Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats

Abstract Objective Cholinergic‐induced status epilepticus (SE) is associated with a loss of synaptic gamma‐aminobutyric acid A receptors (GABAAR) and an increase in N‐methyl‐D‐aspartate receptors (NMDAR) and amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPAR) that may contribute to...

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Autores principales:	Lucille A. Lumley, Brenda Marrero‐Rosado, Franco Rossetti, Caroline R. Schultz, Michael F. Stone, Jerome Niquet, Claude G. Wasterlain
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	barbiturate benzodiazepine ketamine organophosphorus nerve agent refractory status epilepticus Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/8353077f8b364edd90a8daf425f335b3
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spelling	oai:doaj.org-article:8353077f8b364edd90a8daf425f335b32021-12-01T06:09:19ZCombination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats2470-923910.1002/epi4.12552https://doaj.org/article/8353077f8b364edd90a8daf425f335b32021-12-01T00:00:00Zhttps://doi.org/10.1002/epi4.12552https://doaj.org/toc/2470-9239Abstract Objective Cholinergic‐induced status epilepticus (SE) is associated with a loss of synaptic gamma‐aminobutyric acid A receptors (GABAAR) and an increase in N‐methyl‐D‐aspartate receptors (NMDAR) and amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic 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 GABAAR to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate‐induced currents through AMPA/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman‐induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist. Methods We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABAAR 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‐dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI‐6 one min after exposure and with antiseizure medication(s) 40 minutes after seizure onset. Results The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40 minutes after seizure onset effectively prevented soman‐induced 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‐induced toxicity. Significance Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine‐refractory cholinergic‐induced 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.Lucille A. LumleyBrenda Marrero‐RosadoFranco RossettiCaroline R. SchultzMichael F. StoneJerome NiquetClaude G. WasterlainWileyarticlebarbituratebenzodiazepineketamineorganophosphorus nerve agentrefractory status epilepticusNeurology. Diseases of the nervous systemRC346-429ENEpilepsia Open, Vol 6, Iss 4, Pp 757-769 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	barbiturate benzodiazepine ketamine organophosphorus nerve agent refractory status epilepticus Neurology. Diseases of the nervous system RC346-429
spellingShingle	barbiturate benzodiazepine ketamine organophosphorus nerve agent refractory status epilepticus Neurology. Diseases of the nervous system RC346-429 Lucille A. Lumley Brenda Marrero‐Rosado Franco Rossetti Caroline R. Schultz Michael F. Stone Jerome Niquet Claude G. Wasterlain Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats
description	Abstract Objective Cholinergic‐induced status epilepticus (SE) is associated with a loss of synaptic gamma‐aminobutyric acid A receptors (GABAAR) and an increase in N‐methyl‐D‐aspartate receptors (NMDAR) and amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic 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 GABAAR to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate‐induced currents through AMPA/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman‐induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist. Methods We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABAAR 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‐dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI‐6 one min after exposure and with antiseizure medication(s) 40 minutes after seizure onset. Results The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40 minutes after seizure onset effectively prevented soman‐induced 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‐induced toxicity. Significance Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine‐refractory cholinergic‐induced 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.
format	article
author	Lucille A. Lumley Brenda Marrero‐Rosado Franco Rossetti Caroline R. Schultz Michael F. Stone Jerome Niquet Claude G. Wasterlain
author_facet	Lucille A. Lumley Brenda Marrero‐Rosado Franco Rossetti Caroline R. Schultz Michael F. Stone Jerome Niquet Claude G. Wasterlain
author_sort	Lucille A. Lumley
title	Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats
title_short	Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats
title_full	Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats
title_fullStr	Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats
title_full_unstemmed	Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats
title_sort	combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/8353077f8b364edd90a8daf425f335b3
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Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats

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