title: Transient increase of interleukin-1β after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling.
abstract: It remains unclear how infantile febrile seizures (FS) enhance adult seizure susceptibility. Here we showed that the transient increase of interleukin-1β (IL-1β) after prolonged FS promoted adult seizure susceptibility, which was blocked by interleukin-1 receptor antagonist (IL-1Ra) within a critical time window. Postnatal administered IL-1β alone mimicked the effect of FS on adult seizure susceptibility. IL-1R1 knockout mice were not susceptible to adult seizure after prolonged FS or IL-1β treatment. Prolonged FS or early-life IL-1β treatment increased the expression of cannabinoid type 1 receptor (CB1R) for over 50 days, which was blocked by IL-1Ra or was absent in IL-1R1 knockout mice. CB1R antagonist, knockdown and endocannabinoid synthesis inhibitor abolished FS or IL-1β-enhanced seizure susceptibility. Thus, this work identifies a pathogenic role of postnatal IL-1β/IL-1R1 pathway and subsequent prolonged prominent increase of endocannabinoid signaling in adult seizure susceptibility following prolonged FS, and highlights IL-1R1 as a potential therapeutic target for preventing the development of epilepsy after infantile FS.
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Zhejiang University, 310058, 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 Medicine, Zhejiang University, 310058, 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 Medicine, Zhejiang University, 310058, 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 Medicine, Zhejiang University, 310058, China.
authors.forename: Cenglin
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Zhejiang University, 310058, 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 Medicine, Zhejiang University, 310058, China.
authors.forename: Yunjian
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Zhejiang University, 310058, China.|Department of Neurology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University, China.
authors.forename: Dengchang
authors.initials: D
authors.lastname: Wu
authors.affiliation: Epilepsy Center, Department of Neurology, Second Affiliated Hospital, Zhejiang University, China.
authors.forename: Junmin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Epilepsy Center, Department of Neurology, Second Affiliated Hospital, Zhejiang University, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Zhejiang University, 310058, China.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Basic Medical Science, Hangzhou Normal University, Hangzhou, China.
authors.forename: Liyun
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Zhejiang University, 310058, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Hu
authors.affiliation: University of Ottawa Institute of Mental Health Research at the Royal, Department of Psychiatry, and Department of Cellular and Molecular Medicine, Ottawa K1Z 7K4, Canada.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Zhejiang University, 310058, China.|Department of Neurology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University, China.|Epilepsy Center, Department of Neurology, Second Affiliated Hospital, Zhejiang University, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D003512:Cyclohexanones / Q000494:pharmacology; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000077285:Rimonabant; D012640:Seizures / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003294:Seizures, Febrile / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D046509:Tissue Culture Techniques
chemical_list: D048588:Benzoxazines; D063387:Cannabinoid Receptor Antagonists; D003512:Cyclohexanones; C587672:IL1B protein, mouse; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; D008071:Lipoprotein Lipase; D000077285:Rimonabant