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Inflammatory processes have been implicated in the pathophysiology of epilepsy. However, whether caspase\u20101 is involved in FS generation and could be a target for the treatment of FS is still unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>By using pharmacological and gene intervention methods in C57BL\/6J mice, we assessed the role of caspase\u20101 in FS generation. We used structural virtual screening against the active site of caspase\u20101, to screen compounds for druggable and safe low MW inhibitors of caspase\u20101 in vitro. One compound was chosen to test in vivo for therapeutic potential, using FS models in neonatal mice and epileptogenesis in adult mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In mice, levels of cleaved caspase\u20101 increased prior to FS onset.<jats:italic>Caspase\u20101<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>mice were resistant to FS and showed lower neuronal excitability than wild\u2010type littermates. Conversely, overexpression of caspase\u20101 using<jats:italic>in utero<\/jats:italic>electroporation increased neuronal excitability and enhanced susceptibility to FS. The structural virtual screening, using molecular docking approaches for the active site of caspase\u20101 of over 1 million compounds yielded CZL80, a brain\u2010penetrable, low MW inhibitor of caspase\u20101. In neonatal mice, CZL80 markedly reduced neuronal excitability and incidence of FS generation, and, in adult mice, relieved later enhanced epileptogenic susceptibility. CZL80 was devoid of acute diazepam\u2010like respiratory depression and chronic liver toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Caspase\u20101 is essential for FS generation. CZL80 is a promising low MW inhibitor of FS and later enhanced epileptogenic susceptibility.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15076","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T01:40:26Z","timestamp":1588124426000},"page":"3519-3534","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Structure\u2010based discovery of CZL80, a caspase\u20101 inhibitor with therapeutic potential for febrile seizures and later enhanced epileptogenic susceptibility"],"prefix":"10.1111","volume":"177","author":[{"given":"Yangshun","family":"Tang","sequence":"first","affiliation":[{"name":"Institute of Pharmacology and Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences Zhejiang University Hangzhou China"},{"name":"College of Pharmaceutical Science Zhejiang Chinese Medical University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Feng","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences Zhejiang University Hangzhou China"},{"name":"College of Pharmaceutical Science Zhejiang Chinese Medical University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyong","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmachemistry, College of Pharmaceutical Sciences Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"You","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yu","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science Zhejiang Chinese Medical University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cenglin","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeping","family":"Ruan","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science Zhejiang Chinese Medical University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunliang","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Pharmachemistry, College of Pharmaceutical Sciences Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine and Life Sciences Nanjing University of Chinese Medicine Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingjun","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Pharmachemistry, College of Pharmaceutical Sciences Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4755-9357","authenticated-orcid":false,"given":"Zhong","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences Zhejiang University Hangzhou China"},{"name":"College of Pharmaceutical Science Zhejiang Chinese Medical University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6]]},"reference":[{"issue":"1","key":"e_1_2_10_2_1","first-page":"S297","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: Enzymes","volume":"176","author":"Alexander S. 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