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

• Published in: Acta pharmacologica Sinica Vol. 45; no. 7; pp. 1381 - 1392
• Main Authors: Wang, Fei, Wang, Yu, Zhang, Qing-yang, Hu, Ke-yu, Song, Ying-jie, Yang, Lin, Fei, Fan, Xu, Ceng-lin, Cui, Sun-liang, Ruan, Ye-ping, Wang, Yi, Chen, Zhong
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.07.2024; Nature Publishing Group
• Subjects: Acids; Animals; Anticonvulsants - pharmacology; Anticonvulsants - therapeutic use; Biomedical and Life Sciences; Biomedicine; Caspase 1 - metabolism; Caspase Inhibitors - pharmacology; Caspase Inhibitors - therapeutic use; Caspase-1; Convulsions & seizures; Cytokines; Diazepam; Diazepam - pharmacology; Diazepam - therapeutic use; Drug resistance; Epilepsy; Glutamatergic transmission; Glutamic Acid - metabolism; Immunology; Internal Medicine; Kainic acid; Kainic Acid - pharmacology; Laboratory animals; Life sciences; Male; Medical Microbiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurosciences; Peptides; Pharmaceutical sciences; Pharmacology/Toxicology; Photometry; Pilocarpine; Seizures; Status Epilepticus - drug therapy; Synaptic Transmission - drug effects; Vaccine; status epilepticus; caspase-1 inhibitor; therapeutic time window; diazepam; glutamatergic synaptic transmission
• ISSN: 1671-4083; 1745-7254; 1745-7254
• DOI: 10.1038/s41401-024-01257-0

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.