5 research outputs found

    The Effects of Pharmacological Inhibition of Histone Deacetylase 3 (HDAC3) in Huntington’s Disease Mice

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    <div><p>An important epigenetic modification in Huntington’s disease (HD) research is histone acetylation, which is regulated by histone acetyltransferase and histone deacetylase (HDAC) enzymes. HDAC inhibitors have proven effective in HD model systems, and recent work is now focused on functional dissection of the individual HDAC enzymes in these effects. Histone deacetylase 3 (HDAC3), a member of the class I subfamily of HDACs, has previously been implicated in neuronal toxicity and huntingtin-induced cell death. Hence, we tested the effects of RGFP966 ((<i>E</i>)-N-(2-amino-4-fluorophenyl)-3-(1-cinnamyl-1<i>H</i>-pyrazol-4-yl)acrylamide), a benzamide-type HDAC inhibitor that selectively targets HDAC3, in the N171-82Q transgenic mouse model of HD. We found that RGFP966 at doses of 10 and 25 mg/kg improves motor deficits on rotarod and in open field exploration, accompanied by neuroprotective effects on striatal volume. In light of previous studies implicating HDAC3 in immune function, we measured gene expression changes for 84 immune-related genes elicited by RGFP966 using quantitative PCR arrays. RGFP966 treatment did not cause widespread changes in cytokine/chemokine gene expression patterns, but did significantly alter the striatal expression of macrophage migration inhibitory factor (<i>Mif)</i>, a hormone immune modulator associated with glial cell activation, in N171-82Q transgenic mice, but not WT mice. Accordingly, RGFP966-treated mice showed decreased glial fibrillary acidic protein (GFAP) immunoreactivity, a marker of astrocyte activation, in the striatum of N171-82Q transgenic mice compared to vehicle-treated mice. These findings suggest that the beneficial actions of HDAC3 inhibition could be related, in part, with lowered <i>Mif</i> levels and its associated downstream effects.</p></div

    Summary of cytokines array gene expression changes in striatum due to RGFP966 treatment.

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    <p>A. Heatmap of expression values for 84 cytokine/chemokine genes showing two-way clustering of expression levels and treatment groups. Red denotes increased relative gene expression levels for the indicated groups, with green denoting decreased expression levels. B. Volcano plots of expression changes due to RGFP966 treatment showing three different comparisons, as indicated. Dotted line on y-axis denotes the significance cut-off of p-value<0.05, using one-way ANOVA. Dotted lines on x-axis denote a fold-change cut-off of > +/- 2.</p

    Real-time qPCR results showing altered expression of <i>Mif</i> and <i>Il1b</i> in striatum and cortex of RGFP966 treated WT and N171-82Q mice.

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    <p>Groups of mice were treated with RGFP966 (25 mg/kg) for 12 weeks beginning at 8 weeks of age. Bar graphs shown the mean +/- S.E.M. expression value from n = 5–6 mice per group normalized to the expression of <i>Hprt</i>. Significant differences of p<0.05 were measured by a two-tailed, unpaired Student’s <i>t</i> test and are indicated by an asterisk (*).</p

    The effects of RGFP966 (25 mg/kg) on striatal volume in WT and N171-82Q transgenic mice.

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    <p>Representative photomicrographs of the striatum at ~0.62 Bregma under each condition are shown on the left. Scale bar = 40 μm. Bar graphs show quantitation of striatal volume. The total area of the striatum was assessed using sections 125 μm apart spanning the striatum from ~bregma, 1.18 to 0.38 mm. One-way ANOVA (Dunnett’s post-test) revealed significant differences between vehicle-treated wild type and N171-82Q transgenic mice and also a significant difference between vehicle-treated and RGFP966-treated N171-82Q mice (*, P<0.05). Bars represent mean score ± SEM (n = 6 to 7 per group).</p