Chlorzoxazone, A BKCa Channel Agonist, Rescues The Pathological Phenotypes Of Williams-Beuren Syndrome In A Preclinical Model
| Autor: | Marion Piquemal, Noura Abdulkarim-Abdalla, Paula Ortiz-Romero, Valerie Lemaire-Mayo, Wim E. Crusio, Eric Louette, Victoria Campuzano, Susanna Pietropaolo |
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| Přispěvatelé: | Centre National de la Recherche Scientifique (CNRS), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Chromosome 7 (human)
Agonist 0303 health sciences congenital hereditary and neonatal diseases and abnormalities medicine.drug_class business.industry [SDV]Life Sciences [q-bio] Mutant Locus (genetics) medicine.disease Phenotype 3. Good health Developmental disorder 03 medical and health sciences 0302 clinical medicine Chlorzoxazone medicine Cancer research cardiovascular diseases business Pathological 030217 neurology & neurosurgery 030304 developmental biology medicine.drug |
| Popis: | Williams-Beuren syndrome (WBS) is a rare developmental disorder caused by the deletion of a 1.5 Mb region in chromosome 7 (7q11.23). WBS has been recently modelled by a mutant mouse line having a complete deletion (CD) of the equivalent locus on mouse chromosome 5, thus resembling the genetic defect found in WBS patients. CD mice have been shown to have physical and neurobehavioral abnormalities that recapitulate most of the symptoms associated with human WBS, including cardiovascular, motor, social, emotional and sensory alterations. This model has been largely used to investigate the etiopathological mechanisms of WBS; nonetheless, pharmacological therapies for this syndrome have not been identified yet. Here we propose a novel treatment for WBS, chlorzoxazone (CHLOR), i.e., a molecule targeting calcium-activated large conductance potassium (BKCa) channels, since a reduction in the expression of these channels has been recently described in neurons from WBS patients, as well as in other rare developmental pathologies. Our results demonstrate both the acute and chronic effects of CHLOR on some major pathological phenotypes of CD mice, including several behavioural alterations and cardiac hypertrophy. We conclude that BKCa channels are a therapeutic target of high potential for clinical applications and are likely to play a key role in the etiopathology of WBS. |
| Databáze: | OpenAIRE |
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