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Published on: May 16, 2019
Small-molecule caspase-1 inhibitor CZL80 terminates refractory status epilepticus via inhibition of glutamatergic
Fei Wang1, Yu Wang1, Qing-Yang Zhang1
1Key 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.
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.
Insights
CZL80, a caspase-1 inhibitor, effectively terminates diazepam-resistant status epilepticus (SE) by reversing neuroinflammation-driven glutamatergic transmission. This offers a promising therapeutic strategy for refractory SE.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Status epilepticus (SE) is a critical neurological emergency with limited treatment options.
- Current first-line anti-seizure medications often fail, leading to drug resistance and neuronal damage.
- Timely intervention is crucial, but therapeutic windows are narrow for refractory SE.
Purpose of the Study:
- To investigate the therapeutic potential of CZL80, a novel caspase-1 inhibitor, for terminating status epilepticus (SE).
- To elucidate the mechanisms underlying CZL80's efficacy in SE, particularly in drug-resistant models.
- To assess CZL80's impact on neuroinflammation and glutamatergic transmission during SE.
Main Methods:
- Induction of status epilepticus (SE) in mouse models using kainic acid (KA) and pilocarpine.
- Administration of diazepam and the caspase-1 inhibitor CZL80 at varying time points post-SE induction.
- Assessment of SE termination, neuronal damage, and survival rates.
- Utilizing Caspase-1 knockout (Caspase-1-/-) and IL-1 receptor knockout (IL1R1-/-) mice to investigate pathway dependency.
- In vivo calcium fiber photometry to measure glutamatergic transmission and neuroinflammation.
Main Results:
- Delayed diazepam treatment induced resistance in KA-induced SE.
- CZL80 dose-dependently terminated diazepam-resistant SE, extending the therapeutic window to 3 hours and reducing neuronal damage.
- CZL80's efficacy was model-dependent, ineffective in pilocarpine-induced SE.
- SE termination by CZL80 required caspase-1 but was not solely dependent on the IL-1β pathway.
- CZL80 reversed neuroinflammation-augmented glutamatergic transmission in KA-induced SE.
Conclusions:
- CZL80 demonstrates significant therapeutic potential for terminating diazepam-resistant status epilepticus (SE).
- The mechanism involves the inhibition of caspase-1 and the reversal of neuroinflammation-induced glutamatergic hyperactivity.
- CZL80 offers a promising new avenue for treating refractory SE, potentially widening the therapeutic window.
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