Cenglin Xu1, Shuo Zhang2, Yiwei Gong3, Jiazhen Nao3, Yujia Shen3, Bei Tan1, Shuheng Xu4, Sunliang Cui4, Yeping Ruan1, Shuang Wang5, Yi Wang1,3, Zhong Chen1,3,5. 1. Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China. 2. Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China. 3. Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. 4. Department of Pharmachemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. 5. Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Abstract
OBJECTIVE: Unidentified mechanisms largely restrict the viability of effective therapies in pharmacoresistant epilepsy. Our previous study revealed that hyperactivity of the subiculum is crucial for the genesis of pharmacoresistance in temporal lobe epilepsy (TLE), but the underlying molecular mechanism is not clear. METHODS: Here, we examined the role of subicular caspase-1, a key neural pro-inflammatory enzyme, in pharmacoresistant TLE. RESULTS: We found that the expression of activated caspase-1 in the subiculum, but not the CA1, was upregulated in pharmacoresistant amygdaloid-kindled rats. Early overexpression of caspase-1 in the subiculum was sufficient to induce pharmacoresistant TLE in rats, whereas genetic ablation of caspase-1 interfered with the genesis of pharmacoresistant TLE in both kindled rats and kainic acid-treated mice. The pro-pharmacoresistance effect of subicular caspase-1 was mediated by its downstream inflammasome-dependent interleukin-1β. Further electrophysiological results showed that inhibiting caspase-1 decreased the excitability of subicular pyramidal neurons through influencing the excitation/inhibition balance of pre-synaptic input. Importantly, a small-molecular caspase-1 inhibitor CZL80 attenuated seizures in pharmacoresistant TLE models, and decreased the neural excitability in the brain slices obtained from pharmacoresistant TLE patients. INTERPRETATION: These results support the subicular caspase-1-interleukin-1β inflammatory pathway as a novel alternative mechanism hypothesis for pharmacoresistant TLE, and present caspase-1 as a potential target. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
OBJECTIVE: Unidentified mechanisms largely restrict the viability of effective therapies in pharmacoresistant epilepsy. Our previous study revealed that hyperactivity of the subiculum is crucial for the genesis of pharmacoresistance in temporal lobe epilepsy (TLE), but the underlying molecular mechanism is not clear. METHODS: Here, we examined the role of subicular caspase-1, a key neural pro-inflammatory enzyme, in pharmacoresistant TLE. RESULTS: We found that the expression of activated caspase-1 in the subiculum, but not the CA1, was upregulated in pharmacoresistant amygdaloid-kindled rats. Early overexpression of caspase-1 in the subiculum was sufficient to induce pharmacoresistant TLE in rats, whereas genetic ablation of caspase-1 interfered with the genesis of pharmacoresistant TLE in both kindled rats and kainic acid-treated mice. The pro-pharmacoresistance effect of subicular caspase-1 was mediated by its downstream inflammasome-dependent interleukin-1β. Further electrophysiological results showed that inhibiting caspase-1 decreased the excitability of subicular pyramidal neurons through influencing the excitation/inhibition balance of pre-synaptic input. Importantly, a small-molecular caspase-1 inhibitor CZL80attenuated seizures in pharmacoresistant TLE models, and decreased the neural excitability in the brain slices obtained from pharmacoresistant TLEpatients. INTERPRETATION: These results support the subicular caspase-1-interleukin-1β inflammatory pathway as a novel alternative mechanism hypothesis for pharmacoresistant TLE, and present caspase-1 as a potential target. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.