Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease Journal Article
| Authors: | Hockly, E.; Richon, V. M.; Woodman, B.; Smith, D. L.; Zhou, X.; Rosa, E.; Sathasivam, K.; Ghazi-Noori, S.; Mahal, A.; Lowden, P. A. S.; Steffan, J. S.; Marsh, J. L.; Thompson, L. M.; Lewis, C. M.; Marks, P. A.; Bates, G. P. |
| Article Title: | Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease |
| Abstract: | 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. |
| Keywords: | controlled study; histone deacetylase inhibitor; placebo; nonhuman; mouse; animals; mice; complex formation; enzyme inhibition; animal model; drug effect; animalia; mice, transgenic; rna; brain; reverse transcriptase polymerase chain reaction; enzyme inhibitors; histone; blood brain barrier; blood-brain barrier; vorinostat; hydroxamic acids; base sequence; dna primers; motor dysfunction; disease models, animal; neurologic disease; histones; histone deacetylases; aqueous solution; degenerative disease; transgenes; acetylation; drug formulation; movement disorders; huntington chorea; huntington disease; polyglutamine; female; priority journal; article; 2 hydroxypropyl beta cyclodextrin |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 100 |
| Issue: | 4 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2003-02-18 |
| Start Page: | 2041 |
| End Page: | 2046 |
| Language: | English |
| DOI: | 10.1073/pnas.0437870100 |
| PUBMED: | 12576549 |
| PROVIDER: | scopus |
| PMCID: | PMC149955 |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
