{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T21:28:19Z","timestamp":1793482099466,"version":"4.5.0"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,5,11]],"date-time":"2018-05-11T00:00:00Z","timestamp":1525996800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007812","name":"University of Washington","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007812","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Despite numerous treatments for epilepsy, over 30% of patients remain resistant to available antiseizure drugs (<jats:styled-content style=\"fixed-case\">ASD<\/jats:styled-content>s). Thus, there is a strong need for more effective<jats:styled-content style=\"fixed-case\">ASD<\/jats:styled-content>s for these individuals. Early<jats:styled-content style=\"fixed-case\">ASD<\/jats:styled-content>discovery has historically relied on acute in\u00a0vivo seizure models (maximal electroshock, subcutaneous pentylenetetrazol, 6\u00a0Hz), which lack the pathophysiology that defines chronic epilepsy. Etiologically relevant rodent models of pharmacoresistant epilepsy exist (eg, phenytoin (<jats:styled-content style=\"fixed-case\">PHT<\/jats:styled-content>)\u2010 and lamotrigine (<jats:styled-content style=\"fixed-case\">LTG<\/jats:styled-content>)\u2010resistant amygdala\u2010kindled rat and focal kainic acid mouse), but these models are resource\u2010 and labor\u2010intensive and thus unsuitable for frontline<jats:styled-content style=\"fixed-case\">ASD<\/jats:styled-content>discovery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We adapted the<jats:styled-content style=\"fixed-case\">LTG<\/jats:styled-content>\u2010resistant amygdala\u2010kindled rat protocol to the 60\u00a0Hz corneal\u2010kindled mouse (<jats:styled-content style=\"fixed-case\">CKM<\/jats:styled-content>) to develop a medium\u2010throughput model of pharmacoresistant chronic seizures. Male<jats:styled-content style=\"fixed-case\">CF<\/jats:styled-content>\u20101 mice were administered either vehicle (<jats:styled-content style=\"fixed-case\">VEH<\/jats:styled-content>; 0.5% methylcellulose) or<jats:styled-content style=\"fixed-case\">LTG<\/jats:styled-content>(8.5\u00a0mg\/kg, ip) 30\u00a0minutes prior to each twice\u2010daily corneal stimulation until mice achieved kindling criterion. Prototype<jats:styled-content style=\"fixed-case\">ASD<\/jats:styled-content>s were then evaluated in fully kindled mice. Compounds with specific mechanisms of action of interest to epilepsy (fluoxetine, minocycline, and celecoxib) were also evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">LTG<\/jats:styled-content>did not modify kindling acquisition. A challenge dose of 17\u00a0mg\/kg (ip)<jats:styled-content style=\"fixed-case\">LTG<\/jats:styled-content>did not block the secondarily generalized kindled seizure in<jats:styled-content style=\"fixed-case\">LTG<\/jats:styled-content>\u2010kindled mice (mean seizure score [<jats:styled-content style=\"fixed-case\">MSS<\/jats:styled-content>]\u00a0\u00b1\u00a0standard error of the mean: 5.67\u00a0\u00b1\u00a00.14), whereas<jats:styled-content style=\"fixed-case\">VEH<\/jats:styled-content>\u2010treated mice were sensitive (<jats:styled-content style=\"fixed-case\">MSS<\/jats:styled-content>: 2.25\u00a0\u00b1\u00a00.30); confirming<jats:styled-content style=\"fixed-case\">LTG<\/jats:styled-content>\u2010resistance.<jats:styled-content style=\"fixed-case\">LTG<\/jats:styled-content>\u2010resistant<jats:styled-content style=\"fixed-case\">CKM<\/jats:styled-content>were also resistant to carbamazepine, retigabine, and valproic acid at doses that significantly reduced<jats:styled-content style=\"fixed-case\">MSS<\/jats:styled-content>in<jats:styled-content style=\"fixed-case\">VEH<\/jats:styled-content>\u2010treated kindled mice. Fluoxetine, minocycline, and celecoxib were ineffective at the doses tested in either kindled cohort. Finally, the behavioral phenotype of<jats:styled-content style=\"fixed-case\">LTG<\/jats:styled-content>\u2010resistant<jats:styled-content style=\"fixed-case\">CKM<\/jats:styled-content>was also characterized.<jats:styled-content style=\"fixed-case\">CKM<\/jats:styled-content>demonstrated exacerbated hyperexcitability and increased anxiety\u2010like behavior in an open field relative to sham\u2010kindled mice regardless of<jats:styled-content style=\"fixed-case\">LTG<\/jats:styled-content>sensitivity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>The pharmacoresistant<jats:styled-content style=\"fixed-case\">LTG<\/jats:styled-content>\u2010resistant<jats:styled-content style=\"fixed-case\">CKM<\/jats:styled-content>provides an etiologically relevant moderate\u2010throughput platform that is suitable for early compound discovery before advancing to more resource\u2010intensive models of epilepsy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.14190","type":"journal-article","created":{"date-parts":[[2018,5,11]],"date-time":"2018-05-11T14:22:06Z","timestamp":1526048526000},"page":"1245-1256","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Lamotrigine\u2010resistant corneal\u2010kindled mice: A model of pharmacoresistant partial epilepsy for moderate\u2010throughput drug discovery"],"prefix":"10.1111","volume":"59","author":[{"given":"Zachery","family":"Koneval","sequence":"first","affiliation":[{"name":"Department of Pharmacy University of Washington Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin M.","family":"Knox","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Washington Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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