title: Blocking GluN2B subunits reverses the enhanced seizure susceptibility after prolonged febrile seizures with a wide therapeutic time-window.
abstract: Febrile seizures (FSs), the most common type of convulsive events in infants, are closely associated with temporal lobe epilepsy (TLE) in adulthood. It is urgent to investigate how FSs promote epileptogenesis and find the potential therapeutic targets. In the present study, we showed that the phosphorylation of GluN2B Tyr1472 gradually reached peak level at 24h after prolonged FSs and remained elevated during 7days thereafter. IL-1β treatment alone, which in previous study mimicked the effect of prolonged FSs on adult seizure susceptibility, increased GluN2B Tyr1472 phosphorylation. Both IL-1 receptor antagonist (IL-1Ra) and IL-1R1 deletion were sufficient to reverse the prolonged FSs induced hyper-phosphorylation of GluN2B Tyr1472. GluN2B antagonist ifenprodil showed a wide therapeutic time-window (3days) to reverse the enhanced seizure susceptibility after prolonged FSs or IL-1β treatment. Our study demonstrated that GluN2B phosphorylation at Tyr1472 site mediated by the transient increase of IL-1β was involved in the enhanced adult seizure susceptibility after prolonged FSs, implicating GluN2B-containing NMDAR is a new potential drug target with a wide therapeutic time window to prevent epileptogenesis in patients with infantile FSs.
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yangshun
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: You
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Hou
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address: huww@zju.edu.cn.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China; Epilepsy Center, Department of Neurology, Second Affiliated Hospital, Zhejiang University, Hangzhou, China. Electronic address: chenzhong@zju.edu.cn.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000378:metabolism*; D004597:Electroshock / Q000009:adverse effects; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000627:therapeutic use; D007608:Kainic Acid / Q000633:toxicity; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010880:Piperidines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D003294:Seizures, Febrile / Q000209:etiology / Q000378:metabolism / Q000628:therapy*
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C583355:IL1R1 protein, mouse; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C121001:NR2B NMDA receptor; D010880:Piperidines; D053573:Receptors, Interleukin-1 Type I; D016194:Receptors, N-Methyl-D-Aspartate; C010739:ifenprodil; D007608:Kainic Acid
keywords: Febrile seizures; GluN2B; IL-1β; Ifenprodil; Seizure susceptibility