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. 2003 Feb 18;100(4):2041-6.
doi: 10.1073/pnas.0437870100. Epub 2003 Feb 7.

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

Emma Hockly  1 , 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
Affiliations

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

Emma Hockly et al. Proc Natl Acad Sci U S A. .

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.

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Figures

Figure 1
Figure 1
SAHA crosses the blood–brain barrier and increases histone acetylation. Histones H2B and H4 are dramatically hyperacetylated 2 h post-s.c. administration of the SAHA HOP-β-CD complex in both brain and spleen. There is no difference in acetylation between genotypes.
Figure 2
Figure 2
Dose escalation strategy for oral SAHA administration in WT mice. (a) To determine the maximum dose of SAHA, which when complexed with HOP-β-CD could be administered to WT mice in drinking water, a dose escalation strategy was used (Table 1). Our initial intention was to assess the tolerability of 2.67 g/liter (400 mg/kg) and 4 g/liter (600 mg/kg). (b) Doses of 2.67 g/liter SAHA and above caused dramatic weight loss. On lowering the dose from 3.33 g/liter to 2 g/liter (300 mg/kg), the formulation was well tolerated.
Figure 3
Figure 3
Study design and outcome measures for the SAHA preclinical trial. (a) Comparison of the variation in age, weight, grip strength, and Rotarod performance between treatment groups and before SAHA or placebo administration. (b) R6/2 mice treated with 0.67 g/liter SAHA show a highly significant improvement in Rotarod performance. Latency to fall at 8 weeks of age was 207 versus 144 s (P = 0.003), at 10 weeks was 187 versus 113 s (P = 0.0001), and at 12 weeks was 144 versus 72 s (P = 0.0006). There was no significant difference in the performance of SAHA- and placebo-treated WT mice (P = 0.28 at 8 weeks, P = 0.14 at 10 weeks, P = 0.38 at 12 weeks). (c) Administration of SAHA does not improve mean grip strength in either WT or R6/2 mice. However, correction for weight revealed a relative improvement in grip strength in the R6/2 mice treated with SAHA (P = 0.012). (d) Both WT and R6/2 mice treated with SAHA failed to gain weight to the same extent as compared with their littermates taking the placebo control. Also, we found no treatment-related difference in the magnitude of weight loss of R6/2 mice compared with WT.
Figure 4
Figure 4
Effect of SAHA on gross and cellular brain morphology. Frozen brain sections were cut from mice at 13 weeks of age, between Bregma 0 and 0.5 mm in the region of 0.26 mm and stained for Nissl substance with cresyl violet. (a) There is no marked change in gross morphology between R6/2 and WT mice in either treatment group. (b) Cellular atrophy is apparent in Nissl-stained sections from R6/2 brains. Treatment of R6/2 mice with SAHA resulted in Nissl staining more closely resembling that seen in WT mice.
Figure 5
Figure 5
SAHA does not inhibit polyQ aggregation or decrease transgene protein levels. (a) Quantification of aggregate load in hippocampal slice cultures that have been incubated in the presence of SAHA or HOP-β-CD for 4 weeks. SAHA has no effect on aggregate count, aggregate fluorescence intensity, or aggregate area. Error bars = SD. (b) Immunodetection of polyQ aggregates (arrow) using antibodies raised against huntingtin (S830) and ubiquitin in postmortem brains from R6/2 mice at 13 weeks of age that had been administered SAHA or placebo for 8 weeks (age 13 weeks). (c) Real-time PCR to determine the level of expression of the R6/2 transgene and c-abl oncogene. R6/2 mice (10–11 weeks) had been treated with 0.67 g/liter SAHA (n = 7) or placebo (n = 7) for 17 days.
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