Login Register Cart 0
Generic placeholder image

Current Drug Targets

Editor-in-Chief

ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Central Effects of Ivermectin in Alleviation of Covid-19-induced Dysautonomia

Author(s): Hayder M. Al-kuraishy, Ali I. Al-Gareeb, Athanasios Alexiou* and Gaber El-Saber Batiha*

Volume 23, Issue 13, 2022

Published on: 05 September, 2022

Page: [1277 - 1287] Pages: 11

DOI: 10.2174/1389450123666220810102406

Price: $65

Abstract

Covid-19 may be associated with various neurological disorders, including dysautonomia, a dysfunction of the autonomic nervous system (ANS). In Covid-19, hypoxia, immunoinflammatory abnormality, and deregulation of the renin-angiotensin system (RAS) may increase sympathetic discharge with dysautonomia development. Direct SARS-CoV-2 cytopathic effects and associated inflammatory reaction may lead to neuroinflammation, affecting different parts of the central nervous system (CNS), including the autonomic center in the hypothalamus, causing dysautonomia. High circulating AngII, hypoxia, oxidative stress, high pro-inflammatory cytokines, and emotional stress can also provoke autonomic deregulation and high sympathetic outflow with the development of the sympathetic storm. During SARS-CoV-2 infection with neuro-invasion, GABA-ergic neurons and nicotinic acetylcholine receptor (nAChR) are inhibited in the hypothalamic pre-sympathetic neurons leading to sympathetic storm and dysautonomia. Different therapeutic modalities are applied to treat SARS-CoV-2 infection, like antiviral and anti-inflammatory drugs. Ivermectin (IVM) is a robust repurposed drug widely used to prevent and manage mild-moderate Covid-19. IVM activates both GABA-ergic neurons and nAChRs to mitigate SARS-CoV-2 infection- induced dysautonomia. Therefore, in this brief report, we try to identify the potential role of IVM in managing Covid-19-induced dysautonomia.

Keywords: Covid-19, GABA-ergic neurons, ivermectin, dysautonomia, nicotinic acetylcholine receptor, neuroinflammation.

