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

Fei Wang1, Yu Wang1, Qing-yang Zhang1, Ke-yu Hu1, Ying-jie Song1, Lin Yang1, Fan Fei1, Ceng-lin Xu1, Sun-liang Cui2, Ye-ping Ruan1, Yi Wang1,2, Zhong Chen1,2
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
Correspondence to: Yi Wang:, Zhong Chen:,
DOI: 10.1038/s41401-024-01257-0
Received: 15 November 2023
Accepted: 29 February 2024
Advance online: 21 March 2024


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-1β pathway. 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.
Keywords: status epilepticus; diazepam; caspase-1 inhibitor; therapeutic time window; glutamatergic synaptic transmission

Article Options

Download Citation

Cited times in Scopus