{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:27:36Z","timestamp":1786976856986,"version":"build-2736575974"},"reference-count":55,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T00:00:00Z","timestamp":1628640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we examined the role of subicular caspase\u20101, a key neural pro\u2010inflammatory enzyme, in pharmacoresistant TLE.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found that the expression of activated caspase\u20101 in the subiculum, but not the CA1, was upregulated in pharmacoresistant amygdaloid\u2010kindled rats. Early overexpression of caspase\u20101 in the subiculum was sufficient to induce pharmacoresistant TLE in rats, whereas genetic ablation of caspase\u20101 interfered with the genesis of pharmacoresistant TLE in both kindled rats and kainic acid\u2010treated mice. The pro\u2010pharmacoresistance effect of subicular caspase\u20101 was mediated by its downstream inflammasome\u2010dependent interleukin\u20101\u03b2. Further electrophysiological results showed that inhibiting caspase\u20101 decreased the excitability of subicular pyramidal neurons through influencing the excitation\/inhibition balance of presynaptic input. Importantly, a small molecular caspase\u20101 inhibitor CZL80 attenuated seizures in pharmacoresistant TLE models, and decreased the neuronal excitability in the brain slices obtained from patients with pharmacoresistant TLE.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>These results support the subicular caspase\u20101\u2010interleukin\u20101\u03b2 inflammatory pathway as a novel alternative mechanism hypothesis for pharmacoresistant TLE, and present caspase\u20101 as a potential target. ANN NEUROL 2021;90:377\u2013390<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.26173","type":"journal-article","created":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T00:25:17Z","timestamp":1626827117000},"page":"377-390","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Subicular Caspase\u20101 Contributes to Pharmacoresistance in Temporal Lobe Epilepsy"],"prefix":"10.1002","volume":"90","author":[{"given":"Cenglin","family":"Xu","sequence":"first","affiliation":[{"name":"Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Gong","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiazhen","family":"Nao","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Shen","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Tan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuheng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmachemistry, College of Pharmaceutical Sciences Zhejiang 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":"Yeping","family":"Ruan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Wang","sequence":"additional","affiliation":[{"name":"Epilepsy Center, Second Affiliated Hospital, School of Medicine Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences Zhejiang Chinese Medical University  Hangzhou China"},{"name":"Institute of Pharmacology and Toxicology, 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":"Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences Zhejiang Chinese Medical University  Hangzhou China"},{"name":"Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences Zhejiang University  Hangzhou China"},{"name":"Epilepsy Center, Second Affiliated Hospital, School of Medicine Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,11]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200002033420503"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2009.02397.x"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2005.54904.x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2019.107790"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2019.07.031"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.120.019539"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2017.00301"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25554"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.06.004"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0217-x"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.01.040"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-014-0233-0"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-014-0212-5"},{"key":"e_1_2_8_15_1","first-page":"43","article-title":"ICE\/caspase 1 inhibitors and IL\u20101beta receptor antagonists as potential therapeutics in epilepsy","volume":"11","author":"Vezzani A","year":"2010","journal-title":"Curr Opin Investig Drugs"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-016-0727-z"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0b013e3282f36ccd"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474-4422(02)00073-x"},{"key":"e_1_2_8_19_1","first-page":"483","article-title":"Kindling as a model of drug\u2010resistant partial epilepsy: selection of phenytoin\u2010resistant and nonresistant rats","volume":"258","author":"Loscher W","year":"1991","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15076"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2012.05.011"},{"key":"e_1_2_8_22_1","volume-title":"The rat brain in stereotaxic coordinates","author":"Paxinos G","year":"2007"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0013-4694(72)90177-0"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14648-8"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2019.11.014"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(00)00194-7"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.11.014"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2019"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2013.10.011"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2016.06.007"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2014.11.008"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.01170.2003"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-14-05833.2002"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12191"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000031792.89992.EC"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2003.02710.x"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1192-7"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep21931"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1960"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1535-7511.2005.00049.x"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2017.08.018"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2021.102029"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1515\/revneuro-2020-0091"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(200005)47:5<571::AID-ANA3>3.0.CO;2-A"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-011-0039-z"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-020-00482-x"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2017.07.014"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4126"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1430"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0b013e32833735b5"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2019.05.010"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2017.08.039"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-018-8971-z"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10473"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1769-10.2010"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3008065"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.26173","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ana.26173","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.26173","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T00:51:49Z","timestamp":1692233509000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.26173"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,11]]},"references-count":55,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,9]]}},"alternative-id":["10.1002\/ana.26173"],"URL":"https:\/\/doi.org\/10.1002\/ana.26173","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,11]]},"assertion":[{"value":"2021-01-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-07-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-08-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}