« Previous
Graphical Abstract

[1]
Al-Kuraishy HM, Al-Gareeb AI, Alblihed M, Cruz-Martins N, Batiha GE. COVID-19 and risk of acute ischemic stroke and acute lung injury in patients with type ii diabetes mellitus: The anti-inflammatory role of metformin. Front Med (Lausanne) 2021; 8: 644295.
[http://dx.doi.org/10.3389/fmed.2021.644295] [PMID: 33718411]
[2]
Al-Kuraishy HM, Al-Gareeb AI, Alzahrani KJ, Cruz-Martins N, Batiha GE. The potential role of neopterin in Covid-19: A new perspective. Mol Cell Biochem 2021; 476(11): 4161-6.
[http://dx.doi.org/10.1007/s11010-021-04232-z] [PMID: 34319496]
[3]
Al-Kuraishy HM, Al-Gareeb AI, Qusty N, Cruz-Martins N, El-Saber Batiha G. Sequential doxycycline and colchicine combination therapy in Covid-19: The salutary effects. Pulm Pharmacol Ther 2021; 67: 102008.
[http://dx.doi.org/10.1016/j.pupt.2021.102008] [PMID: 33727066]
[4]
Lugnier C, Al-Kuraishy HM, Rousseau E. PDE4 inhibition as a therapeutic strategy for improvement of pulmonary dysfunctions in Covid-19 and cigarette smoking. Biochem Pharmacol 2021; 185: 114431-8.
[http://dx.doi.org/10.1016/j.bcp.2021.114431] [PMID: 33515531]
[5]
Al-Kuraishy HM, Al-Gareeb AI, Almulaiky YQ, Cruz-Martins N, El-Saber Batiha G. Role of leukotriene pathway and montelukast in pulmonary and extrapulmonary manifestations of Covid-19: The enigmatic entity. Eur J Pharmacol 2021; 904: 174196.
[http://dx.doi.org/10.1016/j.ejphar.2021.174196] [PMID: 34004207]
[6]
Al-Kuraishy HM, Al-Gareeb AI, Al-Niemi MS, Al-Buhadily AK, Al-Harchan NA, Lugnier C. COVID-19 and phosphodiesterase enzyme type 5 inhibitors. J Microsc Ultrastruct 2020; 8(4): 141-5.
[http://dx.doi.org/10.4103/JMAU.JMAU_63_20] [PMID: 33623736]
[7]
Poddighe D, Marseglia GL. Is there any relationship between extra-pulmonary manifestations of Mycoplasma pneumoniae infection and atopy/respiratory allergy in children? Pediatr Rep 2016; 8(1): 6395.
[http://dx.doi.org/10.4081/pr.2016.6395] [PMID: 27114818]
[8]
Dhaliwal K, Enright K. Rare extrapulmonary complications of Mycoplasma pneumoniae infection. BMJ Case Rep 2016; 2016: bcr2015214044.
[http://dx.doi.org/10.1136/bcr-2015-214044] [PMID: 26837942]
[9]
Sellers SA, Hagan RS, Hayden FG, Fischer WA II. The hidden burden of influenza: A review of the extra-pulmonary complications of influenza infection. Influenza Other Respir Viruses 2017; 11(5): 372-93.
[http://dx.doi.org/10.1111/irv.12470] [PMID: 28745014]
[10]
Goodman BP, Khoury JA, Blair JE, Grill MF. COVID-19 dysautonomia. Front Neurol 2021; 12: 624968.
[http://dx.doi.org/10.3389/fneur.2021.624968] [PMID: 33927679]
[11]
Dolce G, Quintieri M, Leto E, et al. Dysautonomia and clinical outcome in vegetative state. J Neurotrauma 2021; 38(10): 1441-4.
[http://dx.doi.org/10.1089/neu.2008.0536] [PMID: 18771395]
[12]
Wig R, Oakley CB. Dysautonomia and headache in the pediatric population. Headache 2019; 59(9): 1582-8.
[http://dx.doi.org/10.1111/head.13659] [PMID: 31549738]
[13]
Dani M, Dirksen A, Taraborrelli P, et al. Autonomic dysfunction in ‘long COVID’: Rationale, physiology and management strategies. Clin Med (Lond) 2021; 21(1): e63-7.
[http://dx.doi.org/10.7861/clinmed.2020-0896] [PMID: 33243837]
[14]
Martínez-Lavín M. Fibromyalgia and small fiber neuropathy: The plot thickens! Clin Rheumatol 2018; 37(12): 3167-71.
[http://dx.doi.org/10.1007/s10067-018-4300-2] [PMID: 30238382]
[15]
Poddighe D, Castelli L, Marseglia GL, Bruni P. A sudden onset of a pseudo-neurological syndrome after HPV-16/18 AS04-adjuvated vaccine: Might it be an Autoimmune/inflammatory Syndrome by Adjuvants (ASIA) presenting as a somatoform disorder? Immunol Res 2014; 60(2-3): 236-46.
