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.
Highlights
Overstimulation of glutamate receptors, especially neuronal N-methyl-D-aspartate receptor (NMDAR), mediates excitatory neurotoxicity in multiple neurodegenerative diseases
The results revealed that Japanese encephalitis virus (JEV) infection significantly increased the activity of NMDAR by enhancing the phosphorylation levels of NMDAR subunits in N2a cells and mice brain tissues in a time-dependent manner (Fig. 1a, b)
The JEV-induced hyperphosphorylation of NMDAR subunits was further analyzed in primary mouse neuron/glia cultures infected with JEV
Summary
Overstimulation of glutamate receptors, especially neuronal N-methyl-D-aspartate receptor (NMDAR), mediates excitatory neurotoxicity in multiple neurodegenerative diseases. 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. JEV breaches the blood-brain barrier and subsequently invades the central nervous system (CNS), wherein virus replication induces a colossal inflammatory response and causes neuronal cell death [3]. (IL-1β), IL-6, chemokine (C-C motif ) ligand 5 (CCL5, called RANTES), and monocyte chemotactic protein 1 (MCP1, called CCL2) [4,5,6] These inflammatory and neuronal toxicity factors endorse massive leukocyte incursion into the brain and promote the death of both infected and non-infected neurons [4]. Further studies underlying the molecular mechanisms of JEV-induced neuronal death are still required
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