. Nicotine inhibits the production of pro-inflammatory cytokines in macrophages by mechanism dependent on the α7nAChR.Letter to Editors Medical Hypotheses 143 (2020) 1098712cytokines during infection of COVID-19. In fact, these nicotine agonistscan control allergic inflammation induced by innate immune and cel-lular immune pathways. Taken together according to mentioned lit-erature review it can be concluded that GTS-21, as potent 7nAChR-1receptor agonist, will act as an anti-inflammatory agent against COVID-19- infection-induced cytokine storm and inflammatory disturbances inrespiratory system and reduced the risk of death in infected subjects.Declaration of Competing InterestThe authors declare that they have no known competing financialinterests or personal relationships that could have appeared to influ-ence the work reported in this paper.Appendix A. Supplementary dataSupplementary data to this article can be found online at https://doi.org/10.1016/j.mehy.2020.109871.References[1] De Jonge W, Ulloa LJ. The alpha7 nicotinic acetylcholine receptor as a pharmaco-logical target for inflammation. Br J Pharmacol 2007;151(7):915–29.[2] Ulloa L, Messmer DJC. High-mobility group box 1 (HMGB1) protein: friend and foe.Cytokine Growth Factor Rev 2006;17(3):189–201.[3] D'Elia RV, Harrison K, Oyston PC, Lukaszewski RA, Clark GC. Targeting the “cytokinestorm” for therapeutic benefit. Clin Vaccine Immunol 2013;20(3):319–27.[4] Galle-Treger L, Suzuki Y, Patel N, Sankaranarayanan I, Aron JL, Maazi H, et al.Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hy-perreactivity. Nature Commun 2016;7(1):1–13.[5] Kox M, Van Velzen JF, Pompe JC, Hoedemaekers CW, Van Der Hoeven JG, PickkersPJ. GTS-21 inhibits pro-inflammatory cytokine release independent of the Toll-likereceptor stimulated via a transcriptional mechanism involving JAK2 activation.Biochem Pharmacol 2009;78(7):863–72.M. Allahverdi Khania,⁎, M. SalehiRadb, S. Darbeheshtic,M. Motaghinejadda Clinical Research Development Center, Najafabad Branch, Islamic AzadUniversity, Najafabad, Iranb Department of Pharmaceutical Chemistry, Faculty of PharmaceuticalChemistry, Tehran Medical Sciences, Islamic Azad University, Tehran, IrancDepartment of Clinical Biochemistry, Faculty of Medicine, Shahid BeheshtiUniversity of Medical Sciences, Tehran, Irand Razi Drug Research Center, Iran University of Medical Sciences, Tehran,IranE-mail address: Allahverdy.maryam@yahoo.com (M. Allahverdi Khani).Fig. 2. Schematic design of the virus-induced inflammatory pathway whichprobably block by the nicotine agonist.⁎ Corresponding author at: Shariati Hospital, Isfahan, Iran.Letter to Editors Medical Hypotheses 143 (2020) 1098713

Survival of COVID-19 patients requires precise immune regulation: The hypothetical immunoprotective role of nicotinic agonists

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Survival of COVID-19 patients requires precise immune regulation: The hypothetical immunoprotective role of nicotinic agonists

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