浙江中医药大学Zhong Chen等研究人员合作发现，小分子caspase-1抑制剂CZL80通过抑制谷氨酸能传导终止难治性癫痫持续状态。相关论文于2024年3月21日发表在《中国药理学报》上。

研究人员重点研究了抑制caspase-1的小分子CZL80在癫痫持续状态（SE）终止中的治疗潜力及其相关机制。研究人员发现，安定的延迟治疗（0.5 h）很容易引起红藻氨酸（KA）诱导的SE产生耐药性。CZL80剂量依赖性地终止了安定抗性SE，将治疗时间窗延长至SE后的3小时，同时还保护了神经元免受损伤。有趣的是，CZL80对SE终止的作用与模型有关，在毛果芸香碱诱导的SE中无效就是证明。

此外，研究人员还发现，CZL80不能终止Caspase-1^-/-小鼠中KA诱导的SE，但能部分终止IL1R1^-/-小鼠中的SE，这表明CZL80的SE终止效应依赖于caspase-1，而不是完全通过下游的IL-1β途径。此外，体内钙纤维光度法显示，CZL80能完全逆转SE中神经炎症增强的谷氨酸能传导。综上所述，这些研究结果表明，caspase-1抑制剂CZL80可通过阻断谷氨酸能传导终止安定耐药的SE。这可能对难治性SE的临床治疗具有重要意义。

据了解，SE是一种严重的、往往危及生命的紧急医疗状况，其特点是异常延长的癫痫发作。目前的一线抗癫痫药物无法有效控制这种情况，如果不及时治疗，很容易产生耐药性。

附：英文原文

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

Author: 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

Issue&Volume: 2024-03-21

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 (0.5h) easily induces resistance in kainic acid (KA)-induced SE. CZL80 dose-dependently terminated diazepam-resistant SE, extending the therapeutic time window to 3h 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.

DOI: 10.1038/s41401-024-01257-0

Source: https://www.nature.com/articles/s41401-024-01257-0