Potential role of memantine in the prevention and treatment of COVID-19: its antagonism of nicotinic acetylcholine receptors and beyond

Hasanagić, Senad; Serdarević, Fadila

doi:10.1183/13993003.01610-2020

Cited by 23 publications

(19 citation statements)

References 10 publications

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“…More recent studies support the antiviral potential of aminoadamantanes, including development of novel compounds (Kesel et al 2013 ) and treatment of virus replication (Leibowitz and Reneker 1993 ) including HCoV-OC43 replication by memantine (Brison et al 2014 ). Most recently, Hasanagic and Serdarevic ( 2020 ) suggested that memantine (besides its NMDA-R channel blocking properties) through its α7-nAChR antagonism may counteract proinflammatory cytokines induced in cell cultures by HCoV-OC43. This is of special interest, because α7-nAChR is localized in lungs and in the CNS.…”

Section: Implications For Neurodegenerative Disordersmentioning

confidence: 99%

Coronaviruses: a challenge of today and a call for extended human postmortem brain analyses

Riederer

Meulen

2020

J Neural Transm

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While there is abounding literature on virus-induced pathology in general and coronavirus in particular, recent evidence accumulates showing distinct and deleterious brain affection. As the respiratory tract connects to the brain without protection of the blood-brain barrier, SARS-CoV-2 might in the early invasive phase attack the cardiorespiratory centres located in the medulla/pons areas, giving rise to disturbances of respiration and cardiac problems. Furthermore, brainstem regions are at risk to lose their functional integrity. Therefore, long-term neurological as well as psychiatric symptomatology and eventual respective disorders cannot be excluded as evidenced from influenza-A triggered post-encephalitic Parkinsonism and HIV-1 triggered AIDS-dementia complex. From the available evidences for coronavirus-induced brain pathology, this review concludes a number of unmet needs for further research strategies like human postmortem brain analyses. SARS-CoV-2 mirroring experimental animal brain studies, characterization of time-dependent and region-dependent spreading behaviours of coronaviruses, enlightening of pathological mechanisms after coronavirus infection using long-term animal models and clinical observations of patients having had COVID-19 infection are calling to develop both protective strategies and drug discoveries to avoid early and late coronavirus-induced functional brain disturbances, symptoms and eventually disorders. To fight SARS-CoV-2, it is an urgent need to enforce clinical, molecular biological, neurochemical and genetic research including brain-related studies on a worldwide harmonized basis.

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Section: Implications For Neurodegenerative Disordersmentioning

confidence: 99%

Coronaviruses: a challenge of today and a call for extended human postmortem brain analyses

Riederer

Meulen

2020

J Neural Transm

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“…Against excessive extracellular glutamate accumulation triggered by diverse inflammatory and oxidative processes, memantine protects cells from glutamate excitotoxicity by blocking the extrasynaptic NMDA receptors [ 57 ]. Since memantine, is an antagonist of NMDA receptors, it diminishes the SARS-CoV-2-related oxidative stress and inflammation in neurons [ 58 ].…”

Section: Functions Of Receptors In Brain Invasion Of Sars-cov-2mentioning

confidence: 99%

Current opinion in neurological manifestations of SARS-CoV-2 infection

Engin

2021

Current Opinion in Toxicology

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Neurological symptoms occur in approximately one third of hospitalized patients with coronavirus disease 2019 (COVID-19). Among these symptoms, hypoxic encephalopathy develops in one-fifth of severe cases, while ischemic strokes due to thrombotic complications are common in one-third of COVID-19 intensive care patients. Brain involvement of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is eventuated by several routes, including hematogenous spread, trans-synaptic entry through infected neurons, olfactory nerve, ocular epithelium, vascular endothelium and impaired blood–brain barrier. Besides the high angiotensin converting enzyme-2 (ACE2) binding affinity, and FURIN preactivation, SARS-CoV-2 maintains efficient neuronal entry while evading immune surveillance by utilizing basigin, and neuropilin-1 receptors. However, the neurological manifestations and their pathogenic mechanisms are still debated in COVID-19 patients.

