Small-molecule caspase-1 inhibitor CZL80 terminates refractory status epilepticus via inhibition of glutamatergic transmission  

作　　者：Fei Wang Yu Wang Qing-yang Zhang Ke-yu Hu Ying-jie Song Lin Yang Fan Fei Ceng-lin Xu Sun-liang Cui Ye-ping Ruan Yi Wang Zhong Chen 

机构地区：[1]Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province,Department of Neurology,The First Affiliated Hospital,School of Pharmaceutical Sciences,Zhejiang Chinese Medical University,Hangzhou,310053,China [2]Key Laboratory of Medical Neurobiology of The Ministry of Health of China,College of Pharmaceutical Sciences,School of Medicine,Zhejiang University,Hangzhou,310058,China

出　　处：《Acta Pharmacologica Sinica》2024年第7期1381-1392,共12页中国药理学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China (82330116 and 82022071);the Natural Science Foundation of Zhejiang Province (LD22H310003).

摘　　要：Status epilepticus(SE),a serious and often life-threatening medical emergency,is characterized by abnormally prolonged seizures.It is not effectively managed by present first-line anti-seizure medications and could readily develop into drug resistance without timely treatment.In this study,we highlight the therapeutic potential of CZL80,a small molecule that inhibits caspase-1,in SE termination and its related mechanisms.We found that delayed treatment of diazepam(0.5 h)easily induces resistance in kainic acid(KA)-induced SE.CZL80 dose-dependently terminated diazepam-resistant SE,extending the therapeutic time window to 3 h following SE,and also protected against neuronal damage.Interestingly,the effect of CZL80 on SE termination was model-dependent,as evidenced by ineffectiveness in the pilocarpine-induced SE.Further,we found that CZL80 did not terminate KA-induced SE in Caspase-1^(-/-)mice but partially terminated SE in IL1R1^(-/-)mice,suggesting the SE termination effect of CZL80 was dependent on the caspase-1,but not entirely through the downstream IL-1βpathway.Furthermore,in vivo calcium fiber photometry revealed that CZL80 completely reversed the neuroinflammation-augmented glutamatergic transmission in SE.Together,our results demonstrate that caspase-1 inhibitor CZL80 terminates diazepam-resistant SE by blocking glutamatergic transmission.This may be of great therapeutic significance for the clinical treatment of refractory SE.

关 键 词：status epilepticus DIAZEPAM caspase-1 inhibitor therapeutic time window glutamatergic synaptic transmission 

分 类 号：R96[医药卫生—药理学]