PMID- 30144801 OWN - NLM STAT- MEDLINE DCOM- 20181123 LR - 20181123 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 15 IP - 1 DP - 2018 Aug 25 TI - Activation of neuronal N-methyl-D-aspartate receptor plays a pivotal role in Japanese encephalitis virus-induced neuronal cell damage. PG - 238 LID - 10.1186/s12974-018-1280-8 [doi] LID - 238 AB - BACKGROUND: Overstimulation 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. METHODS: The 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. RESULTS: JEV 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. CONCLUSION: NMDAR 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. FAU - Chen, Zheng AU - Chen Z AD - State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, People's Republic of China. FAU - Wang, Xugang AU - Wang X AD - State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, People's Republic of China. FAU - Ashraf, Usama AU - Ashraf U AD - State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, People's Republic of China. FAU - Zheng, Bohan AU - Zheng B AD - State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, People's Republic of China. FAU - Ye, Jing AU - Ye J AD - State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. yej@webmail.hzau.edu.cn. AD - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. yej@webmail.hzau.edu.cn. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, People's Republic of China. yej@webmail.hzau.edu.cn. FAU - Zhou, Dengyuan AU - Zhou D AD - State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, People's Republic of China. FAU - Zhang, Hao AU - Zhang H AD - State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, People's Republic of China. FAU - Song, Yunfeng AU - Song Y AD - State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, People's Republic of China. FAU - Chen, Huanchun AU - Chen H AD - State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, People's Republic of China. FAU - Zhao, Shuhong AU - Zhao S AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, People's Republic of China. AD - Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education, Huazhong Agricultural University, Wuhan, China. FAU - Cao, Shengbo AU - Cao S AD - State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. sbcao@mail.hzau.edu.cn. AD - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, People's Republic of China. sbcao@mail.hzau.edu.cn. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, People's Republic of China. sbcao@mail.hzau.edu.cn. LA - eng GR - 31502065/the National Natural Science Foundation of China/ GR - 31572517/the National Natural Science Foundation of China/ GR - 2017YFD0501800/the National Key Research and Development Program of China/ GR - 2016YFD0500407/the National Key Research and Development Program of China/ GR - 2013PY051, 2662016Q003, and 2662015PY083/the Fundamental Research Funds for the Central Universities/ PT - Journal Article DEP - 20180825 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Annexin A5) RN - 0 (Cytokines) RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 6LR8C1B66Q (Dizocilpine Maleate) RN - EC 3.4.22.- (Caspase 3) RN - EC 4.2.1.11 (Phosphopyruvate Hydratase) SB - IM MH - Animals MH - Annexin A5/metabolism MH - Caspase 3/metabolism MH - Cell Survival/drug effects MH - Cells, Cultured MH - Cytokines/genetics/metabolism MH - Disease Models, Animal MH - Dizocilpine Maleate/therapeutic use MH - Embryo, Mammalian MH - Encephalitis Virus, Japanese/*pathogenicity MH - Encephalitis, Japanese/drug therapy/*pathology MH - Excitatory Amino Acid Antagonists/therapeutic use MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Neuroglia/drug effects/metabolism/pathology MH - Neurons/*metabolism/pathology/virology MH - Phosphopyruvate Hydratase/metabolism MH - Phosphorylation/drug effects MH - Receptors, N-Methyl-D-Aspartate/*metabolism PMC - PMC6109458 OTO - NOTNLM OT - Activation OT - JEV OT - MK-801 OT - NMDAR OT - Neuronal death COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All animal experiments were performed in accordance with the National Institutes of Health's Guide for the Care and Use of Laboratory Animals, and the experimental protocols were approved by the Research Ethics Committee of the College of Veterinary Medicine, Huazhong Agricultural University, Hubei, Wuhan, China. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/08/27 06:00 MHDA- 2018/11/24 06:00 PMCR- 2018/08/25 CRDT- 2018/08/27 06:00 PHST- 2018/04/20 00:00 [received] PHST- 2018/08/15 00:00 [accepted] PHST- 2018/08/27 06:00 [entrez] PHST- 2018/08/27 06:00 [pubmed] PHST- 2018/11/24 06:00 [medline] PHST- 2018/08/25 00:00 [pmc-release] AID - 10.1186/s12974-018-1280-8 [pii] AID - 1280 [pii] AID - 10.1186/s12974-018-1280-8 [doi] PST - epublish SO - J Neuroinflammation. 2018 Aug 25;15(1):238. doi: 10.1186/s12974-018-1280-8.