[http://dx.doi.org/10.1007/s12026-014-8575-3] [PMID: 25388965]
[16]
Barizien N, Le Guen M, Russel S, Touche P, Huang F, Vallée A. Clinical characterization of dysautonomia in long COVID-19 patients. Sci Rep 2021; 11(1): 14042.
[http://dx.doi.org/10.1038/s41598-021-93546-5] [PMID: 34234251]
[17]
Díaz HS, Toledo C, Andrade DC, Marcus NJ, Del Rio R. Neuroinflammation in heart failure: New insights for an old disease. J Physiol 2020; 598(1): 33-59.
[http://dx.doi.org/10.1113/JP278864] [PMID: 31671478]
[18]
Porzionato A, Emmi A, Barbon S, et al. Sympathetic activation: A potential link between comorbidities and COVID-19. FEBS J 2020; 287(17): 3681-8.
[http://dx.doi.org/10.1111/febs.15481] [PMID: 32779891]
[19]
Wolff D, Nee S, Hickey NS, Marschollek M. Risk factors for Covid-19 severity and fatality: A structured literature review. Infection 2021; 49(1): 15-28.
[http://dx.doi.org/10.1007/s15010-020-01509-1] [PMID: 32860214]
[20]
Johansson M, Ståhlberg M, Runold M, et al. Long-haul post-COVID-19 symptoms presenting as a variant of postural orthostatic tachycardia syndrome: The Swedish experience. JACC Case Rep 2021; 3(4): 573-80.
[http://dx.doi.org/10.1016/j.jaccas.2021.01.009] [PMID: 33723532]
[21]
Shouman K, Vanichkachorn G, Cheshire WP, et al. Autonomic dysfunction following COVID-19 infection: An early experience. Clin Auton Res 2021; 31(3): 385-94.
[http://dx.doi.org/10.1007/s10286-021-00803-8] [PMID: 33860871]
[22]
Shoumann WM, Hegazy AA, Nafae RM, et al. Use of ivermectin as a potential chemoprophylaxis for COVID-19 in Egypt: A randomized clinical trial. J Clin Diagn Res 2021; 15(2): 2021.
[http://dx.doi.org/10.7860/JCDR/2021/46795.14529]
[23]
Juarez M, Schcolnik-Cabrera A, Dueñas-Gonzalez A. The multitargeted drug ivermectin: From an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res 2018; 8(2): 317-31.
[PMID: 29511601]
[24]
Guzzo CA, Furtek CI, Porras AG, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol 2002; 42(10): 1122-33.
[http://dx.doi.org/10.1177/009127002401382731] [PMID: 12362927]
[25]
Sharun K, Shyamkumar TS, Aneesha VA, Dhama K, Pawde AM, Pal A. Current therapeutic applications and pharmacokinetic modulations of ivermectin. Vet World 2019; 12(8): 1204-11.
[http://dx.doi.org/10.14202/vetworld.2019.1204-1211] [PMID: 31641298]
[26]
Meyers JI, Gray M, Kuklinski W, et al. Characterization of the target of ivermectin, the glutamate-gated chloride channel, from Anopheles gambiae. J Exp Biol 2015; 218(Pt 10): 1478-86.
[http://dx.doi.org/10.1242/jeb.118570] [PMID: 25994631]
[27]
Ménez C, Sutra JF, Prichard R, Lespine A. Relative neurotoxicity of ivermectin and moxidectin in Mdr1ab (-/-) mice and effects on mammalian GABA(A) channel activity. PLoS Negl Trop Dis 2012; 6(11): e1883.
[http://dx.doi.org/10.1371/journal.pntd.0001883] [PMID: 23133688]
[28]
Rendic SP. Metabolism and interactions of ivermectin with human cytochrome P450 enzymes and drug transporters, possible adverse and toxic effects. Arch Toxicol 2021; 95(5): 1535-46.
[http://dx.doi.org/10.1007/s00204-021-03025-z] [PMID: 33719007]
[29]
Chen IS, Kubo Y. Ivermectin and its target molecules: Shared and unique modulation mechanisms of ion channels and receptors by ivermectin. J Physiol 2018; 596(10): 1833-45.
[http://dx.doi.org/10.1113/JP275236] [PMID: 29063617]
[30]
Jin L, Feng X, Rong H, et al. The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. Nat Commun 2013; 4(1): 1937.
[http://dx.doi.org/10.1038/ncomms2924] [PMID: 23728580]
[31]
Kauthale RR, Dadarkar SS, Husain R, Karande VV, Gatne MM. Assessment of temperature-induced hERG channel blockade variation by drugs. J Appl Toxicol 2015; 35(7): 799-05.
