<italic toggle="yes">N</italic>-Methyl-<sc>d</sc>-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection

ABSTRACT Zika virus (ZIKV) infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N-methyl-d-aspartate receptor (NMDAR)-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegenera...

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Autores principales:	Vivian V. Costa, Juliana L. Del Sarto, Rebeca F. Rocha, Flavia R. Silva, Juliana G. Doria, Isabella G. Olmo, Rafael E. Marques, Celso M. Queiroz-Junior, Giselle Foureaux, Julia Maria S. Araújo, Allysson Cramer, Ana Luíza C. V. Real, Lucas S. Ribeiro, Silvia I. Sardi, Anderson J. Ferreira, Fabiana S. Machado, Antônio C. de Oliveira, Antônio L. Teixeira, Helder I. Nakaya, Danielle G. Souza, Fabiola M. Ribeiro, Mauro M. Teixeira
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	NMDA receptor Zika virus intraocular pressure memantine microgliosis mouse model Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bbf9d30cd04e4a1ab4713f7591e40595
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spelling	oai:doaj.org-article:bbf9d30cd04e4a1ab4713f7591e405952021-11-15T15:51:00Z<italic toggle="yes">N</italic>-Methyl-<sc>d</sc>-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection10.1128/mBio.00350-172150-7511https://doaj.org/article/bbf9d30cd04e4a1ab4713f7591e405952017-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00350-17https://doaj.org/toc/2150-7511ABSTRACT Zika virus (ZIKV) infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N-methyl-d-aspartate receptor (NMDAR)-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801), agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivo experiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP) induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration. IMPORTANCE Zika virus (ZIKV) infection is a global health emergency associated with serious neurological complications, including microcephaly and Guillain-Barré syndrome. Infection of experimental animals with ZIKV causes significant neuronal damage and microgliosis. Treatment with drugs that block NMDARs prevented neuronal damage both in vitro and in vivo. These results suggest that overactivation of NMDARs contributes significantly to the neuronal damage induced by ZIKV infection, and this is amenable to inhibition by drug treatment.Vivian V. CostaJuliana L. Del SartoRebeca F. RochaFlavia R. SilvaJuliana G. DoriaIsabella G. OlmoRafael E. MarquesCelso M. Queiroz-JuniorGiselle FoureauxJulia Maria S. AraújoAllysson CramerAna Luíza C. V. RealLucas S. RibeiroSilvia I. SardiAnderson J. FerreiraFabiana S. MachadoAntônio C. de OliveiraAntônio L. TeixeiraHelder I. NakayaDanielle G. SouzaFabiola M. RibeiroMauro M. TeixeiraAmerican Society for MicrobiologyarticleNMDA receptorZika virusintraocular pressurememantinemicrogliosismouse modelMicrobiologyQR1-502ENmBio, Vol 8, Iss 2 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	NMDA receptor Zika virus intraocular pressure memantine microgliosis mouse model Microbiology QR1-502
spellingShingle	NMDA receptor Zika virus intraocular pressure memantine microgliosis mouse model Microbiology QR1-502 Vivian V. Costa Juliana L. Del Sarto Rebeca F. Rocha Flavia R. Silva Juliana G. Doria Isabella G. Olmo Rafael E. Marques Celso M. Queiroz-Junior Giselle Foureaux Julia Maria S. Araújo Allysson Cramer Ana Luíza C. V. Real Lucas S. Ribeiro Silvia I. Sardi Anderson J. Ferreira Fabiana S. Machado Antônio C. de Oliveira Antônio L. Teixeira Helder I. Nakaya Danielle G. Souza Fabiola M. Ribeiro Mauro M. Teixeira <italic toggle="yes">N</italic>-Methyl-<sc>d</sc>-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection
description	ABSTRACT Zika virus (ZIKV) infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N-methyl-d-aspartate receptor (NMDAR)-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801), agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivo experiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP) induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration. IMPORTANCE Zika virus (ZIKV) infection is a global health emergency associated with serious neurological complications, including microcephaly and Guillain-Barré syndrome. Infection of experimental animals with ZIKV causes significant neuronal damage and microgliosis. Treatment with drugs that block NMDARs prevented neuronal damage both in vitro and in vivo. These results suggest that overactivation of NMDARs contributes significantly to the neuronal damage induced by ZIKV infection, and this is amenable to inhibition by drug treatment.
format	article
author	Vivian V. Costa Juliana L. Del Sarto Rebeca F. Rocha Flavia R. Silva Juliana G. Doria Isabella G. Olmo Rafael E. Marques Celso M. Queiroz-Junior Giselle Foureaux Julia Maria S. Araújo Allysson Cramer Ana Luíza C. V. Real Lucas S. Ribeiro Silvia I. Sardi Anderson J. Ferreira Fabiana S. Machado Antônio C. de Oliveira Antônio L. Teixeira Helder I. Nakaya Danielle G. Souza Fabiola M. Ribeiro Mauro M. Teixeira
author_facet	Vivian V. Costa Juliana L. Del Sarto Rebeca F. Rocha Flavia R. Silva Juliana G. Doria Isabella G. Olmo Rafael E. Marques Celso M. Queiroz-Junior Giselle Foureaux Julia Maria S. Araújo Allysson Cramer Ana Luíza C. V. Real Lucas S. Ribeiro Silvia I. Sardi Anderson J. Ferreira Fabiana S. Machado Antônio C. de Oliveira Antônio L. Teixeira Helder I. Nakaya Danielle G. Souza Fabiola M. Ribeiro Mauro M. Teixeira
author_sort	Vivian V. Costa
title	<italic toggle="yes">N</italic>-Methyl-<sc>d</sc>-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection
title_short	<italic toggle="yes">N</italic>-Methyl-<sc>d</sc>-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection
title_full	<italic toggle="yes">N</italic>-Methyl-<sc>d</sc>-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection
title_fullStr	<italic toggle="yes">N</italic>-Methyl-<sc>d</sc>-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection
title_full_unstemmed	<italic toggle="yes">N</italic>-Methyl-<sc>d</sc>-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection
title_sort	<italic toggle="yes">n</italic>-methyl-<sc>d</sc>-aspartate (nmda) receptor blockade prevents neuronal death induced by zika virus infection
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/bbf9d30cd04e4a1ab4713f7591e40595
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<italic toggle="yes">N</italic>-Methyl-<sc>d</sc>-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection

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