TY  - JOUR
AU  - Costa, Vivian V.
AU  - Del Sarto, Juliana L.
AU  - Rocha, Rebeca F.
AU  - Silva, Flavia R.
AU  - Doria, Juliana G.
AU  - Olmo, Isabella G.
AU  - Marques, Rafael E.
AU  - Queiroz-Junior, Celso M.
AU  - Foureaux, Giselle
AU  - Araújo, Julia Maria S.
AU  - Cramer, Allysson
AU  - Real, Ana Luíza C. V.
AU  - Secchim Ribeiro, Lucas
AU  - Sardi, Silvia I.
AU  - Ferreira, Anderson J.
AU  - Machado, Fabiana S.
AU  - de Oliveira, Antônio C.
AU  - Teixeira, Antônio L.
AU  - Nakaya, Helder I.
AU  - Souza, Danielle G.
AU  - Ribeiro, Fabiola M.
AU  - Teixeira, Mauro M.
TI  - N -Methyl- d -Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection
JO  - mBio
VL  - 8
IS  - 2
SN  - 2161-2129
CY  - Washington, DC
PB  - American Society for Microbiology
M1  - DZNE-2026-00098
SP  - e00350-17
PY  - 2017
AB  - 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.
KW  - Animals
KW  - Disease Models, Animal
KW  - Mice
KW  - Neurodegenerative Diseases: drug therapy
KW  - Neurodegenerative Diseases: pathology
KW  - Neuroprotective Agents: administration & dosage
KW  - Receptors, N-Methyl-D-Aspartate: antagonists & inhibitors
KW  - Treatment Outcome
KW  - Zika Virus: growth & development
KW  - Zika Virus Infection: complications
KW  - Zika Virus Infection: pathology
KW  - NMDA receptor (Other)
KW  - Zika virus (Other)
KW  - intraocular pressure (Other)
KW  - memantine (Other)
KW  - microgliosis (Other)
KW  - mouse model (Other)
KW  - neuronal death (Other)
KW  - Neuroprotective Agents (NLM Chemicals)
KW  - Receptors, N-Methyl-D-Aspartate (NLM Chemicals)
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1128/mBio.00350-17
UR  - https://pub.dzne.de/record/284090
ER  -