N -Methyl- d -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 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.

Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies

“…), or NMDA receptors (Costa et al . ). While most of these mechanistic studies have focused on cytotoxic response in proliferating NPCs, mechanisms of ZIKV‐induced neuronal apoptosis may involve similar or other mediators that act either in a cell autonomous or cell non‐autonomous manner.…”

Host Calcium Channels and Pumps in Viral Infections

“…The Zika virus infection is a "neurodegenerative" disease. Costa and colleagues showed that blockage of the NMDAr channel activity with FDA-approved memantine or other antagonists prevents neuronal cell death and microgliosis induced by Zika in vitro and in vivo, without affecting the ability of Zika to replicate in the host [58,59]. It seems that NMDAr mainly contributes to Zika, triggering the neuronal cell death progress.…”

Host-Directed Antivirals: a Realistic Alternative to Fight Zika Virus

“…In this regard, ZIKV infection leads to massive neuronal damage, especially of neural progenitor cells, and neurodegeneration [124][125][126], via both direct replication in neuronal cells and possibly through increased excitotoxicity via over activation of N-methyl-d-aspartate receptor (NMDAR)-dependent neuronal excitotoxicity in nearby cells. Memantine, a pregnancy category B FDA-approved drug widely used to treat patients with Alzheimer's disease, as well as other NMDAR blockers (dizocilpine, agmatine sulfate, or ifenprodil), prevents neuronal death without interfering with the ability of ZIKV to replicate, thwarts the increase of intraocular pressure (IOP) induced by infection, and massively reduces neurodegeneration and microgliosis in the brain of infected mice, thus providing potent neuroprotective effects against ZIKV-induced neuronal damage that might prevent and/or minimize ZIKV-related microcephaly in infected pregnant women [127]. Ebselen (EBS), an antioxidant that reduces oxidative stress and improves histopathological features in a testicular injury study model and is currently in clinical trials for various diseases, showed minor effects in reducing ZIKV progeny production and viral E protein expression and on overall survival and viremia level of challenged AG129 mice; however, the drug significantly reduced ZIKV-induced testicular oxidative stress, leucocyte infiltration, and production of pro-inflammatory response.…”