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Therapeutic efficacy of the BKCa channel opener chlorzoxazone in a mouse model of Fragile X syndrome

dc.rights.licenseopenen_US
hal.structure.identifierInstitut de Neurosciences cognitives et intégratives d'Aquitaine [INCIA]
dc.contributor.authorFERRAGUTO, Celeste
hal.structure.identifierInstitut de Neurosciences cognitives et intégratives d'Aquitaine [INCIA]
dc.contributor.authorPIQUEMAL-LAGOUEILLAT, Marion
hal.structure.identifierInstitut de Neurosciences cognitives et intégratives d'Aquitaine [INCIA]
dc.contributor.authorLEMAIRE-MAYO, Valerie
hal.structure.identifierNeurocentre Magendie : Physiopathologie de la Plasticité Neuronale [U1215 Inserm - UB]
dc.contributor.authorMOREAU, Maite
IDREF: 11490247X
hal.structure.identifierAlma Mater Studiorum Università di Bologna = University of Bologna [UNIBO]
dc.contributor.authorTRAZZI, Stefania
hal.structure.identifierAlma Mater Studiorum Università di Bologna = University of Bologna [UNIBO]
dc.contributor.authorUGUAGLIATI, Beatrice
hal.structure.identifierAlma Mater Studiorum Università di Bologna = University of Bologna [UNIBO]
dc.contributor.authorCIANI, Elisabetta
hal.structure.identifierInstitut de Neurosciences cognitives et intégratives d'Aquitaine [INCIA]
dc.contributor.authorBERTRAND, Sandrine
ORCID: 0000-0002-3020-7980
IDREF: 237520958
dc.contributor.authorLOUETTE, Eric
hal.structure.identifierInstitut de Neurosciences cognitives et intégratives d'Aquitaine [INCIA]
dc.contributor.authorBONTEMPI, Bruno
hal.structure.identifierInstitut de Neurosciences cognitives et intégratives d'Aquitaine [INCIA]
dc.contributor.authorPIETROPAOLO, Susanna
dc.date.accessioned2025-04-25T08:14:26Z
dc.date.available2025-04-25T08:14:26Z
dc.date.issued2024-12
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/206426
dc.description.abstractEnFragile X syndrome (FXS) is an X-linked neurodevelopmental disorder characterized by several behavioral abnormalities, including hyperactivity, anxiety, sensory hyper-responsiveness, and autistic-like symptoms such as social deficits. Despite considerable efforts, effective pharmacological treatments are still lacking, prompting the need for exploring the therapeutic value of existing drugs beyond their original approved use. One such repurposed drug is chlorzoxazone which is classified as a large-conductance calcium-dependent potassium (BKCa) channel opener. Reduced BKCa channel functionality has been reported in FXS patients, suggesting that molecules activating these channels could serve as promising treatments for this syndrome. Here, we sought to characterize the therapeutic potential of chlorzoxazone using the Fmr1-KO mouse model of FXS which recapitulates the main phenotypes of FXS, including BKCa channel alterations. Chlorzoxazone, administered either acutely or chronically, rescued hyperactivity and acoustic hyper-responsiveness as well as impaired social interactions exhibited by Fmr1-KO mice. Chlorzoxazone was more efficacious in alleviating these phenotypes than gaboxadol and metformin, two repurposed treatments for FXS that do not target BKCa channels. Systemic administration of chlorzoxazone modulated the neuronal activity-dependent gene c-fos in selected brain areas of Fmr1-KO mice, corrected aberrant hippocampal dendritic spines, and was able to rescue impaired BKCa currents recorded from hippocampal and cortical neurons of these mutants. Collectively, these findings provide further preclinical support for BKCa channels as a valuable therapeutic target for treating FXS and encourage the repurposing of chlorzoxazone for clinical applications in FXS and other related neurodevelopmental diseases. © The Author(s), under exclusive licence to American College of Neuropsychopharmacology 2024.
dc.description.sponsorshipInitiative d'excellence de l'Université de Bordeaux - ANR-10-IDEX-0003en_US
dc.description.sponsorshipContrôle des engrammes de la mémoire dans le cortex rétrosplénial par le thalamusen_US
dc.language.isoENen_US
dc.subject.enAnimals
dc.subject.enChlorzoxazone* / pharmacology
dc.subject.enDisease Models Animal
dc.subject.enFragile X Mental Retardation Protein* / genetics
dc.subject.enFragile X Syndrome* / drug therapy
dc.subject.enFragile X Syndrome* / genetics
dc.subject.enFragile X Syndrome* / metabolism
dc.subject.enHippocampus / drug effects
dc.subject.enHippocampus / metabolism
dc.subject.enLarge-Conductance Calcium-Activated Potassium Channel alpha Subunits* / genetics
dc.subject.enLarge-Conductance Calcium-Activated Potassium Channel alpha Subunits* / metabolism
dc.subject.enMale
dc.subject.enMice
dc.subject.enMice Inbred C57BL
dc.subject.enMice Knockout
dc.title.enTherapeutic efficacy of the BKCa channel opener chlorzoxazone in a mouse model of Fragile X syndrome
dc.title.alternativeNeuropsychopharmacologyen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1038/s41386-024-01956-6en_US
dc.subject.halSciences du Vivant [q-bio]/Neurosciences [q-bio.NC]en_US
dc.identifier.pubmed39223257en_US
bordeaux.journalNeuropsychopharmacologyen_US
bordeaux.page2032-2041en_US
bordeaux.volume49en_US
bordeaux.hal.laboratoriesNeurocentre Magendie - U1215en_US
bordeaux.issue13en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.institutionCNRS
bordeaux.teamPolarité planaire et plasticitéen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.identifier.funderIDFondation Pour l'Auditionen_US
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exportfalse
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Neuropsychopharmacology&rft.date=2024-12&rft.volume=49&rft.issue=13&rft.spage=2032-2041&rft.epage=2032-2041&rft.au=FERRAGUTO,%20Celeste&PIQUEMAL-LAGOUEILLAT,%20Marion&LEMAIRE-MAYO,%20Valerie&MOREAU,%20Maite&TRAZZI,%20Stefania&rft.genre=article


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