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“…Therefore, it is likely that antagonists of α7-nAChR could have the potential, by virtue of their ability to decrease ACE2 receptor expression in respiratory epithelium and prevent SARS-CoV-2 invasion of pulmonary epithelial cells. Searches for such agents are currently ongoing and, interestingly, memantine, in addition to its well-established action as a non-competitive antagonist of NMDA receptors, is a very potent antagonist of α7-nAChR [30]. It also exerts protective anti-inflammatory effects by suppression of cytokine expression as shown in an experimental model of lung injury [31].…”

Section: The Nicotinic Cholinergic Receptor and Covid-19mentioning

confidence: 99%

Repurposing of Adamantanes with Transmitter Receptor Antagonist Properties for the Prevention/Treatment of COVID-19

Brenner¹

2020

J Pharm Pharmacol

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Members of the adamantane family of agents in general and two such members, amantadine and memantine, in particular, have established beneficial actions across a wide range of infectious diseases including those caused by coronaviruses. Increasing evidence suggests that the protective effects of these agents is the result of actions on neurotransmitter systems namely the NMDA receptor subclass of the glutamatergic system and by the α7-nACh subclass of nicotinic cholinergic receptor. The potent NMDA receptor antagonist, memantine, prevents motor disabilities and reduces replication of the neuroinvasive/neurotropic human respiratory virus HCoV-OC43 dose-dependently. Moreover, the lysosomotrophic adamantanes amantadine and memantine also limit viral replication. Known lysomotrophic agents such as ammonium chloride inhibit cellular entry of SARS-CoV-2 on laboratory testing. Inhibiting clathrinmediated endocytosis (cellular entry) of the SARS-CoV-2/ACE2 complex by amantadine or rimantadine may block viral entry into vulnerable cellular populations, and also reduce platelet activating factor-priming of Polymorphonuclear [PMN] cells, potentially lessening PMN cell-mediated tissue damage and excess Neutrophil Extracellular Traps [NETs] seen in advanced cases of COVID-19. Rimantadine has inhibitory effects of SARS-CoV-1, a closely-related virus to SARS-CoV-2, which may indicate the need for further evaluation as a treatment for COVID-19. Amantadine increases Dopamine [DA] release and blocks its reuptake, increasing its action on DA receptors on T cells thus activating resting effector T cells and suppressing regulator T cells, which may have a beneficial immunomodulating function in infectious diseases. Proposed adverse effects of smoking on COVID-19 outcomes are attributed to the effects of nicotine via the α7-nACh receptor located on bronchial and alveolar epithelial cells. As an antagonist of this receptor, memantine has the potential to prevent the entry of SARS-CoV-2 into these cells. Independent case reports provide evidence of protective effects of amantadine and/or memantine against COVID-19. Additional epidemiologic studies however indicate a lower incidence of smoking in hospitalized patients, stimulating investigations of nicotine-related aspects, and amino acid sequence analysis indicate homologous sequences with those of neurotoxins seen in snake venoms blocking the α7-nAChR suggesting that COVID-19 may be a disease of the nicotinic cholinergic system; α7-nAChR is involved in the cholinergic anti-inflammatory pathway or reflex. COVID-19 is a biphasic disease, the initial aspect involved with the initial infection and viral replication which stimulates a prominent innate immune response. This then transitions to the adaptive immune response with suppression of infection and recovery, while the innate response is suppressed via the cholinergic anti-inflammatory pathway. Severe disease may occur when the initial innate immune response continues, the cholinergic anti-inflammatory pathway being arrested by the neu...

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Potential role of memantine in the prevention and treatment of COVID-19: its antagonism of nicotinic acetylcholine receptors and beyond

Cited by 23 publications

References 10 publications

Coronaviruses: a challenge of today and a call for extended human postmortem brain analyses

Coronaviruses: a challenge of today and a call for extended human postmortem brain analyses

Current opinion in neurological manifestations of SARS-CoV-2 infection

Repurposing of Adamantanes with Transmitter Receptor Antagonist Properties for the Prevention/Treatment of COVID-19

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