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Neuronal injury is associated with profound increases in cytoplasmic chloride ([Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub>) resulting in depolarizing <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content> signaling, higher seizure propensity and limited efficacy of <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>ergic anticonvulsants. The Na<jats:sup>+<\/jats:sup>\u2010K<jats:sup>+<\/jats:sup>\u20102Cl<jats:sup>\u2212<\/jats:sup> (<jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>1) cotransporter blocker bumetanide reduces [Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub> and causes more negative <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content> equilibrium potential in injured neurons. We therefore tested both the acute and chronic efficacy of bumetanide on early posttraumatic ictal\u2010like epileptiform discharges and epileptogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Acute hippocampal slices were used as a model of severe traumatic brain injury and posttraumatic epileptogenesis. Hippocampal slices were then incubated for 3\u00a0weeks. After a 1\u2010week latent period, slice cultures developed chronic spontaneous ictal\u2010like discharges. The anticonvulsant and anti\u2010epileptogenic efficacy of bumetanide, phenobarbital, and the combination of these drugs was studied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Bumetanide reduced the frequency and power of early posttraumatic ictal\u2010like discharges <jats:italic>in vitro<\/jats:italic> and enhanced the anticonvulsant efficacy of phenobarbital. Continuous 2\u20133\u00a0weeks administration of bumetanide as well as phenobarbital in combination with bumetanide failed to prevent posttraumatic ictal\u2010like discharges and epileptogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data demonstrate a persistent contribution of <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>1 cotransport in posttraumatic ictal\u2010like activity, presumably as a consequence of chronic alterations in neuronal chloride homeostasis and <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>\u2010mediated inhibition. New strategies for more effective reduction in posttraumatic and seizure\u2010induced [Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub> accumulation could provide the basis for effective treatments for posttraumatic epileptogenesis and the resultant seizures.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.12369","type":"journal-article","created":{"date-parts":[[2014,12,12]],"date-time":"2014-12-12T12:29:40Z","timestamp":1418387380000},"page":"173-180","source":"Crossref","is-referenced-by-count":27,"title":["Acute and Chronic Efficacy of Bumetanide in an <i>in vitro<\/i> Model of Posttraumatic Epileptogenesis"],"prefix":"10.1111","volume":"21","author":[{"given":"Volodymyr","family":"Dzhala","sequence":"first","affiliation":[{"name":"Neurology Department Massachusetts General Hospital Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J.","family":"Staley","sequence":"additional","affiliation":[{"name":"Neurology Department Massachusetts General 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