[http://dx.doi.org/10.1002/jat.3074] [PMID: 25348819]
[32]
Chen IS, Tateyama M, Fukata Y, Uesugi M, Kubo Y. Ivermectin activates GIRK channels in a PIP2 -dependent, Gβγ -independent manner and an amino acid residue at the slide helix governs the activation. J Physiol 2017; 595(17): 5895-912.
[http://dx.doi.org/10.1113/JP274871] [PMID: 28715108]
[33]
González Canga A, Sahagún Prieto AM, Diez Liébana MJ, Fernández Martínez N, Sierra Vega M, García Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans-A mini-review. AAPS J 2008; 10(1): 42-6.
[http://dx.doi.org/10.1208/s12248-007-9000-9] [PMID: 18446504]
[34]
Preissner S, Kroll K, Dunkel M, et al. SuperCYP: A comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res 2010; 38(Database issue): D237-43.
[http://dx.doi.org/10.1093/nar/gkp970] [PMID: 19934256]
[35]
Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 1995; 96(4): 1698-705.
[http://dx.doi.org/10.1172/JCI118214] [PMID: 7560060]
[36]
Dowling P. Pharmacogenetics: It’s not just about ivermectin in collies. Can Vet J 2006; 47(12): 1165-8.
[PMID: 17217086]
[37]
Jani M, Makai I, Kis E, et al. Ivermectin interacts with human ABCG2. J Pharm Sci 2011; 100(1): 94-7.
[http://dx.doi.org/10.1002/jps.22262] [PMID: 20574995]
[38]
Baraka OZ, Mahmoud BM, Marschke CK, Geary TG, Homeida MM, Williams JF. Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus. Eur J Clin Pharmacol 1996; 50(5): 407-10.
[http://dx.doi.org/10.1007/s002280050131] [PMID: 8839664]
[39]
Merck & Co. Stromectrol. FDA approved Package insert 2009. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050742s026lbl.pdf (Accessed on Oct 2016).
[40]
Zeng Z, Andrew NW, Arison BH, Luffer-Atlas D, Wang RW. Identification of cytochrome P4503A4 as the major enzyme responsible for the metabolism of ivermectin by human liver microsomes. Xenobiotica 1998; 28(3): 313-21.
[http://dx.doi.org/10.1080/004982598239597] [PMID: 9574819]
[41]
Tipthara P, Kobylinski KC, Godejohann M, et al. Identification of the metabolites of ivermectin in humans. Pharmacol Res Perspect 2021; 9(1): e00712.
[http://dx.doi.org/10.1002/prp2.712] [PMID: 33497030]
[42]
Xu TL, Han Y, Liu W, et al. Antivirus effectiveness of ivermectin on dengue virus type 2 in Aedes albopictus. PLoS Negl Trop Dis 2018; 12(11): e0006934.
[http://dx.doi.org/10.1371/journal.pntd.0006934] [PMID: 30452439]
[43]
Nguyen C, Burton T, Kuklinski W, Gray M, Foy BD. Ivermectin for the control of west nile virus transmission. New Horiz Transl Med 2015; 2(4-5): 127.
[44]
Jans DA, Wagstaff KM. The broad spectrum host-directed agent ivermectin as an antiviral for SARS-CoV-2? Biochem Biophys Res Commun 2021; 538: 163-72.
[http://dx.doi.org/10.1016/j.bbrc.2020.10.042] [PMID: 33341233]
[45]
Mudatsir M, Yufika A, Nainu F, et al. Antiviral activity of ivermectin against SARS-CoV-2: An old-fashioned dog with a new trick—A literature review. Sci Pharm 2020; 88(3): 36.
[http://dx.doi.org/10.3390/scipharm88030036]
[46]
King CR, Tessier TM, Dodge MJ, Weinberg JB, Mymryk JS. Inhibition of human adenovirus replication by the importin α/β1 nuclear import inhibitor ivermectin. J Virol 2020; 94(18): e00710-20.
[http://dx.doi.org/10.1128/JVI.00710-20] [PMID: 32641484]
[47]
Caly L, Wagstaff KM, Jans DA. Nuclear trafficking of proteins from RNA viruses: Potential target for antivirals? Antiviral Res 2012; 95(3): 202-6.
[http://dx.doi.org/10.1016/j.antiviral.2012.06.008] [PMID: 22750233]
[48]
Jans DA, Wagstaff KM. Ivermectin as a broad-spectrum host-directed antiviral: The real deal? Cells 2020; 9(9): 2100.
