{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T20:13:01Z","timestamp":1785442381279,"version":"3.56.0"},"reference-count":50,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,10,23]],"date-time":"2021-10-23T00:00:00Z","timestamp":1634947200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["U01 NS074926"],"award-info":[{"award-number":["U01 NS074926"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Cholinergic\u2010induced status epilepticus (SE) is associated with a loss of synaptic gamma\u2010aminobutyric acid A receptors (GABA<jats:sub>A<\/jats:sub>R) and an increase in N\u2010methyl\u2010D\u2010aspartate receptors (NMDAR) and amino\u20103\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazolepropionic acid receptors (AMPAR) that may contribute to pharmacoresistance when treatment with benzodiazepine antiseizure medication is delayed. The barbiturate phenobarbital enhances inhibitory neurotransmission by binding to a specific site in the GABA<jats:sub>A<\/jats:sub>R to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate\u2010induced currents through AMPA\/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman\u2010induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABA<jats:sub>A<\/jats:sub>R modulator (midazolam and phenobarbital, respectively) to correct loss of inhibition, and ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDA\u2010dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI\u20106 one min after exposure and with antiseizure medication(s) 40\u00a0minutes after seizure onset.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40\u00a0minutes after seizure onset effectively prevented soman\u2010induced epileptogenesis and reduced neurodegeneration. In addition, dual therapy with phenobarbital and midazolam or ketamine was more effective than monotherapy (midazolam or phenobarbital) in reducing cholinergic\u2010induced toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine\u2010refractory cholinergic\u2010induced SE, simultaneous drug combination to include drugs that target both the loss of inhibition (eg, midazolam, phenobarbital) and the increased excitatory response (eg, ketamine) is more effective than benzodiazepine or barbiturate monotherapy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.12552","type":"journal-article","created":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T14:11:20Z","timestamp":1634652680000},"page":"757-769","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman\u2010induced epileptogenesis and brain pathology in rats"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4162-8817","authenticated-orcid":false,"given":"Lucille 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