Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model

Autores
Fuentes Mejia, Monserrat; Fallico, Maximiliano José; Talevi, Alan; Gavernet, Luciana; Orozco Suárez, Sandra A.; Rocha, Luisa
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Drug resistance affects 30% of patients with epilepsy. Cannabidiol (CBD)decreases the expression of drug-resistant seizures in specific syndromes.However, it is unknown if CBD prevents the development of drug-resistantcondition in epilepsy. This research was conducted to investigate ifsubchronic administration of CBD with sodium channel blockers modifies themortality associated with clonic-tonic seizures and the development of the drug-resistant phenotype induced by subchronic administration of 3-mercaptopropionic acid (3-MP) in rats. These effects were compared withthose elicited by antiseizure medications acting on the GABAA receptors. MaleWistar rats were used to evaluate CBD combined with different antiseizuremedications (phenobarbital, diazepam, valproic acid, lamotrigine andoxcarbazepine) during the repetitive administration of 3-MP. The mortalityrate and development of drug-resistant seizures were estimated.Computational experiments explored interactions between CBD and sodiumchannel blockers in the NaV1.7 receptor. Subchronic administration of CBD alonedid not modify neither the mortality rate nor the development of drug-resistantseizures. CBD combined with phenobarbital or diazepam reduced the mortalityrate and prevalence of drug-resistant seizures. In contrast, coadministration ofCBD with valproic acid or lamotrigine did not modify neither the mortality rate northe expression of drug-resistant seizures. Contrariwise, combining CBD withoxcarbazepine at ED50 increases the incidence of drug-resistant seizures.Computational experiments suggested that CBD acting on NaV1.7 interfereswith the action of sodium channel blockers and precludes their inhibitoryeffects. Our results indicate that repeated administration of CBD withGABAergic antiseizure medications, but not sodium channel blockers,decreases the mortality and prevents the development of the drug-resistantphenotype induced by repeatedly provoked severe seizures.
Fil: Fuentes Mejia, Monserrat. No especifíca;
Fil: Fallico, Maximiliano José. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Talevi, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Gavernet, Luciana. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Orozco Suárez, Sandra A.. Hospital, “Dr. Bernardo Sepúlveda"; México
Fil: Rocha, Luisa. No especifíca;
Materia
DRUG RESISTANCE
SEIZURES
CANNABIDIOL
GABAERGIC DRUGS
SODIUM CHANNEL BLOCKERS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/272723
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/272723
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical modelFuentes Mejia, MonserratFallico, Maximiliano JoséTalevi, AlanGavernet, LucianaOrozco Suárez, Sandra A.Rocha, LuisaDRUG RESISTANCESEIZURESCANNABIDIOLGABAERGIC DRUGSSODIUM CHANNEL BLOCKERShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Drug resistance affects 30% of patients with epilepsy. Cannabidiol (CBD)decreases the expression of drug-resistant seizures in specific syndromes.However, it is unknown if CBD prevents the development of drug-resistantcondition in epilepsy. This research was conducted to investigate ifsubchronic administration of CBD with sodium channel blockers modifies themortality associated with clonic-tonic seizures and the development of the drug-resistant phenotype induced by subchronic administration of 3-mercaptopropionic acid (3-MP) in rats. These effects were compared withthose elicited by antiseizure medications acting on the GABAA receptors. MaleWistar rats were used to evaluate CBD combined with different antiseizuremedications (phenobarbital, diazepam, valproic acid, lamotrigine andoxcarbazepine) during the repetitive administration of 3-MP. The mortalityrate and development of drug-resistant seizures were estimated.Computational experiments explored interactions between CBD and sodiumchannel blockers in the NaV1.7 receptor. Subchronic administration of CBD alonedid not modify neither the mortality rate nor the development of drug-resistantseizures. CBD combined with phenobarbital or diazepam reduced the mortalityrate and prevalence of drug-resistant seizures. In contrast, coadministration ofCBD with valproic acid or lamotrigine did not modify neither the mortality rate northe expression of drug-resistant seizures. Contrariwise, combining CBD withoxcarbazepine at ED50 increases the incidence of drug-resistant seizures.Computational experiments suggested that CBD acting on NaV1.7 interfereswith the action of sodium channel blockers and precludes their inhibitoryeffects. Our results indicate that repeated administration of CBD withGABAergic antiseizure medications, but not sodium channel blockers,decreases the mortality and prevents the development of the drug-resistantphenotype induced by repeatedly provoked severe seizures.Fil: Fuentes Mejia, Monserrat. No especifíca;Fil: Fallico, Maximiliano José. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Talevi, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; ArgentinaFil: Gavernet, Luciana. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Orozco Suárez, Sandra A.. Hospital, “Dr. Bernardo Sepúlveda"; MéxicoFil: Rocha, Luisa. No especifíca;Frontiers Media2025-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/272723Fuentes Mejia, Monserrat; Fallico, Maximiliano José; Talevi, Alan; Gavernet, Luciana; Orozco Suárez, Sandra A.; et al.; Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model; Frontiers Media; Frontiers in Pharmacology; 16; 9-2025; 1-111663-9812CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fphar.2025.1644018/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fphar.2025.1644018info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:23:57Zoai:ri.conicet.gov.ar:11336/272723instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:23:57.384CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model
title Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model
spellingShingle Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model
Fuentes Mejia, Monserrat
DRUG RESISTANCE
SEIZURES
CANNABIDIOL
GABAERGIC DRUGS
SODIUM CHANNEL BLOCKERS
title_short Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model
title_full Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model
title_fullStr Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model
title_full_unstemmed Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model
title_sort Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model
dc.creator.none.fl_str_mv Fuentes Mejia, Monserrat
Fallico, Maximiliano José
Talevi, Alan
Gavernet, Luciana
Orozco Suárez, Sandra A.
Rocha, Luisa
author Fuentes Mejia, Monserrat
author_facet Fuentes Mejia, Monserrat
Fallico, Maximiliano José
Talevi, Alan
Gavernet, Luciana
Orozco Suárez, Sandra A.
Rocha, Luisa
author_role author
author2 Fallico, Maximiliano José
Talevi, Alan
Gavernet, Luciana
Orozco Suárez, Sandra A.
Rocha, Luisa
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv DRUG RESISTANCE
SEIZURES
CANNABIDIOL
GABAERGIC DRUGS
SODIUM CHANNEL BLOCKERS
topic DRUG RESISTANCE
SEIZURES
CANNABIDIOL
GABAERGIC DRUGS
SODIUM CHANNEL BLOCKERS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Drug resistance affects 30% of patients with epilepsy. Cannabidiol (CBD)decreases the expression of drug-resistant seizures in specific syndromes.However, it is unknown if CBD prevents the development of drug-resistantcondition in epilepsy. This research was conducted to investigate ifsubchronic administration of CBD with sodium channel blockers modifies themortality associated with clonic-tonic seizures and the development of the drug-resistant phenotype induced by subchronic administration of 3-mercaptopropionic acid (3-MP) in rats. These effects were compared withthose elicited by antiseizure medications acting on the GABAA receptors. MaleWistar rats were used to evaluate CBD combined with different antiseizuremedications (phenobarbital, diazepam, valproic acid, lamotrigine andoxcarbazepine) during the repetitive administration of 3-MP. The mortalityrate and development of drug-resistant seizures were estimated.Computational experiments explored interactions between CBD and sodiumchannel blockers in the NaV1.7 receptor. Subchronic administration of CBD alonedid not modify neither the mortality rate nor the development of drug-resistantseizures. CBD combined with phenobarbital or diazepam reduced the mortalityrate and prevalence of drug-resistant seizures. In contrast, coadministration ofCBD with valproic acid or lamotrigine did not modify neither the mortality rate northe expression of drug-resistant seizures. Contrariwise, combining CBD withoxcarbazepine at ED50 increases the incidence of drug-resistant seizures.Computational experiments suggested that CBD acting on NaV1.7 interfereswith the action of sodium channel blockers and precludes their inhibitoryeffects. Our results indicate that repeated administration of CBD withGABAergic antiseizure medications, but not sodium channel blockers,decreases the mortality and prevents the development of the drug-resistantphenotype induced by repeatedly provoked severe seizures.
Fil: Fuentes Mejia, Monserrat. No especifíca;
Fil: Fallico, Maximiliano José. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Talevi, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Gavernet, Luciana. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Orozco Suárez, Sandra A.. Hospital, “Dr. Bernardo Sepúlveda"; México
Fil: Rocha, Luisa. No especifíca;
description Drug resistance affects 30% of patients with epilepsy. Cannabidiol (CBD)decreases the expression of drug-resistant seizures in specific syndromes.However, it is unknown if CBD prevents the development of drug-resistantcondition in epilepsy. This research was conducted to investigate ifsubchronic administration of CBD with sodium channel blockers modifies themortality associated with clonic-tonic seizures and the development of the drug-resistant phenotype induced by subchronic administration of 3-mercaptopropionic acid (3-MP) in rats. These effects were compared withthose elicited by antiseizure medications acting on the GABAA receptors. MaleWistar rats were used to evaluate CBD combined with different antiseizuremedications (phenobarbital, diazepam, valproic acid, lamotrigine andoxcarbazepine) during the repetitive administration of 3-MP. The mortalityrate and development of drug-resistant seizures were estimated.Computational experiments explored interactions between CBD and sodiumchannel blockers in the NaV1.7 receptor. Subchronic administration of CBD alonedid not modify neither the mortality rate nor the development of drug-resistantseizures. CBD combined with phenobarbital or diazepam reduced the mortalityrate and prevalence of drug-resistant seizures. In contrast, coadministration ofCBD with valproic acid or lamotrigine did not modify neither the mortality rate northe expression of drug-resistant seizures. Contrariwise, combining CBD withoxcarbazepine at ED50 increases the incidence of drug-resistant seizures.Computational experiments suggested that CBD acting on NaV1.7 interfereswith the action of sodium channel blockers and precludes their inhibitoryeffects. Our results indicate that repeated administration of CBD withGABAergic antiseizure medications, but not sodium channel blockers,decreases the mortality and prevents the development of the drug-resistantphenotype induced by repeatedly provoked severe seizures.
publishDate 2025
dc.date.none.fl_str_mv 2025-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/272723
Fuentes Mejia, Monserrat; Fallico, Maximiliano José; Talevi, Alan; Gavernet, Luciana; Orozco Suárez, Sandra A.; et al.; Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model; Frontiers Media; Frontiers in Pharmacology; 16; 9-2025; 1-11
1663-9812
CONICET Digital
CONICET
url http://hdl.handle.net/11336/272723
identifier_str_mv Fuentes Mejia, Monserrat; Fallico, Maximiliano José; Talevi, Alan; Gavernet, Luciana; Orozco Suárez, Sandra A.; et al.; Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model; Frontiers Media; Frontiers in Pharmacology; 16; 9-2025; 1-11
1663-9812
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fphar.2025.1644018/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fphar.2025.1644018
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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