Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease.
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.
Hockly
Emma
E
Medical and Molecular Genetics, Guy's, King's and St. Thomas' School of Medicine, King's College London, Eighth Floor Guy's Tower, Guy's Hospital, London SE1 9RT, United Kingdom.
Richon
Victoria M
VM
Woodman
Benjamin
B
Smith
Donna L
DL
Zhou
Xianbo
X
Rosa
Eddie
E
Sathasivam
Kirupa
K
Ghazi-Noori
Shabnam
S
Mahal
Amarbirpal
A
Lowden
Philip A S
PA
Steffan
Joan S
JS
Marsh
J Lawrence
JL
Thompson
Leslie M
LM
Lewis
Cathryn M
CM
Marks
Paul A
PA
Bates
Gillian P
GP
D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006816:Huntington Disease / Q000503:physiopathology*; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000188:drug therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes; D000077337:Vorinostat
D017931:DNA Primers; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D000077337:Vorinostat