Memantine can relieve the neuronal impairment caused by neurotropic virus infection

Sun, Leqiang; Zhou, Meiling; Liu, Chuangang; Tang, Ya‐Jie; Xiao, Ke; Dai, Jinxia; Gao, Zhisong; Siew, Leonard; Cao, Gang; Wu, Xiang; Li, Liang; Zhang, Ran

doi:10.1002/jmv.25396

Cited by 10 publications

(9 citation statements)

References 34 publications

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“…1) is an aminoadamantane drug, employed mostly for the treatment of Alzheimer's disease (AD). This AD drug has been reported through in vitro assays as a possible antiviral agent against influenza A virus [16,17], human coronavirus strain OC-43 (HCoV-OC43), rabies virus (RABV), Japanese encephalitis virus (JEV) [18,19], Zika virus [20] and, most recently, SARS-CoV-2 infections [21].…”

Section: Introductionmentioning

confidence: 99%

Memantine hydrochloride: a drug to be repurposed against Chikungunya virus?

et al. 2021

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Background Chikungunya fever is an endemic disease caused by the Chikungunya virus (CHIKV) to which there is no vaccine or effective antiviral drug treatment so far. Our study aimed to evaluate the potential anti-CHIKV activity of memantine hydrochloride (mtnH), a drug from the class of the aminoadamantanes approved for the treatment of Alzheimer´s disease, as a possible drug to be repurposed to the treatment of Chikungunya fever. Methods MtnH antiviral activity against CHIKV was determined by infecting BHK-21 cells with CHIKV-nanoluc, a virus carrying the marker nanoluciferase reporter, in the presence or absence of mtnH at concentrations ranging from 500 to 1.45 µM. The effective concentration of 50% inhibition (EC 50 ) was calculated. Cell viability assay (determination of CC 50 ) was also performed employing BHK-21 cells. Mutagenic assays were performed by the Salmonella Typhimurium/microsome assay (Ames test). Results MtnH presented a CC 50 of 248.4 ± 31.9 µM and an EC 50 of 32.4 ± 4 µM against CHIKV in vitro. The calculated selectivity index (SI) was 7.67. MtnH did not induce genetic mutation in Salmonella strains with or without an external metabolizing system. Conclusion With the data herein presented, it is possible to hypothesize mtnH as a viable candidate to be repurposed as an anti-CHIKV drug. Clinical assays are, therefore, encouraged due to the promising in vitro results.

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Section: Introductionmentioning

confidence: 99%

Memantine hydrochloride: a drug to be repurposed against Chikungunya virus?

et al. 2021

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“…Memantine ameliorated these motor disturbances, reduced mortality rates and inhibited coronavirus replication rate in the central nervous system, dose-dependently [7,9]. Additionally, memantine might exert anti-inflammatory effects by reducing angiogenesis and brain lymphocyte infiltration, as shown in mice infected with Japanese encephalitis virus [10]. In conclusion, we hypothesise that memantine may reduce virulence and pathogenicity of SARS-CoV-2 and potentially exert its effects both in lungs and brain.…”

mentioning

confidence: 60%

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

Hasanagić

Serdarević

2020

Eur Respir J

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Recently, LEUNG et al. [1] proposed that α7-subtype nicotinic acetylcholine receptor (α7-nAChR) antagonists might decrease angiotensin-converting enzyme (ACE)2 receptor expression in respiratory epithelium and, hence, prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion of pulmonary epithelial cells. Let us further theoretically evaluate this assertion and contribute to the quest for potential medications that might reduce virulence and pathogenicity of coronavirus disease 2019 (COVID-19). Smoking may be associated with progression and negative outcome of COVID-19 [1]. The receptor-binding domain of the S protein (spike) on the surface of SARS-CoV-2 interacts with the ACE2 receptor, which is an entry point of the virus into host respiratory cells [2]. On the respiratory epithelium cells of smokers and patients with COPD there is higher expression of this "viral receptor" (ACE2 receptor) [1]. Nicotine binds and stimulates nAChR, specifically the α7 subtype, which are localised in lungs and various other tissues, especially in the central nervous system. Increased expression of ACE2 receptors is mediated by stimulation of α7-nAChR. Nicotine, by its agonism on α7-nAChR, might promote entry of SARS-CoV-2 into the respiratory epithelium through ACE2 receptors [1]. Additionally, some evidence suggests that SARS-CoV-2, along with other human coronaviruses, is neurotropic and neurovirulent [3]. Altogether, it is of utmost importance to search for medications that might exert protective effects both at the periphery, at the entry point of SARS-CoV-2 infection, but also in the central nervous system where the virus might propagate.

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“…Memantine relieves the neuronal impairment and damage caused by the neurotropic Japanese Encephalitis Virus (JEV) where survival times in JEV-infected mice were significantly prolonged, inflammatory cell infiltrates and intravascular cuffing were significantly reduced and mouse brain JEV content was reduced [10]. Memantine is also able to prevent neuronal cell death due to ZIKA virus infection by blocking NMDA receptors but had no effect on viral replication [11].…”

Section: Issn: 2327-204xmentioning

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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Memantine can relieve the neuronal impairment caused by neurotropic virus infection

Cited by 10 publications

References 34 publications

Memantine hydrochloride: a drug to be repurposed against Chikungunya virus?

Memantine hydrochloride: a drug to be repurposed against Chikungunya virus?

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

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

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