{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T16:40:36Z","timestamp":1772728836918,"version":"3.50.1"},"reference-count":44,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2020,8,5]],"date-time":"2020-08-05T00:00:00Z","timestamp":1596585600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100001454","name":"American Epilepsy Society","doi-asserted-by":"publisher","award":["Junior Investigator Award"],"award-info":[{"award-number":["Junior Investigator Award"]}],"id":[{"id":"10.13039\/100001454","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013382","name":"Institute of Translational Health Sciences","doi-asserted-by":"publisher","award":["KL2 TR002317"],"award-info":[{"award-number":["KL2 TR002317"]}],"id":[{"id":"10.13039\/100013382","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013350","name":"Office of Research Central, University of Washington","doi-asserted-by":"publisher","award":["Department of Pharmacy"],"award-info":[{"award-number":["Department of Pharmacy"]}],"id":[{"id":"10.13039\/100013350","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Initial identification of new investigational drugs for the treatment of epilepsy is commonly conducted in well\u2010established mouse acute and chronic seizure models: for example, maximal electroshock (MES), 6\u00a0Hz, and corneal kindling. Comparison of the median effective dose (ED50) of approved antiseizure drugs (ASDs) vs investigational agents in these models provides evidence of their potential for clinical efficacy. Inbred and outbred mouse strains exhibit differential seizure susceptibility. However, few comparisons exist of the ED50 or median behaviorally impairing dose (TD50) of prototype ASDs in these models in inbred C57Bl\/6 vs outbred CF\u20101 mice, both of which are often used for ASD discovery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We defined the strain\u2010related ED50s and TD50s of several mechanistically distinct ASDs across established acute seizure models (MES, 6\u00a0Hz, and corneal\u2010kindled mouse). We further quantified the strain\u2010related effect of the MES ED50 of each ASD on gross behavior in a locomotor activity assay. Finally, we describe a novel pharmacoresistant corneal\u2010kindling protocol that is suitable for moderate\u2010throughput ASD screening and demonstrates highly differentiated ASD sensitivity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We report significant strain\u2010related differences in the MES ED50 of valproic acid (CF\u20101 ED50: 90\u00a0mg\/kg [95% confidence interval (CI) 165\u2013214] vs C57Bl\/6: 276\u00a0mg\/kg [226\u2013366]), as well as significant differences in the ED50 of levetiracetam in the pharmacoresistant 6\u00a0Hz test (CF\u20101: 22.5\u00a0mg\/kg [14.7\u201330.2] vs C57Bl\/6: &gt;500\u00a0mg\/kg [CI not defined]). There were no differences in the calculated TD50 of these ASDs between strains. Furthermore, the MES ED50 of phenobarbital significantly enhanced locomotor activity of outbred CF\u20101, but not C57Bl\/6, mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Altogether, this study provides strain\u2010related information to differentiate investigational agents from ASD standards\u2010of\u2010care in commonly employed preclinical discovery models and describes a novel kindled seizure model to further explore the mechanisms of drug\u2010resistant epilepsy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16624","type":"journal-article","created":{"date-parts":[[2020,8,5]],"date-time":"2020-08-05T13:18:42Z","timestamp":1596633522000},"page":"2022-2034","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Antiseizure drug efficacy and tolerability in established and novel drug discovery seizure models in outbred vs inbred mice"],"prefix":"10.1111","volume":"61","author":[{"given":"Zachery","family":"Koneval","sequence":"first","affiliation":[{"name":"Department of Pharmacy School of Pharmacy University of Washington Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin M.","family":"Knox","sequence":"additional","affiliation":[{"name":"Department of Pharmacy School of Pharmacy University of Washington Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Memon","sequence":"additional","affiliation":[{"name":"Neuroscience Undergraduate Program University of Washington Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dannielle K.","family":"Zierath","sequence":"additional","affiliation":[{"name":"Department of Pharmacy School of Pharmacy University of Washington Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H. 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