Transient increase of interleukin-1β after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling

Bo Feng; Yangshun Tang; Bin Chen; Cenglin Xu; Yi Wang; Yunjian Dai; Dengchang Wu; Junmin Zhu; Shuang Wang; Yudong Zhou; Liyun Shi; Weiwei Hu; Xia Zhang; Zhong Chen

doi:10.1038/srep21931

Transient increase of interleukin-1β after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling

Sci Rep. 2016 Feb 23:6:21931. doi: 10.1038/srep21931.

Authors

Bo Feng¹, Yangshun Tang¹, Bin Chen¹, Cenglin Xu¹, Yi Wang¹, Yunjian Dai¹, Dengchang Wu^{1

2}, Junmin Zhu³, Shuang Wang³, Yudong Zhou¹, Liyun Shi⁴, Weiwei Hu¹, Xia Zhang⁵, Zhong Chen^{1

2

3}

Affiliations

¹ Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Zhejiang University, 310058, China.
² Department of Neurology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University, China.
³ Epilepsy Center, Department of Neurology, Second Affiliated Hospital, Zhejiang University, China.
⁴ Department of Basic Medical Science, Hangzhou Normal University, Hangzhou, China.
⁵ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics*
Animals
Benzoxazines / pharmacology
Cannabinoid Receptor Antagonists / pharmacology
Cyclohexanones / pharmacology
Gene Expression Regulation
Hippocampus / metabolism
Hippocampus / pathology
Humans
Interleukin 1 Receptor Antagonist Protein / antagonists & inhibitors
Interleukin 1 Receptor Antagonist Protein / genetics*
Interleukin 1 Receptor Antagonist Protein / metabolism
Interleukin-1beta / antagonists & inhibitors
Interleukin-1beta / genetics*
Interleukin-1beta / metabolism
Lipoprotein Lipase / antagonists & inhibitors
Lipoprotein Lipase / genetics
Lipoprotein Lipase / metabolism
Mice
Mice, Knockout
Morpholines / pharmacology
Naphthalenes / pharmacology
Piperidines / pharmacology
Pyrazoles / pharmacology
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Rats, Sprague-Dawley
Receptor, Cannabinoid, CB1 / antagonists & inhibitors
Receptor, Cannabinoid, CB1 / genetics*
Receptor, Cannabinoid, CB1 / metabolism
Rimonabant
Seizures / genetics*
Seizures / metabolism
Seizures / pathology
Seizures / physiopathology
Seizures, Febrile / genetics*
Seizures, Febrile / metabolism
Seizures, Febrile / pathology
Seizures, Febrile / physiopathology
Signal Transduction
Tissue Culture Techniques

Substances

Benzoxazines
Cannabinoid Receptor Antagonists
Cyclohexanones
IL1B protein, mouse
Il1rn protein, mouse
Interleukin 1 Receptor Antagonist Protein
Interleukin-1beta
Morpholines
Naphthalenes
Piperidines
Pyrazoles
RNA, Small Interfering
Receptor, Cannabinoid, CB1
(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
1,6-bis(cyclohexyloximinocarbonyl)hexane
Lipoprotein Lipase
Rimonabant