[http://dx.doi.org/10.3390/cells9092100] [PMID: 32942671]
[49]
Scheim D. Ivermectin for COVID-19 treatment: Clinical response at quasi-threshold doses via hypothesized alleviation of CD147-mediated vascular occlusion. In: SSRN. 3636557-24. 2020; pp. 1-24.
[http://dx.doi.org/10.2139/ssrn.3636557]
[50]
Rizzo E. Ivermectin, antiviral properties and COVID-19: A possible new mechanism of action. Naunyn Schmiedebergs Arch Pharmacol 2020; 393(7): 1153-6.
[http://dx.doi.org/10.1007/s00210-020-01902-5] [PMID: 32462282]
[51]
Yan S, Ci X, Chen N, et al. Anti-inflammatory effects of ivermectin in mouse model of allergic asthma. Inflamm Res 2011; 60(6): 589-96.
[http://dx.doi.org/10.1007/s00011-011-0307-8] [PMID: 21279416]
[52]
De Ménonville ST, Rosignoli C, Soares E, et al. Topical treatment of rosacea with ivermectin inhibits gene expression of cathelicidin innate immune mediators, LL-37 and KLK5, in reconstructed and ex vivo skin models. Dermatol Ther (Heidelb) 2017; 7(2): 213-25.
[http://dx.doi.org/10.1007/s13555-017-0176-3] [PMID: 28243927]
[53]
Kerr L, Cadegiani FA, Baldi F, et al. Ivermectin prophylaxis used for COVID-19: A citywide, prospective, observational study of 223,128 subjects using propensity score matching. Cureus 2022; 14(1): e21272.
[http://dx.doi.org/10.7759/cureus.21272] [PMID: 35070575]
[54]
Al-Kuraishy HM, Hussien NR, Al-Naimi MS, Al-Buhadily AK, Al-Gareeb AI, Lungnier C. Is Ivermectin-Azithromycin combination the next step for COVID-19? Biomed Biotechnol Res J 2020; 4(5): 101.
[55]
Carod-Artal FJ. Infectious diseases causing autonomic dysfunction. Clin Auton Res 2018; 28(1): 67-81.
[http://dx.doi.org/10.1007/s10286-017-0452-4] [PMID: 28730326]
[56]
Sternberg Z. Autonomic dysfunction: A unifying multiple sclerosis theory, linking chronic cerebrospinal venous insufficiency, vitamin D (3), and epstein-barr virus. Autoimmun Rev 2012; 12(2): 250-9.
[http://dx.doi.org/10.1016/j.autrev.2012.04.004] [PMID: 22564548]
[57]
Lima M, Siokas V, Aloizou AM, et al. Unraveling the possible routes of SARS-COV-2 invasion into the central nervous system. Curr Treat Options Neurol 2020; 22(11): 37.
[http://dx.doi.org/10.1007/s11940-020-00647-z] [PMID: 32994698]
[58]
Hussien NR, Al-Niemi MS, Al-Kuraishy HM, Al-Gareeb AI. Statins and Covid-19: The neglected front of bidirectional effects. J Pak Med Assoc 2021; 71(12)(Suppl. 8): S133-6.
[PMID: 35130236]
[59]
Rahbar A, Shakyba S, Ghaderi M, et al. Ivermectin-functionalized multiwall carbon nanotube enhanced the locomotor activity and neuropathic pain by modulating M1/M2 macrophage and decrease oxidative stress in rat model of spinal cord injury. Heliyon 2021; 7(6): e07311.
[http://dx.doi.org/10.1016/j.heliyon.2021.e07311] [PMID: 34235282]
[60]
Batiha GE, Al-Gareeb DAI, Qusti S, et al. Common NLRP3 inflammasome inhibitors and Covid-19: Divide and conquer. Sci Am 2021; 18: e01084.
[http://dx.doi.org/10.1016/j.sciaf.2021.e01084] [PMID: 34957352]
[61]
Al-Kuraishy HM, Al-Gareeb AI, Alblihed M, Guerreiro SG, Cruz-Martins N, Batiha GE. COVID-19 in relation to hyperglycemia and diabetes mellitus. Front Cardiovasc Med 2021; 8: 644095.
[http://dx.doi.org/10.3389/fcvm.2021.644095] [PMID: 34124187]
[62]
Dey J, Alam MT, Chandra S, et al. Neuroinvasion of SARS-CoV-2 may play a role in the breakdown of the respiratory center of the brain. J Med Virol 2021; 93(3): 1296-303.
[http://dx.doi.org/10.1002/jmv.26521] [PMID: 32964419]
[63]
Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2. In Vivo 2020; 34(5): 3023-6.
[64]
