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      Can an FDA-Approved Alzheimer’s Drug Be Repurposed for Alleviating Neuronal Symptoms of Zika Virus?

      article-commentary
      ,
      mBio
      American Society for Microbiology
      Zika virus, antiviral agents, neurodegeneration, NMDAR, memantine

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          ABSTRACT

          Zika virus caught the world by surprise by its rapid spread and frightening disease outcomes. This major epidemic motivated many scientists to focus their attention on controlling this emerging pathogen. As many as 45 vaccine candidates are being developed, but progress in the antiviral arena has been slower. In a recent article (mBio 8:e00350-17, 2017, https://doi.org/10.1128/mBio.00350-17), Costa and colleagues showed that an FDA-approved drug used to treat Alzheimer’s disease may moderate Zika virus-induced neuronal damage. This work is based on the premise that overstimulation of N-methyl- d-aspartate receptors (NMDARs) may drive neurodegeneration and that this may be responsible for neuronal cell death associated with Zika virus infection of the central nervous system (CNS). Thus, blockage of the NMDAR channel activity with FDA-approved memantine or other antagonists may reduce neurological complications associated with Zika virus infection. Repurposing a preapproved drug and targeting the host represent intriguing strategies and yet require more analysis prior to moving into clinical trials.

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          Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system--too little activation is bad, too much is even worse.

          The neurotransmitter glutamate activates several classes of metabotropic receptor and three major types of ionotropic receptor--alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA). The involvement of glutamate mediated neurotoxicity in the pathogenesis of Alzheimer's disease (AD) is finding increasing scientific acceptance. Central to this hypothesis is the assumption that glutamate receptors, in particular of the NMDA type, are overactivated in a tonic rather than a phasic manner. Such continuous, mild, chronic activation ultimately leads to neuronal damage/death. Additionally, impairment of synaptic plasticity (learning) may result not only from neuronal damage per se but may also be a direct consequence of this continuous, non-contingent NMDA receptor activation. Complete NMDA receptor blockade has also been shown to impair neuronal plasticity, thus, both hypo- and hyperactivity of the glutamatergic system leads to dysfunction. Memantine received marketing authorization from the EMEA (European Medicines Agency) for the treatment of moderate to severe AD in Europe and was subsequently also approved by the FDA (Food and Drug Administration) for use in the same indication in the USA. Memantine is a moderate affinity, uncompetitive NMDA receptor antagonist with strong voltage-dependency and fast kinetics. This review summarizes existing hypotheses on the mechanism of action (MOA) of memantine in an attempt to understand how the accepted interaction with NMDA receptors could allow memantine to provide both neuroprotection and reverse deficits in learning/memory by the same MOA.
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            Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis.

            Molecular, genetic and pathological evidence suggests that deficits in GABAergic parvalbumin-positive interneurons contribute to schizophrenia pathophysiology through alterations in the brain's excitation-inhibition balance that result in impaired behaviour and cognition. Although the factors that trigger these deficits are diverse, there is increasing evidence that they converge on a common pathological hub that involves NMDA receptor hypofunction and oxidative stress. These factors have been separately linked to schizophrenia pathogenesis, but evidence now suggests that they are mechanistically interdependent and contribute to a common schizophrenia-associated pathology.
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              Beyond the role of glutamate as a neurotransmitter.

              Glutamate is the principal excitatory neurotransmitter of the central nervous system, but many studies have expanded its functional repertoire by showing that glutamate receptors are present in a variety of non-excitable cells. How does glutamate receptor activation modulate their activity? Do non-excitable cells release glutamate, and, if so, how? These questions remain enigmatic. Here, we review the current knowledge on glutamatergic signalling in non-neuronal cells, with a special emphasis on astrocytes.
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                Author and article information

                Journal
                mBio
                MBio
                mbio
                mbio
                mBio
                mBio
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2150-7511
                27 June 2017
                May-Jun 2017
                : 8
                : 3
                : e00916-17
                Affiliations
                [1]Department of Biological Sciences, and Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, Indiana, USA
                Author notes
                Address correspondence to Richard J. Kuhn, kuhnr@ 123456purdue.edu .
                Article
                mBio00916-17
                10.1128/mBio.00916-17
                5487734
                28655823
                d87993cc-f95a-43e2-afa3-af9befb32300
                Copyright © 2017 Sirohi and Kuhn.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 30 May 2017
                : 2 June 2017
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 12, Pages: 6, Words: 3272
                Funding
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) https://doi.org/10.13039/100000060
                Award ID: R01AI073755
                Award Recipient : Richard J. Kuhn
                Categories
                Commentary
                Custom metadata
                May/June 2017

                Life sciences
                zika virus,antiviral agents,neurodegeneration,nmdar,memantine
                Life sciences
                zika virus, antiviral agents, neurodegeneration, nmdar, memantine

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