PMID- 32107753 OWN - NLM STAT- MEDLINE DCOM- 20210621 LR - 20210621 IS - 1573-6830 (Electronic) IS - 0272-4340 (Linking) VI - 40 IP - 8 DP - 2020 Nov TI - Inhibition of NMDA Receptors Downregulates Astrocytic AQP4 to Suppress Seizures. PG - 1283-1295 LID - 10.1007/s10571-020-00813-6 [doi] AB - Aquaporin 4 (AQP4), a water-specific channel protein locating on the astrocyte membrane, has been found to be antagonist, agonist and undergone closely related to epilepsy. Our previous study showed that inhibition of an N-methyl-D-aspartate receptor (NMDAR) subunit NR2A can suppress epileptic seizures, suggesting that AQP4 is potentially involved in NR2A-mediated epilepsy treatment. In this study, we aimed to explore the relevance of AQP4 in NR2A-mediated seizures treatment in pentylenetetrazol (PTZ)-induced rat models. We performed electroencephalogram (EEG) recording and examined AQP4 expression at mRNA and protein levels, and the downstream molecules of AQP4 as well. It showed that AQP4 expression was increased after the induction of seizures. Lateral ventricle pretreatment of NR2A inhibitor could mitigate the PTZ-induced seizures severity and counterbalance the increase of AQP4 expression. In contrast, NR2A activator that resulted in seizures aggravation could further augment the seizure-related elevations of AQP4 expression. Pharmacological inhibition of AQP4 alone could also suppress the PTZ-induced seizure activities, with decreased expressions of NF-kappaB p65, interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha in the brain. The results indicated that increased expression of AQP4 might be an important mechanism involved in NR2A of NMDAR-mediated treatment for epileptic seizures, enlightening a potentially new target for seizures treatment. FAU - Lei, Shuisheng AU - Lei S AD - Department of Physiology, Key Laboratory of Neuroscience, School of Basic Medical Sciences, Department of Dermatology, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. FAU - He, Yan AU - He Y AD - Department of Physiology, Key Laboratory of Neuroscience, School of Basic Medical Sciences, Department of Dermatology, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. FAU - Zhu, Ziting AU - Zhu Z AD - Department of Physiology, Key Laboratory of Neuroscience, School of Basic Medical Sciences, Department of Dermatology, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. AD - Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China. FAU - Liu, Zhongrui AU - Liu Z AD - Department of Physiology, Key Laboratory of Neuroscience, School of Basic Medical Sciences, Department of Dermatology, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. FAU - Lin, Yuwan AU - Lin Y AD - Department of Physiology, Key Laboratory of Neuroscience, School of Basic Medical Sciences, Department of Dermatology, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. AD - Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China. FAU - He, Yuehua AU - He Y AD - Department of Physiology, Key Laboratory of Neuroscience, School of Basic Medical Sciences, Department of Dermatology, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. FAU - Du, Sheng AU - Du S AD - Department of Physiology, Key Laboratory of Neuroscience, School of Basic Medical Sciences, Department of Dermatology, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. FAU - Chen, Xiang AU - Chen X AD - Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China. FAU - Xu, Pingyi AU - Xu P AD - Department of Physiology, Key Laboratory of Neuroscience, School of Basic Medical Sciences, Department of Dermatology, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. pingyixu@sina.com. AD - Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China. pingyixu@sina.com. FAU - Zhu, Xiaoqin AU - Zhu X AUID- ORCID: 0000-0002-2801-1217 AD - Department of Physiology, Key Laboratory of Neuroscience, School of Basic Medical Sciences, Department of Dermatology, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. whzhuxiaoqin@163.com. LA - eng GR - 81771401/National Natural Science Foundation of China(CN)/ GR - 81870992/National Natural Science Foundation of China(CN)/ GR - 81870856/National Natural Science Foundation of China(CN)/ GR - 81603681/National Natural Science Foundation of China(CN)/ GR - U1603281/National Natural Science Foundation of China(CN)/ GR - 2020A1515010986/Natural Science Foundation of Guangdong Province of China/ GR - 2017ZC0234/Science and Technology Planning Project of Guangdong Province/ GR - 2018-1202-SF-0019/a Technology Project of Guangzhou/ PT - Journal Article DEP - 20200227 PL - United States TA - Cell Mol Neurobiol JT - Cellular and molecular neurobiology JID - 8200709 RN - 0 (Aqp4 protein, rat) RN - 0 (Aquaporin 4) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - WM5Z385K7T (Pentylenetetrazole) SB - IM MH - Animals MH - Aquaporin 4/*drug effects/metabolism MH - Astrocytes/*drug effects/*metabolism MH - Brain/drug effects/metabolism MH - Pentylenetetrazole/adverse effects/metabolism MH - Rats, Sprague-Dawley MH - Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors/metabolism MH - Seizures/*drug therapy/metabolism OTO - NOTNLM OT - Aquaporin 4 OT - Inflammation OT - NF-kappaB. OT - NMDAR OT - NR2A OT - Seizures EDAT- 2020/02/29 06:00 MHDA- 2021/06/22 06:00 CRDT- 2020/02/29 06:00 PHST- 2019/07/23 00:00 [received] PHST- 2020/02/14 00:00 [accepted] PHST- 2020/02/29 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/02/29 06:00 [entrez] AID - 10.1007/s10571-020-00813-6 [pii] AID - 10.1007/s10571-020-00813-6 [doi] PST - ppublish SO - Cell Mol Neurobiol. 2020 Nov;40(8):1283-1295. doi: 10.1007/s10571-020-00813-6. Epub 2020 Feb 27.