Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease
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- 7 February 2003
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 100 (4) , 2041-2046
- https://doi.org/10.1073/pnas.0437870100
Abstract
Huntington9s 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
This publication has 32 references indexed in Scilit:
- Interaction of Huntington Disease Protein with Transcriptional Activator Sp1Molecular and Cellular Biology, 2002
- Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in DrosophilaNature, 2001
- Interference by Huntingtin and Atrophin-1 with CBP-Mediated Transcription Leading to Cellular ToxicityScience, 2001
- Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcriptionNature Genetics, 2000
- Histone deacetylase inhibitor selectively induces p21 WAF1 expression and gene-associated histone acetylationProceedings of the National Academy of Sciences, 2000
- Decreased expression of striatal signaling genes in a mouse model of Huntington's diseaseHuman Molecular Genetics, 2000
- Chemoprevention of carcinogen-induced mammary tumorigenesis by the hybrid polar cytodifferentiation agent, suberanilohydroxamic acid (SAHA).2000
- Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cellsProceedings of the National Academy of Sciences, 1999
- A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylasesProceedings of the National Academy of Sciences, 1998
- Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutationNature Genetics, 1997