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Phenobarbital (<jats:styled-content style=\"fixed-case\">PB<\/jats:styled-content>) resistance is common and poses a serious challenge in clinical management. Using a newly characterized neonatal mouse model of ischemic seizures, this study investigated a novel strategy for rescuing <jats:styled-content style=\"fixed-case\">PB<\/jats:styled-content> resistance. A small\u2010molecule TrkB antagonist, <jats:styled-content style=\"fixed-case\">ANA<\/jats:styled-content>12, used to selectively and transiently block post\u2010ischemic <jats:styled-content style=\"fixed-case\">BDNF<\/jats:styled-content>\u2010TrkB signaling <jats:italic>in\u00a0vivo<\/jats:italic>, determined whether rescuing TrkB\u2010mediated post\u2010ischemic degradation of the K<jats:sup>+<\/jats:sup>\u2013Cl<jats:sup>\u2212<\/jats:sup> co\u2010transporter (<jats:styled-content style=\"fixed-case\">KCC<\/jats:styled-content>2) rescued <jats:styled-content style=\"fixed-case\">PB<\/jats:styled-content>\u2010resistant seizures. The anti\u2010seizure efficacy of <jats:styled-content style=\"fixed-case\">ANA<\/jats:styled-content>12\u00a0+\u00a0<jats:styled-content style=\"fixed-case\">PB<\/jats:styled-content> was quantified by (i) electrographic seizure burden using acute continuous video\u2010electroencephalograms and (ii) post\u2010treatment expression levels of <jats:styled-content style=\"fixed-case\">KCC<\/jats:styled-content>2 and <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>1 using Western blot analysis in postnatal day (P)7 and P10 <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>1 pups with unilateral carotid ligation. <jats:styled-content style=\"fixed-case\">ANA<\/jats:styled-content>12 significantly rescued <jats:styled-content style=\"fixed-case\">PB<\/jats:styled-content>\u2010resistant seizures at P7 and improved <jats:styled-content style=\"fixed-case\">PB<\/jats:styled-content> efficacy at P10. A single dose of <jats:styled-content style=\"fixed-case\">ANA<\/jats:styled-content>12\u00a0+\u00a0<jats:styled-content style=\"fixed-case\">PB<\/jats:styled-content> prevented the post\u2010ischemic degradation of <jats:styled-content style=\"fixed-case\">KCC<\/jats:styled-content>2 for up to 24\u00a0h. As anticipated, <jats:styled-content style=\"fixed-case\">ANA<\/jats:styled-content>12 by itself had no anti\u2010seizure properties and was unable to prevent <jats:styled-content style=\"fixed-case\">KCC<\/jats:styled-content>2 degradation at 24\u00a0h without follow\u2010on <jats:styled-content style=\"fixed-case\">PB<\/jats:styled-content>. This indicates that unsubdued seizures can independently lead to <jats:styled-content style=\"fixed-case\">KCC<\/jats:styled-content>2 degradation via non\u2010TrkB\u2010dependent pathways. This study, for the first time as a proof\u2010of\u2010concept, reports the potential therapeutic value of <jats:styled-content style=\"fixed-case\">KCC<\/jats:styled-content>2 modulation for the management of <jats:styled-content style=\"fixed-case\">PB<\/jats:styled-content>\u2010resistant seizures in neonates. Future investigations are required to establish the mechanistic link between <jats:styled-content style=\"fixed-case\">ANA<\/jats:styled-content>12 and the prevention of <jats:styled-content style=\"fixed-case\">KCC<\/jats:styled-content>2 degradation.<\/jats:p>","DOI":"10.1111\/ejn.13094","type":"journal-article","created":{"date-parts":[[2015,10,9]],"date-time":"2015-10-09T13:23:01Z","timestamp":1444396981000},"page":"2792-2804","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Acute TrkB inhibition rescues phenobarbital\u2010resistant seizures in a mouse model of neonatal ischemia"],"prefix":"10.1111","volume":"42","author":[{"given":"S. K.","family":"Kang","sequence":"first","affiliation":[{"name":"Neuroscience Laboratory Hugo Moser Research Institute at Kennedy Krieger 716 North Broadway Baltimore MD 21205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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