Franco M, Bautista-Pérez R, Cano A, Pacheco U, Pérez-Mendez O. ATP and activation Of P2X1 And P2X7 renal receptors. A new concept in the pathophysiology of renal vasoconstriction in angiotensin II-induced hypertension. FASEB J 2016; 30: 739-2.
[65]
Sriram K, Insel PA. Inflammation and thrombosis in COVID-19 pathophysiology: Proteinase-activated and purinergic receptors as drivers and candidate therapeutic targets. Physiol Rev 2021; 101(2): 545-67.
[http://dx.doi.org/10.1152/physrev.00035.2020] [PMID: 33124941]
[66]
Asatryan L, Popova M, Perkins D, Trudell JR, Alkana RL, Davies DL. Ivermectin antagonizes ethanol inhibition in purinergic P2X4 receptors. J Pharmacol Exp Ther 2010; 334(3): 720-8.
[http://dx.doi.org/10.1124/jpet.110.167908] [PMID: 20543096]
[67]
Pijacka W, Moraes DJ, Ratcliffe LE, et al. Purinergic receptors in the carotid body as a new drug target for controlling hypertension. Nat Med 2016; 22(10): 1151-9.
[http://dx.doi.org/10.1038/nm.4173] [PMID: 27595323]
[68]
Minic Z, O’Leary DS, Reynolds CA. Purinergic receptor antagonism: A viable strategy for the management of autonomic dysreflexia? Auton Neurosci 2021; 230: 102741.
[http://dx.doi.org/10.1016/j.autneu.2020.102741] [PMID: 33220530]
[69]
Al-Kuraishy HM, Al-Gareeb AI, Faidah H, Al-Maiahy TJ, Cruz-Martins N, Batiha GE. The looming effects of estrogen in Covid-19: A rocky rollout. Front Nutr 2021; 8: 649128.
[http://dx.doi.org/10.3389/fnut.2021.649128] [PMID: 33816542]
[70]
Al-Kuraishy HM, Al-Gareeb AI, Mostafa-Hedeab G, et al. Effects of β-blockers on the sympathetic and cytokines storms in Covid-19. Front Immunol 2021; 12: 749291.
[http://dx.doi.org/10.3389/fimmu.2021.749291] [PMID: 34867978]
[71]
Forsythe P. The parasympathetic nervous system as a regulator of mast cell function. Mast Cells 2015; 141-54.
[http://dx.doi.org/10.1007/978-1-4939-1568-2_9]
[72]
Alexandris N, Lagoumintzis G, Chasapis CT, et al. Nicotinic cholinergic system and COVID-19: In silico evaluation of nicotinic acetylcholine receptor agonists as potential therapeutic interventions. Toxicol Rep 2020; 8: 73-83.
[http://dx.doi.org/10.1016/j.toxrep.2020.12.013] [PMID: 33425684]
[73]
Ahmad F. COVID-19 induced ARDS, and the use of galantamine to activate the cholinergic anti-inflammatory pathway. Med Hypotheses 2020; 145: 110331.
[http://dx.doi.org/10.1016/j.mehy.2020.110331] [PMID: 33038588]
[74]
Krause RM, Buisson B, Bertrand S, et al. Ivermectin: A positive allosteric effector of the α7 neuronal nicotinic acetylcholine receptor. Mol Pharmacol 1998; 53(2): 283-94.
[http://dx.doi.org/10.1124/mol.53.2.283] [PMID: 9463487]
[75]
Zbarsky V, Thomas J, Greenfield S. Bioactivity of a peptide derived from acetylcholinesterase: Involvement of an ivermectin-sensitive site on the alpha 7 nicotinic receptor. Neurobiol Dis 2004; 16(1): 283-9.
[http://dx.doi.org/10.1016/j.nbd.2004.02.009] [PMID: 15207285]
[76]
Mukerjee S, Gao H, Xu J, Sato R, Zsombok A, Lazartigues E. ACE2 and ADAM17 interaction regulates the activity of presympathetic neurons. Hypertension 2019; 74(5): 1181-91.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13133] [PMID: 31564162]
[77]
Jin S, Dai J, Teng X, Wu YM. Adverse effects of sympathetic activation should not be neglected during the coronavirus disease 2019 pandemic. Chin Med J (Engl) 2020; 134(4): 413-4.
[http://dx.doi.org/10.1097/CM9.0000000000001106] [PMID: 32941242]
[78]
Chen Q, Pan HL. Signaling mechanisms of angiotensin II-induced attenuation of GABAergic input to hypothalamic presympathetic neurons. J Neurophysiol 2007; 97(5): 3279-87.
[http://dx.doi.org/10.1152/jn.01329.2006] [PMID: 17287434]
[79]
