N-Methyl-d-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection

mBio

Giselle Foureaux¹  Celso M. Queiroz-Junior¹  Anderson J. Ferreira¹  Julia Maria S. Araújo²  Fabiana S. Machado³  Juliana L. Del Sarto³  Mauro M. Teixeira³  Allysson Cramer³  Vivian V. Costa³  Rebeca F. Rocha³  Danielle G. Souza³  Rafael E. Marques³  Lucas S. Ribeiro³  Helder I. Nakaya⁴  Isabella G. Olmo⁵  Flavia R. Silva⁵  Ana Luíza C. V. Real⁵  Juliana G. Doria⁵  Fabiola M. Ribeiro⁵  Antônio C. de Oliveira⁶  Antônio L. Teixeira⁷  Silvia I. Sardi⁸ 

[1] Cardiac Biology Lab, Department of Morphology, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil;Host-Interaction Microorganism Lab, Department of Microbiology, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil;Immunopharmacology Lab, Department of Biochemistry and Immunology, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil;Metabolomics Applied to Health Lab, Department of Clinical Analyses and Toxicology, School of Pharmaceutical Science, Universidade de Sao Paulo (USP), Sao Paulo, Brazil;Neurobiochemistry Lab, Department of Biochemistry and Immunology, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil;Neuropharmacology Lab, Department of Pharmacology, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil;Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical Houston, University of Texas Health Science Center at Houston, Houston, Texas, USA;Virology Lab, Department of Virology, Universidade Federal da Bahia (UFBA), Salvador, Bahia, Brazil;

关键词: NMDA receptor;    Zika virus;    intraocular pressure;    memantine;    microgliosis;    mouse model;   

DOI  :  10.1128/mBio.00350-17

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown