Dantrolene paradoxically exacerbates short-term brain glucose hypometabolism, hippocampal damage and neuroinflammation induced by status epilepticus in the rat lithium-pilocarpine model

Status epilepticus (SE) is a neurologic emergency characterized by prolonged or rapidly recurring seizures. Increased intracellular calcium concentration ([Ca2+]i) occurring after SE is a key mediator of excitotoxicity that contributes to the brain damage associated with the development of epilepsy....

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Detalhes bibliográficos
Autores: García García, Luis, Gómez Oliver, Francisca, Fernández de La Rosa, Rubén, Pozo García, Miguel Ángel
Formato: artículo
Fecha de publicación:2024
País:España
Recursos:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/110047
Acesso em linha:https://hdl.handle.net/20.500.14352/110047
Access Level:acceso abierto
Palavra-chave:615.03
lithium-pilocarpine model
status epilepticus
dantrolene
PET
brain glucose metabolism
neuroprotection
Farmacología (Farmacia)
Farmacología (Medicina)
3209.90 Farmacología Experimental
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oai_identifier_str oai:docta.ucm.es:20.500.14352/110047
network_acronym_str ES
network_name_str España
repository_id_str
spelling Dantrolene paradoxically exacerbates short-term brain glucose hypometabolism, hippocampal damage and neuroinflammation induced by status epilepticus in the rat lithium-pilocarpine modelGarcía García, LuisGómez Oliver, FranciscaFernández de La Rosa, RubénPozo García, Miguel Ángel615.03lithium-pilocarpine modelstatus epilepticusdantrolenePETbrain glucose metabolismneuroprotectionFarmacología (Farmacia)Farmacología (Medicina)3209.90 Farmacología ExperimentalStatus epilepticus (SE) is a neurologic emergency characterized by prolonged or rapidly recurring seizures. Increased intracellular calcium concentration ([Ca2+]i) occurring after SE is a key mediator of excitotoxicity that contributes to the brain damage associated with the development of epilepsy. Accumulated evidence indicates that dantrolene, a ryanodine receptor (RyR) blocker may have protective effects against the SE-induced damage. We evaluated whether dantrolene (10 mg/kg, i.p.) administered twice, 5 min and 24 h after the lithium-pilocarpine-induced SE in rats, had neuroprotective effects. Dantrolene by itself had no effects on control rats. However, it exacerbated the signs of damage in rats that underwent SE, increasing brain glucose hypometabolism as measured by PET neuroimaging 3 days after SE. Likewise, the neurohistochemical studies revealed that dantrolene aggravated signs of hippocampal neurodegeneration, neuronal death and microglia-induced neuroinflammation. Besides, the damaging effects were reflected by severe body weight loss. Overall, our results point towards a deleterious effect of dantrolene in the lithium-pilocarpine-induced SE model. Nonetheless, our results are in opposition to the reported neuroprotective effects of dantrolene. Whether the mechanisms underlying [Ca2+]i increase might significantly differ depending on the particularities of the model of epilepsy used and general experimental conditions need further studies. Besides, it is yet to be determined which isoform of RyRs significantly contributes to Ca2+-induced excitotoxicity in the lithium-pilocarpine SE rat model.ElsevierUniversidad Complutense de Madrid20242024-01-0120242024-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/110047reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1100472026-06-02T12:44:21Z
dc.title.none.fl_str_mv Dantrolene paradoxically exacerbates short-term brain glucose hypometabolism, hippocampal damage and neuroinflammation induced by status epilepticus in the rat lithium-pilocarpine model
title Dantrolene paradoxically exacerbates short-term brain glucose hypometabolism, hippocampal damage and neuroinflammation induced by status epilepticus in the rat lithium-pilocarpine model
spellingShingle Dantrolene paradoxically exacerbates short-term brain glucose hypometabolism, hippocampal damage and neuroinflammation induced by status epilepticus in the rat lithium-pilocarpine model
García García, Luis
615.03
lithium-pilocarpine model
status epilepticus
dantrolene
PET
brain glucose metabolism
neuroprotection
Farmacología (Farmacia)
Farmacología (Medicina)
3209.90 Farmacología Experimental
title_short Dantrolene paradoxically exacerbates short-term brain glucose hypometabolism, hippocampal damage and neuroinflammation induced by status epilepticus in the rat lithium-pilocarpine model
title_full Dantrolene paradoxically exacerbates short-term brain glucose hypometabolism, hippocampal damage and neuroinflammation induced by status epilepticus in the rat lithium-pilocarpine model
title_fullStr Dantrolene paradoxically exacerbates short-term brain glucose hypometabolism, hippocampal damage and neuroinflammation induced by status epilepticus in the rat lithium-pilocarpine model
title_full_unstemmed Dantrolene paradoxically exacerbates short-term brain glucose hypometabolism, hippocampal damage and neuroinflammation induced by status epilepticus in the rat lithium-pilocarpine model
title_sort Dantrolene paradoxically exacerbates short-term brain glucose hypometabolism, hippocampal damage and neuroinflammation induced by status epilepticus in the rat lithium-pilocarpine model
dc.creator.none.fl_str_mv García García, Luis
Gómez Oliver, Francisca
Fernández de La Rosa, Rubén
Pozo García, Miguel Ángel
author García García, Luis
author_facet García García, Luis
Gómez Oliver, Francisca
Fernández de La Rosa, Rubén
Pozo García, Miguel Ángel
author_role author
author2 Gómez Oliver, Francisca
Fernández de La Rosa, Rubén
Pozo García, Miguel Ángel
author2_role author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 615.03
lithium-pilocarpine model
status epilepticus
dantrolene
PET
brain glucose metabolism
neuroprotection
Farmacología (Farmacia)
Farmacología (Medicina)
3209.90 Farmacología Experimental
topic 615.03
lithium-pilocarpine model
status epilepticus
dantrolene
PET
brain glucose metabolism
neuroprotection
Farmacología (Farmacia)
Farmacología (Medicina)
3209.90 Farmacología Experimental
description Status epilepticus (SE) is a neurologic emergency characterized by prolonged or rapidly recurring seizures. Increased intracellular calcium concentration ([Ca2+]i) occurring after SE is a key mediator of excitotoxicity that contributes to the brain damage associated with the development of epilepsy. Accumulated evidence indicates that dantrolene, a ryanodine receptor (RyR) blocker may have protective effects against the SE-induced damage. We evaluated whether dantrolene (10 mg/kg, i.p.) administered twice, 5 min and 24 h after the lithium-pilocarpine-induced SE in rats, had neuroprotective effects. Dantrolene by itself had no effects on control rats. However, it exacerbated the signs of damage in rats that underwent SE, increasing brain glucose hypometabolism as measured by PET neuroimaging 3 days after SE. Likewise, the neurohistochemical studies revealed that dantrolene aggravated signs of hippocampal neurodegeneration, neuronal death and microglia-induced neuroinflammation. Besides, the damaging effects were reflected by severe body weight loss. Overall, our results point towards a deleterious effect of dantrolene in the lithium-pilocarpine-induced SE model. Nonetheless, our results are in opposition to the reported neuroprotective effects of dantrolene. Whether the mechanisms underlying [Ca2+]i increase might significantly differ depending on the particularities of the model of epilepsy used and general experimental conditions need further studies. Besides, it is yet to be determined which isoform of RyRs significantly contributes to Ca2+-induced excitotoxicity in the lithium-pilocarpine SE rat model.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-01-01
2024
2024-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/110047
url https://hdl.handle.net/20.500.14352/110047
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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