Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease

Emma Hockly, Victoria M. Richon, Benjamin Woodman, Donna L. Smith, Xianbo Zhou, Eddie Rosa, Kirupa Sathasivam, Shabnam Ghazi-Noori, Amarbirpal Mahal, Philip A.S. Lowden, Joan S. Steffan, J. Lawrence Marsh, Leslie M. Thompson, Cathryn M. Lewis, Paul A. Marks, Gillian P. Bates

Research output: Contribution to journalArticlepeer-review

738 Scopus citations

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.

Original languageEnglish
Pages (from-to)2041-2046
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number4
DOIs
StatePublished - 18 Feb 2003
Externally publishedYes

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