Versace V, Sebastianelli L, Ferrazzoli D, et al. Intracortical GABAergic dysfunction in patients with fatigue and dysexecutive syndrome after COVID-19. Clin Neurophysiol 2021; 132(5): 1138-43.
[http://dx.doi.org/10.1016/j.clinph.2021.03.001] [PMID: 33774378]
[80]
Trailović SM, Nedeljković JT. Central and peripheral neurotoxic effects of Ivermectin in rats. J Vet Med Sci 2010; 101: 2080409.
[81]
Li N, Zhao L, Zhan X. Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol 2021; 236(4): 2959-75.
[http://dx.doi.org/10.1002/jcp.30055] [PMID: 32959892]
[82]
Li Y, Yang J, Zhang Y, Meng Q, Bender A, Chen X. Computational drug repositioning for ischemic stroke: Neuroprotective drug discovery. Future Med Chem 2021; 13(15): 1271-83.
[http://dx.doi.org/10.4155/fmc-2021-0022]
[83]
Costa LHA, Santos BM, Branco LGS. Can selective serotonin reuptake inhibitors have a neuroprotective effect during COVID-19? Eur J Pharmacol 2020; 889: 173629.
[http://dx.doi.org/10.1016/j.ejphar.2020.173629] [PMID: 33022271]
[84]
Adiraju RK. Dysautonomia: A novel approach to understanding of vasculitis and type Ii diabetes. J Rheumatol Arthritic Dis 2017; 2(3): 12.
[85]
Jiang L, Wang P, Sun YJ, Wu YJ. Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway. J Exp Clin Cancer Res 2019; 38(1): 1-8.
[http://dx.doi.org/10.1186/s13046-019-1251-7] [PMID: 30606223]
[86]
Wu Y, Ma L, Cai S, Zhuang Z, Zhao Z, Jin S, et al. RNA-induced liquid phase separation of SARS-CoV-2 nucleocapsid protein facilitates NF-κB hyper-activation and inflammation. Signal Transduct Target Ther 2021; 6(1): 1-3.
[http://dx.doi.org/10.1038/s41392-021-00575-7] [PMID: 33384407]
[87]
Zhao M, Zhou A, Xu L, Zhang X. The role of TLR4-mediated PTEN/PI3K/AKT/NF-κB signaling pathway in neuroinflammation in hippocampal neurons. Neuroscience 2014; 269: 93-101.
[http://dx.doi.org/10.1016/j.neuroscience.2014.03.039] [PMID: 24680857]
[88]
Close P, Hawkes N, Cornez I, et al. Transcription impairment and cell migration defects in elongator-depleted cells: Implication for familial dysautonomia. Mol Cell 2006; 22(4): 521-31.
[http://dx.doi.org/10.1016/j.molcel.2006.04.017] [PMID: 16713582]
[89]
Dominguez-Gomez G, Chavez-Blanco A, Medina-Franco JL, et al. Ivermectin as an inhibitor of cancer stem-like cells. Mol Med Rep 2018; 17(2): 3397-403.
[PMID: 29257278]
[90]
Al-Kuraishy HM, Al-Gareeb AI, Al-Hussaniy HA, Al-Harcan NAH, Alexiou A, Batiha GE. Neutrophil Extracellular Traps (NETs) and Covid-19: A new frontiers for therapeutic modality. Int Immunopharmacol 2022; 104: 108516.
[http://dx.doi.org/10.1016/j.intimp.2021.108516] [PMID: 35032828]
[91]
Al-Kuraishy HM, Al-Gareeb AI, Qusti S, Alshammari EM, Gyebi GA, Batiha GE. Covid-19-induced dysautonomia: A menace of sympathetic storm. ASN Neuro 2021; 13: 17590914211057635.
[http://dx.doi.org/10.1177/17590914211057635] [PMID: 34755562]
[92]
Al-Kuraishy HM, Al-Gareeb AI, Qusti S, Alshammari EM, Atanu FO, Batiha GE. Arginine vasopressin and pathophysiology of COVID-19: An innovative perspective. Biomed Pharmacother 2021; 143: 112193.
[http://dx.doi.org/10.1016/j.biopha.2021.112193] [PMID: 34543987]
[93]
Wei M, Li H, Shang Y, Zhou Z, Zhang J. Increased CD147 (EMMPRIN) expression in the rat brain following traumatic brain injury. Brain Res 2014; 1585: 150-8.
[http://dx.doi.org/10.1016/j.brainres.2014.06.018] [PMID: 24968091]
[94]
Zaidi AK, Dehgani-Mobaraki P. The mechanisms of action of ivermectin against SARS-CoV-2: An evidence-based clinical review article. J Antibiot (Tokyo) 2021; 15: 1-3.
[PMID: 34127807]
[95]
Wilson NE, Reaves BJ, Wolstenholme AJ. Lack of detectable short-term effects of a single dose of ivermectin on the human immune system. Parasit Vectors 2021; 14(1): 304.
