scholarly journals Therapeutic effects of Chlorzoxazone, a BKCa channel agonist, in a mouse model of Fragile X syndrome

2020 ◽  
Author(s):  
Valerie Lemaire-Mayo ◽  
Marion Piquemal ◽  
Wim E. Crusio ◽  
Eric Louette ◽  
Susanna Pietropaolo

ABSTRACTFragile 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.

Author(s):  
Patricia Cogram ◽  
Robert M. J. Deacon ◽  
Jennifer L. Warner-Schmidt ◽  
Melanie J. von Schimmelmann ◽  
Brett S. Abrahams ◽  
...  

2012 ◽  
Vol 11 (5) ◽  
pp. 586-600 ◽  
Author(s):  
S. M. Goebel-Goody ◽  
E. D. Wilson-Wallis ◽  
S. Royston ◽  
S. M. Tagliatela ◽  
J. R. Naegele ◽  
...  

2020 ◽  
Author(s):  
Qi Ding ◽  
Xueting Wu ◽  
Xuan Li ◽  
Hongbing Wang

ABSTRACTFragile X syndrome (FXS) is caused by mutations in the FMR1 (fragile X mental retardation 1) gene. It is a significant form of heritable intellectual disability with comorbidity of other symptoms such as autism. Due to the lack of efficacious medication, repurposing the existing FDA-approved drugs may offer an opportunity to advance clinical intervention for FXS. Analysis of the whole-genome transcription signatures predicts new therapeutic action of vorinostat to correct pathological alterations associated with FXS. We further find that the administration of vorinostat restores object location memory and passive avoidance memory in the Fmr1 knockout (KO) mice. For the non-cognitive behavioral symptoms, vorinostat corrects the autism-associated alterations, including repetitive behavior and social interaction deficits. In the open field test, vorinostat dampens hyperactivity in the center area of the arena. Surprisingly, vorinostat does not affect the abnormally elevated protein synthesis in Fmr1 KO neurons, suggesting different outcomes from correcting behavioral symptoms and specific aspects of cellular pathology. Our data reveal the therapeutic effects of the FDA-approved drug vorinostat in a mouse model of FXS and advocate efficacy testing with human patients.


2017 ◽  
Vol 43 (3) ◽  
pp. 492-502 ◽  
Author(s):  
Maria Isabel Carreno-Munoz ◽  
Fabienne Martins ◽  
Maria Carmen Medrano ◽  
Elisabetta Aloisi ◽  
Susanna Pietropaolo ◽  
...  

2017 ◽  
Vol 10 (10) ◽  
pp. 1584-1596 ◽  
Author(s):  
Julie Gaudissard ◽  
Melanie Ginger ◽  
Marika Premoli ◽  
Maurizio Memo ◽  
Andreas Frick ◽  
...  

Cell Reports ◽  
2012 ◽  
Vol 1 (3) ◽  
pp. 225-233 ◽  
Author(s):  
Darrin H. Brager ◽  
Arvin R. Akhavan ◽  
Daniel Johnston

2009 ◽  
Vol 123 (3) ◽  
pp. 677-686 ◽  
Author(s):  
Darci M. Nielsen ◽  
Jeffrey J. Evans ◽  
William J. Derber ◽  
Kenzie A. Johnston ◽  
Mark L. Laudenslager ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document