1. THERAPEUTIC EFFECTS OF CHLORZOXAZONE, A BKCA CHANNEL AGONIST, IN A MOUSE MODEL OF FRAGILE X SYNDROME
- Author
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Louette E, Susanna Pietropaolo, Lemaire-Mayo, Wim E. Crusio, Piquemal M, 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), pietropaolo, susanna, and Centre National de la Recherche Scientifique (CNRS)
- Subjects
Drug ,Agonist ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.drug_class ,media_common.quotation_subject ,[SDV]Life Sciences [q-bio] ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Neurotransmitter ,030304 developmental biology ,media_common ,0303 health sciences ,business.industry ,Therapeutic effect ,medicine.disease ,3. Good health ,Developmental disorder ,Fragile X syndrome ,[SDV] Life Sciences [q-bio] ,Drug repositioning ,chemistry ,Chlorzoxazone ,business ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Fragile X syndrome (FXS) is an X-linked developmental disorder characterized by several behavioral abnormalities, including hyperactivity, sensory hyper-responsiveness and cognitive deficits, as well as autistic symptoms, e.g., reduced social interaction. These behavioural alterations are recapitulated by the major animal model of FXS, i.e., the Fmr1-KO mouse, which has been extensively employed to identify therapeutic targets for FXS, though effective pharmacological treatments are still lacking. Here we focused on the therapeutic role of large-conductance Calcium-dependent potassium (BKCa) channels, playing a crucial role in neuronal excitability and neurotransmitter release. Reduced expression/functionality of these channels has been described in FXS patients and mice, so that molecules activating these channels have been proposed as promising treatments for this syndrome. Here we performed an extensive characterization of the therapeutic impact of a novel BKCa agonist on FXS-like symptoms in the Fmr1-KO mouse model, employing a drug repurposing setting. We evaluated the acute and chronic effects of chlorzoxazone, i.e., a classical drug used for non-developmental muscular pathologies, on the locomotor, social, cognitive and sensory-motor alterations of Fmr1-KO mice and compared them with other pharmacological treatments recently proposed for FXS that instead do not target BKCa channels. Our results clearly demonstrate for the first time the marked efficacy of chlorzoxazone in treating all the behavioral abnormalities of FXS mice, thus encouraging the preferential use of this molecule over others for clinical applications in the field of FXS, and potentially of other neurodevelopmental disorders.
- Published
- 2021