Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease
10.1073/pnas.0437870100
Crossref journal-article
Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences (341)
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.

Bibliography

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. (2003). Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proceedings of the National Academy of Sciences, 100(4), 2041–2046.

Authors 16
  1. Emma Hockly (first)
  2. Victoria M. Richon (additional)
  3. Benjamin Woodman (additional)
  4. Donna L. Smith (additional)
  5. Xianbo Zhou (additional)
  6. Eddie Rosa (additional)
  7. Kirupa Sathasivam (additional)
  8. Shabnam Ghazi-Noori (additional)
  9. Amarbirpal Mahal (additional)
  10. Philip A. S. Lowden (additional)
  11. Joan S. Steffan (additional)
  12. J. Lawrence Marsh (additional)
  13. Leslie M. Thompson (additional)
  14. Cathryn M. Lewis (additional)
  15. Paul A. Marks (additional)
  16. Gillian P. Bates (additional)
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Dates
Type When
Created 22 years, 6 months ago (Feb. 18, 2003, 3:04 p.m.)
Deposited 3 years, 4 months ago (April 12, 2022, 2:19 p.m.)
Indexed 4 days, 13 hours ago (Aug. 28, 2025, 8:02 a.m.)
Issued 22 years, 6 months ago (Feb. 7, 2003)
Published 22 years, 6 months ago (Feb. 7, 2003)
Published Online 22 years, 6 months ago (Feb. 7, 2003)
Published Print 22 years, 6 months ago (Feb. 18, 2003)
Funders 0

None

@article{Hockly_2003, title={Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease}, volume={100}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0437870100}, DOI={10.1073/pnas.0437870100}, number={4}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Hockly, Emma and Richon, Victoria M. and Woodman, Benjamin and Smith, Donna L. and Zhou, Xianbo and Rosa, Eddie and Sathasivam, Kirupa and Ghazi-Noori, Shabnam and Mahal, Amarbirpal and Lowden, Philip A. S. and Steffan, Joan S. and Marsh, J. Lawrence and Thompson, Leslie M. and Lewis, Cathryn M. and Marks, Paul A. and Bates, Gillian P.}, year={2003}, month=feb, pages={2041–2046} }