Therapeutic efficacy of the BKCa channel opener chlorzoxazone in a mouse model of Fragile X syndrome
Neuropsychopharmacol.. 2024-09-02; :
DOI: 10.1038/s41386-024-01956-6
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1. Neuropsychopharmacology. 2024 Sep 2. doi: 10.1038/s41386-024-01956-6. Online
ahead of print.
Therapeutic efficacy of the BKCa channel opener chlorzoxazone in a mouse model
of Fragile X syndrome.
Ferraguto C(#)(1), Piquemal-Lagoueillat M(#)(1), Lemaire V(1), Moreau MM(2),
Trazzi S(3), Uguagliati B(3), Ciani E(3), Bertrand SS(1), Louette E(4), Bontempi
B(1), Pietropaolo S(5).
Author information:
(1)Univ. Bordeaux, CNRS, EPHE, INCIA, UMR 5287, Bordeaux, France.
(2)Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, Bordeaux, France.
(3)Department of Biomedical and Neuromotor Sciences, University of Bologna,
Bologna, Italy.
(4)Assetsup, Le Boulinier, Rueil-Malmaison, France.
(5)Univ. Bordeaux, CNRS, EPHE, INCIA, UMR 5287, Bordeaux, France.
.
(#)Contributed equally
Fragile 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.
© 2024. The Author(s), under exclusive licence to American College of
Neuropsychopharmacology.
DOI: 10.1038/s41386-024-01956-6
PMID: 39223257