Proceedings of the National Academy of Sciences - PNAS, 2003-02, Vol.100 (4), p.2041-2046
2003
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- Autor(en) / Beteiligte
- Titel
- Suberoylanilide Hydroxamic Acid, a Histone Deacetylase Inhibitor, Ameliorates Motor Deficits in a Mouse Model of Huntington's Disease
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2003-02, Vol.100 (4), p.2041-2046
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2003
- Quelle
- EZB-FREE-00999 freely available EZB journals
- Beschreibungen/Notizen
- Huntington's disease (HD) is an inherited, progressive neurological disorder that is caused by a CAG/polyglutamine repeat expansion and for which there is no effective therapy. Recent evidence indicates that transcriptional dysregulation may contribute to the molecular pathogenesis of this disease. Supporting this view, administration of histone deacetylase (HDAC) inhibitors has been shown to rescue lethality and photoreceptor neurodegeneration in a Drosophila model of polyglutamine disease. To further explore the therapeutic potential of HDAC inhibitors, we have conducted preclinical trials with suberoylanilide hydroxamic acid (SAHA), a potent HDAC inhibitor, in the R6/2 HD mouse model. We show that SAHA crosses the blood-brain barrier and increases histone acetylation in the brain. We found that SAHA could be administered orally in drinking water when complexed with cyclodextrins. SAHA dramatically improved the motor impairment in R6/2 mice, clearly validating the pursuit of this class of compounds as HD therapeutics.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.0437870100Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_149955
- Format
- –
- Schlagworte
- Acetylation, Acids, Animals, Base Sequence, Biological Sciences, Blood-Brain Barrier, Brain - drug effects, Brain - metabolism, Brain - pathology, Disease, Disease models, Disease Models, Animal, DNA Primers, Dosage, Enzyme Inhibitors - pharmacokinetics, Enzyme Inhibitors - pharmacology, Enzyme Inhibitors - therapeutic use, Female, Histone Deacetylase Inhibitors, Histones, Histones - metabolism, Huntington disease, Huntington Disease - physiopathology, Hydroxamic Acids - pharmacokinetics, Hydroxamic Acids - pharmacology, Hydroxamic Acids - therapeutic use, Medical treatment, Mice, Mice, Transgenic, Movement Disorders - drug therapy, Placebos, Reverse Transcriptase Polymerase Chain Reaction, Rodents, Transgenes, Vorinostat, Weight loss