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

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

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.

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Fig. 1: CZL80 effectively terminates diazepam-resistant SE.
Fig. 2: CZL80 effectively terminates diazepam-resistant SE with the extended therapeutic window.
Fig. 3: CZL80 relieves the neuron loss after SE.
Fig. 4: CZL80 does not terminate SE in Casp1−/− mice.
Fig. 5: CZL80 partially terminates SE in IL1R1−/− mice.
Fig. 6: CZL80 inhibits the enhanced glutamatergic transmission during SE.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This project was supported by grants from the National Natural Science Foundation of China (82330116 and 82022071), and the Natural Science Foundation of Zhejiang Province (LD22H310003).

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  1. These authors contributed equally: Fei Wang, Yu Wang, Qing-yang Zhang

Authors and Affiliations

  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

    Fei Wang, Yu Wang, Qing-yang Zhang, Ke-yu Hu, Ying-jie Song, Lin Yang, Fan Fei, Ceng-lin Xu, Ye-ping Ruan, Yi Wang & Zhong Chen

  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

    Sun-liang Cui, Yi Wang & Zhong Chen

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Contributions

The main idea of this study was from ZC and Yi W. FW, Yu W, QYZ, KYH, and YJS conducted the experiments. FW, Yu W, and Yi W conducted the data analysis. LY, FF, CLX, SLC, and YPR provided technical guidance and contributed to the data discussion. FW, Yu W, and Yi W wrote the manuscript. Yi W and ZC supervised all aspects of the work.

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Correspondence to Yi Wang or Zhong Chen.

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Wang, F., Wang, Y., Zhang, Qy. et al. Small-molecule caspase-1 inhibitor CZL80 terminates refractory status epilepticus via inhibition of glutamatergic transmission. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01257-0

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