{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T06:02:45Z","timestamp":1788328965143,"version":"build-2803163510"},"reference-count":35,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2016,8,8]],"date-time":"2016-08-08T00:00:00Z","timestamp":1470614400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["#I01 BX000273\u201007"],"award-info":[{"award-number":["#I01 BX000273\u201007"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["UO1 NS074926"],"award-info":[{"award-number":["UO1 NS074926"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Pharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (<jats:styled-content style=\"fixed-case\">SE<\/jats:styled-content>) and in cholinergic <jats:styled-content style=\"fixed-case\">SE<\/jats:styled-content> induced by nerve agent intoxication. <jats:styled-content style=\"fixed-case\">SE<\/jats:styled-content> triggers a rapid internalization of synaptic \u03b3\u2010aminobutyric acid A (<jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub><\/jats:styled-content>) receptors and externalization of <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:sc>d<\/jats:sc>\u2010aspartate (<jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content>) receptors that may explain the loss of potency of standard antiepileptic drugs (<jats:styled-content style=\"fixed-case\">AED<\/jats:styled-content>s). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce <jats:styled-content style=\"fixed-case\">SE<\/jats:styled-content> severity and its long\u2010term consequences.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A severe model of <jats:styled-content style=\"fixed-case\">SE<\/jats:styled-content> was induced in adult Sprague\u2010Dawley rats with a high dose of lithium and pilocarpine. The <jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub><\/jats:styled-content> receptor agonist midazolam, the <jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content> receptor antagonist ketamine, and\/or the <jats:styled-content style=\"fixed-case\">AED<\/jats:styled-content> valproate were injected 40 min after <jats:styled-content style=\"fixed-case\">SE<\/jats:styled-content> onset in combination or as monotherapy. Measures of <jats:styled-content style=\"fixed-case\">SE<\/jats:styled-content> severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (<jats:styled-content style=\"fixed-case\">SRS<\/jats:styled-content>), and Morris water maze (<jats:styled-content style=\"fixed-case\">MWM<\/jats:styled-content>) deficits.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Midazolam\u2013ketamine dual therapy was more efficient than double\u2010dose midazolam or ketamine monotherapy or than valproate\u2013midazolam or valproate\u2013ketamine dual therapy in reducing several parameters of <jats:styled-content style=\"fixed-case\">SE<\/jats:styled-content> severity, suggesting a synergistic mechanism. In addition, midazolam\u2013ketamine dual therapy reduced <jats:styled-content style=\"fixed-case\">SE<\/jats:styled-content>\u2010induced acute neuronal injury, epileptogenesis, and <jats:styled-content style=\"fixed-case\">MWM<\/jats:styled-content> deficits.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>This study showed that a treatment aimed at correcting maladaptive <jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub><\/jats:styled-content> receptor and <jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content> receptor trafficking can stop <jats:styled-content style=\"fixed-case\">SE<\/jats:styled-content> and reduce its long\u2010term consequences. Early midazolam\u2013ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine\u2010refractory <jats:styled-content style=\"fixed-case\">SE<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.13480","type":"journal-article","created":{"date-parts":[[2016,8,8]],"date-time":"2016-08-08T18:43:10Z","timestamp":1470681790000},"page":"1406-1415","source":"Crossref","is-referenced-by-count":75,"title":["Midazolam\u2013ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits"],"prefix":"10.1111","volume":"57","author":[{"given":"Jerome","family":"Niquet","sequence":"first","affiliation":[{"name":"Department of Neurology David Geffen School of Medicine at UCLA Los Angeles California U.S.A"},{"name":"Epilepsy Research Laboratory (151) Veterans Affairs Greater Los Angeles Healthcare System Los Angeles California U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Baldwin","sequence":"additional","affiliation":[{"name":"Epilepsy Research Laboratory (151) Veterans Affairs Greater Los Angeles Healthcare System Los Angeles California U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Norman","sequence":"additional","affiliation":[{"name":"Epilepsy Research Laboratory (151) Veterans Affairs Greater Los Angeles Healthcare System Los Angeles California U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Suchomelova","sequence":"additional","affiliation":[{"name":"Epilepsy Research Laboratory (151) Veterans Affairs Greater Los Angeles Healthcare System Los Angeles California U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucille","family":"Lumley","sequence":"additional","affiliation":[{"name":"US Army Medical Research Institute of Chemical Defense (USAMRICD) Aberdeen 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