frax486 and Fragile-X-Syndrome

frax486 has been researched along with Fragile-X-Syndrome* in 1 studies

Other Studies

1 other study(ies) available for frax486 and Fragile-X-Syndrome

ArticleYear
Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486.
    Proceedings of the National Academy of Sciences of the United States of America, 2013, Apr-02, Volume: 110, Issue:14

    Fragile X syndrome (FXS) is the most common inherited form of autism and intellectual disability and is caused by the silencing of a single gene, fragile X mental retardation 1 (Fmr1). The Fmr1 KO mouse displays phenotypes similar to symptoms in the human condition--including hyperactivity, repetitive behaviors, and seizures--as well as analogous abnormalities in the density of dendritic spines. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect in Fmr1 KO mice may also ameliorate autism-like behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). Our results demonstrate that a potent small molecule inhibitor of group I PAKs reverses dendritic spine phenotypes in Fmr1 KO mice. Moreover, this PAK inhibitor--which we call FRAX486--also rescues seizures and behavioral abnormalities such as hyperactivity and repetitive movements, thereby supporting the hypothesis that a drug treatment that reverses the spine abnormalities can also treat neurological and behavioral symptoms. Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult Fmr1 KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.

    Topics: Actin Cytoskeleton; Animals; Dendritic Spines; Dose-Response Relationship, Drug; Drug Discovery; Epilepsy, Reflex; Fragile X Mental Retardation Protein; Fragile X Syndrome; Male; Mice; Mice, Knockout; Molecular Structure; p21-Activated Kinases; Phenotype; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Rotarod Performance Test; Structure-Activity Relationship

2013
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