Activation of neuronal N-methyl-d-aspartate receptor plays a pivotal role in Japanese encephalitis virus-induced neuronal cell damage

Abstract

BackgroundOverstimulation of glutamate receptors, especially neuronal N-methyl-d-aspartate receptor (NMDAR), mediates excitatory neurotoxicity in multiple neurodegenerative diseases. However, the role of NMDAR in the regulation of Japanese encephalitis virus (JEV)-mediated neuropathogenesis remains undisclosed. The primary objective of this study was to understand the function of NMDAR to JEV-induced neuronal cell damage and inflammation in the central nervous system.MethodsThe effect of JEV-induced NMDAR activation on the progression of Japanese encephalitis was evaluated using the primary mouse neuron/glia cultures and a mouse model of JEV infection. A high-affinity NMDAR antagonist MK-801 was employed to block the activity of NMDAR both in vitro and in vivo. The subsequent impact of NMDAR blockade was assessed by examining the neuronal cell death, glutamate and inflammatory cytokine production, and JEV-induced mice mortality.ResultsJEV infection enhanced the activity of NMDAR which eventually led to increased neuronal cell damage. The data obtained from our in vitro and in vivo assays demonstrated that NMDAR blockade significantly abrogated the neuronal cell death and inflammatory response triggered by JEV infection. Moreover, administration of NMDAR antagonist protected the mice from JEV-induced lethality.ConclusionNMDAR plays an imperative role in regulating the JEV-induced neuronal cell damage and neuroinflammation. Thus, NMDAR targeting may constitute a captivating approach to rein in Japanese encephalitis.

Pathogenicity and virulence of Japanese encephalitis virus: Neuroinflammation and neuronal cell damage

“…Alternatively, the production of ROS and the stimulation of ASK1/ERK1/p38-MAPK pathway in infected cells is also linked to the NS4B-NS3-induced mitochondrion-dependent apoptosis [ 54 , 56 ]. The activation/phosphorylation of NMDAR is also observed as a pathogenic mechanism during JEV of cultured neurons and mice brain tissues, resulting in increased calcium ion influx in infected neurons and enhanced neuronal toxicity [ 46 ].

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Host Calcium Channels and Pumps in Viral Infections

“…Anyway, the blockade of NMDAr may be a viable treatment for patients at risk for Zika infection-induced neurodegeneration [59]. NMDAr blockade also significantly abrogated neuronal cell death and inflammatory response triggered by JEV infection [60]. Therefore, NMDAr are probably common attack targets of flavivirus, inducing host neuron cell death.…”

Low-pathogenic virus induced immunity against TBEV protects mice from disease but not from virus entry into the CNS

“…However, it is not clear if the observed neuronal damage represents a direct effect of virus infection or a secondary consequence of inflammation. It has been shown for other flaviviruses that infection and virus replication can trigger apoptosis and necrosis in neurons (19,(35)(36)(37)(38)(39)(40). Similarly, inflammation as a consequence of neuroinfection can also caus substantial neuronal loss (41,42).…”