title: Interleukin-1 receptor is a target for adjunctive control of diazepam-refractory status epilepticus in mice.
abstract: Proinflammatory cytokine interleukin-1 beta (IL-1β) may accumulate in the brain during status epilepticus, but whether it contributes to the progressive refractoriness of SE remains unclear. By using a kainic acid-induced SE mice model, we tested whether pharmacological blockade or knock-out of interleukin-1 receptor type 1 (IL-1R1) could influence the diazepam-refractory phenomenon of prolonged SE. We confirmed diazepam failed to terminate prolonged SE (allowed to continue for 40min before diazepam administration). The expression level of IL-1β in the hippocampus during prolonged SE was significantly higher than that of baseline. Interestingly, prolonged SE was not diazepam-refractory in IL-1R1 knock-out mice. Moreover, administration of interleukin-1 receptor antagonist (IL-1RA) combined with diazepam terminated established prolonged SE, while IL-1RA alone is not capable to terminate prolonged SE. On the contrary, administration of recombinant human IL-1β weakens the efficacy of diazepam by prolonging its latency to terminate non-prolonged SE. Thus, the present study provides direct evidence that accumulated IL-1β contributed to the diazepam refractoriness of prolonged SE, and suggests that interleukin-1 receptor is a target for adjunctive control of diazepam-refractory SE.
authors.affiliation: Laboratory of Brain Function and Disease in Chinese Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
authors.forename: Zheng-Hao
authors.initials: ZH
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 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, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: An-Feng
authors.initials: AF
authors.lastname: Tao
authors.affiliation: Laboratory of Brain Function and Disease in Chinese Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Laboratory of Brain Function and Disease in Chinese Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Laboratory of Brain Function and Disease in Chinese Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
authors.forename: Yun-Yun
authors.initials: YY
authors.lastname: Zu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Shi-Hong
authors.initials: SH
authors.lastname: Zhang
authors.affiliation: Laboratory of Brain Function and Disease in Chinese Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China; Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: chenzhong@zju.edu.cn.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D004195:Disease Models, Animal; D000069279:Drug Resistant Epilepsy / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D007608:Kainic Acid; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D053573:Receptors, Interleukin-1 Type I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D013226:Status Epilepticus / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000927:Anticonvulsants; C508585:IL1B protein, human; C587672:IL1B protein, mouse; C583355:IL1R1 protein, mouse; D053583:Interleukin-1beta; D053573:Receptors, Interleukin-1 Type I; D011994:Recombinant Proteins; D003975:Diazepam; D007608:Kainic Acid
keywords: diazepam; epilepsy; interleukin-1 beta; interleukin-1 receptor; neuroinflammation; status epilepticus