[http://dx.doi.org/10.1186/s13071-021-04810-6] [PMID: 34090504]
[96]
Deckmyn B, Domenger D, Staels B, Bantubungi K, Farnesoid X. Receptor activation in brain alters brown adipose tissue function via the sympathetic system. Authorea Preprints 2021; 14: 808603.
[http://dx.doi.org/10.22541/au.162151000.01734906/v1]
[97]
Ito K, Okumura A, Takeuchi JS, et al. Dual agonist of farnesoid X receptor and takeda G protein-coupled receptor 5 inhibits hepatitis B virus infection in vitro and in vivo. Hepatology 2021; 74(1): 83-98.
[http://dx.doi.org/10.1002/hep.31712] [PMID: 33434356]
[98]
López-Medina E, López P, Hurtado IC, et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: A randomized clinical trial. JAMA 2021; 325(14): 1426-35.
[http://dx.doi.org/10.1001/jama.2021.3071] [PMID: 33662102]
[99]
Niaee MS, Namdar P, Allami A, et al. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: A randomized multi-center clinical trial. Asian Pac J Trop Med 2021; 14(6): 266.
[http://dx.doi.org/10.4103/1995-7645.318304]
[100]
Zein AFMZ, Sulistiyana CS, Raffaelo WM, Pranata R, Pranata R. Ivermectin and mortality in patients with COVID-19: A systematic review, meta-analysis, and meta-regression of randomized controlled trials. Diabetes Metab Syndr 2021; 15(4): 102186.
[http://dx.doi.org/10.1016/j.dsx.2021.102186] [PMID: 34237554]
[101]
Garegnani LI, Madrid E, Meza N. Misleading clinical evidence and systematic reviews on ivermectin for COVID-19. BMJ Evid Based Med 2022; 27(3): 156-8.
[PMID: 33888547]
[102]
Popp M, Stegemann M, Metzendorf MI, et al. Ivermectin for preventing and treating COVID‐19. Cochrane Database Syst Rev 2021; (7): CD015017.
[103]
Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: The ivermectin in COVID nineteen study. Chest 2021; 159(1): 85-92.
[http://dx.doi.org/10.1016/j.chest.2020.10.009] [PMID: 33065103]
[104]
Alam MT, Murshed R, Bhiuyan E, Saber S, Alam RF, Robin RC. A case series of 100 COVID-19 positive patients treated with combination of ivermectin and doxycycline. J Bangladesh Coll Phys Surg 2020; 12: 10-5.
[http://dx.doi.org/10.3329/jbcps.v38i0.47512]
[105]
Al-Kuraishy HM, Al-Gareeb AI, Alqarni M, Cruz-Martins N, El-Saber BG. Pleiotropic effects of tetracyclines in the management of COVID-19: Emerging perspectives. Front Pharmacol 2021; 12: 642822.
[http://dx.doi.org/10.3389/fphar.2021.642822] [PMID: 33967777]
[106]
Rahman MA, Iqbal SA, Islam MA, Niaz MK, Hussain T, Siddiquee TH. Comparison of viral clearance between Ivermectin with doxycycline and hydroxychloroquine with azithromycin in COVID-19 patients. J Bangladesh Coll Physicians Surg 2020; 125-9.
[http://dx.doi.org/10.3329/jbcps.v38i0.47514]
[107]
Al-Kuraishy HM, Al-Gareeb AI, El-Bouseary MM, Sonbol FI, Batiha GE. Hyperviscosity syndrome in COVID-19 and related vaccines: Exploring of uncertainties. Clin Exp Med 2022; 1-10.
[http://dx.doi.org/10.1007/s10238-022-00836-x] [PMID: 35608715]
[108]
Cadegiani FA, Goren A, Wambier CG, McCoy J. Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly improved COVID-19 outcomes compared to known outcomes in untreated patients. New Microbes New Infect 2021; 43: 100915.
[http://dx.doi.org/10.1016/j.nmni.2021.100915] [PMID: 34249367]
[109]
Ortelli P, Ferrazzoli D, Sebastianelli L, et al. Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: Insights into a challenging symptom. J Neurol Sci 2021; 420: 117271.
[http://dx.doi.org/10.1016/j.jns.2020.117271] [PMID: 33359928]

Rights & Permissions Print Cite
Article Metrics
7
© 2024 Bentham Science Publishers | Privacy Policy