{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:55:25Z","timestamp":1790477725998,"version":"4.1.0"},"reference-count":34,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2014,5,23]],"date-time":"2014-05-23T00:00:00Z","timestamp":1400803200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NS032387"],"award-info":[{"award-number":["NS032387"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2014,8]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Evidence from basic neurophysiology and molecular genetics has implicated persistent sodium current conducted by voltage\u2010gated sodium (Na<jats:sub>V<\/jats:sub>) channels as a contributor to the pathogenesis of epilepsy. Many antiepileptic drugs target Na<jats:sub>V<\/jats:sub> channels and modulate neuronal excitability, mainly by a use\u2010dependent block of transient sodium current, although suppression of persistent current may also contribute to the efficacy of these drugs. We hypothesized that a drug or compound capable of preferential inhibition of persistent sodium current would have antiepileptic activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We examined the antiepileptic activity of two selective persistent sodium current blockers ranolazine, a U.S. Food and Drug Administration (<jats:styled-content style=\"fixed-case\">FDA)<\/jats:styled-content>\u2013approved drug for treatment of angina pectoris, and <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>967, a novel compound with more potent effects on persistent current, in the epileptic <jats:italic>Scn2a<\/jats:italic><jats:sup>Q54<\/jats:sup> mouse model. We also examined the effect of <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>967 in the maximal electroshock model and evaluated effects of the compound on neuronal excitability, propensity for hilar neuron loss, development of mossy fiber sprouting, and survival of <jats:italic>Scn2a<\/jats:italic><jats:sup>Q54<\/jats:sup> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that ranolazine was capable of reducing seizure frequency by approximately 50% in <jats:italic>Scn2a<\/jats:italic><jats:sup>Q54<\/jats:sup> mice. The more potent persistent current blocker <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>967 reduced seizure frequency by &gt;90% in <jats:italic>Scn2a<\/jats:italic><jats:sup>Q54<\/jats:sup> mice and protected against induced seizures in the maximal electroshock model. <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>967 greatly attenuated abnormal spontaneous action potential firing in pyramidal neurons acutely isolated from <jats:italic>Scn2a<\/jats:italic><jats:sup>Q54<\/jats:sup> mice. In addition to seizure suppression in vivo, <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>967 treatment greatly improved the survival of <jats:italic>Scn2a<\/jats:italic><jats:sup>Q54<\/jats:sup> mice, prevented hilar neuron loss, and suppressed the development of hippocampal mossy fiber sprouting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Our findings indicate that the selective persistent sodium current blocker <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>967 has potent antiepileptic activity and that this compound could inform development of new agents.<\/jats:p><jats:p>A PowerPoint slide summarizing this article is available for download in the Supporting Information section <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.12657\/suppinfo\">here<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.12657","type":"journal-article","created":{"date-parts":[[2014,5,23]],"date-time":"2014-05-23T18:19:51Z","timestamp":1400869191000},"page":"1274-1283","source":"Crossref","is-referenced-by-count":76,"title":["Antiepileptic activity of preferential inhibitors of persistent sodium current"],"prefix":"10.1111","volume":"55","author":[{"given":"Lyndsey L.","family":"Anderson","sequence":"first","affiliation":[{"name":"Department of Pharmacology Vanderbilt University Nashville Tennessee U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher H.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Medicine Vanderbilt University Nashville Tennessee U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole A.","family":"Hawkins","sequence":"additional","affiliation":[{"name":"Department of Medicine Vanderbilt University Nashville Tennessee U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi D.","family":"Nath","sequence":"additional","affiliation":[{"name":"Department of Medicine Vanderbilt University Nashville Tennessee U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam A.","family":"Petersohn","sequence":"additional","affiliation":[{"name":"Department of Medicine Vanderbilt University Nashville Tennessee U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sridharan","family":"Rajamani","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc. 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