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HDAC2-dependent Antipsychotic-like Effects of Chronic Treatment with the HDAC Inhibitor SAHA in Mice.

ABSTRACT: Antipsychotic drugs, including both typical such as haloperidol and atypical such as clozapine, remain the current standard for schizophrenia treatment. These agents are relatively effective in treating hallucinations and delusions. However, cognitive deficits are at present essentially either persistent or exacerbated following chronic antipsychotic drug exposure. This underlines the need of new therapeutic approaches to improve cognition in treated schizophrenia patients. Our previous findings suggested that upregulation of histone deacetylase 2 (HDAC2) expression upon chronic antipsychotic treatment may lead to negative effects on cognition and cortical synaptic structure. Here we tested different phenotypes of psychosis, synaptic plasticity, cognition and antipsychotic drug action in HDAC2 conditional knockout (HDAC2-cKO) mice and controls. Conditional depletion of HDAC2 function in glutamatergic pyramidal neurons led to a protective phenotype against behavior models induced by psychedelic and dissociative drugs, such as DOI and MK801, respectively. Immunoreactivity toward synaptophysin, which labels presynaptic terminals of functional synapses, was decreased in the frontal cortex of control mice chronically treated with clozapine - an opposite effect occurred in HDAC2-cKO mice. Chronic treatment with the class I and class II HDAC inhibitor SAHA prevented via HDAC2 the disruptive effects of MK801 on recognition memory. Additionally, chronic SAHA treatment affected transcription of numerous plasticity-related genes in the frontal cortex of control mice, an effect that was not observed in HDAC2-cKO animals. Together, these findings suggest that HDAC2 may represent a novel target to improve synaptic plasticity and cognition in treated schizophrenia patients.

SUBMITTER: de la Fuente Revenga M

PROVIDER: S-EPMC6129430 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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HDAC2-dependent Antipsychotic-like Effects of Chronic Treatment with the HDAC Inhibitor SAHA in Mice.

de la Fuente Revenga Mario M Ibi Daisuke D Saunders Justin M JM Cuddy Travis T Ijaz Maryum K MK Toneatti Rudy R Kurita Mitsumasa M Holloway Terrell T Shen Li L Seto Jeremy J Dozmorov Mikhail G MG González-Maeso Javier J

Neuroscience 20180717

Antipsychotic drugs, including both typical such as haloperidol and atypical such as clozapine, remain the current standard for schizophrenia treatment. These agents are relatively effective in treating hallucinations and delusions. However, cognitive deficits are at present essentially either persistent or exacerbated following chronic antipsychotic drug exposure. This underlines the need of new therapeutic approaches to improve cognition in treated schizophrenia patients. Our previous findings ...[more]

PMID: 30025863

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Project description:Here, we examined mouse brain trancriptional changes 1 hour after the 10th daily i.p. treament with one of the four following treaments: i) vehicle control (45% saline, 45% PEG-400 and 10% DMSO administered at 7.5mL/kg), ii) Cpd-60, 45mg/kg , administered at 7.5mL/kg or iii) SAHA, 25mg/kg, administered at 5mL/kg) or iv) CI-994, 10mg/kg, administered at 5mL/kg. Cpd-60 is a benzamide HDAC inhibitor with selectivity for class I HDAC subtypes HDAC1 and HDAC2; CI-994 is a benzamide inhibitor with selectivity for HDACs1,2 and 3; SAHA is a hydroxamic acid HDAC inhibitor with selectivity for class I HDAC subtypes 1,2, and 3 and the class II HDAC subtype HDAC 6. We examined transcript differences using the Illumnia WG-6 2.0 whole genome expression array and profiled 3 specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from each of 36 mice (n=6 mice / treatment group) . For application to array chips, we pooled two biological replicates from like treatment and brain region-groups such that 36 samples were applied in total: 4 treatment groups x 3 brain regions per treament group x 3 pools of two samples each for each treatment/brain region. Treatment groups: All adult male, C57BL/6 mice (n=6mice/treatment group) were sacrificed by rapid cervical dislocation and decapitation 1 hour after the tenth daily i.p. injection with one of the four following treaments: i) vehicle control (45% saline, 45% PEG-400 and 10% DMSO administered at 7.5mL/kg), ii) Cpd-60, 45mg/kg , administered at 7.5mL/kg or iii) SAHA, 25mg/kg, administered at 5mL/kg) or iv) CI-994, 10mg/kg, administered at 5mL/kg. Brains were removed, frozen immediately on dry ice and stored at -80°C until use. Frozen mouse brains (n = 6/ treatment group) were rapidly dissected at 4°C, isolating medial prefrontal cortex, nucleus accumbens and hippocampus. RNA was isolated using the Qiagen RNeasy Lipid Tissue mini kit, RNA concentration was determined using a NanoDrop spectrophotometer and quality was assessed using Agilent Bioanalyzer PICO chips, with the RNA Integrity Number (RIN) determined at 7.0-8.8 for all samples assayed, indicative of good RNA quality. For microarray experiments on Illumina MouseWG-6 BeadChips, RNA samples were pooled from two biological replicates such that the total number of samples was 36 (3 treatment groups x 3 brain regions x 3 RNA pools representing two mice per pool). All microarray analysis and gene set analysis (GSA) was performed using GeneSpring software (v.11.5.1) with raw signals adjusted using quantile normalization and baseline transformation with the median signal in all samples set to zero. Data were included in subsequent analyses if the normalized signal, thresholded at 0.8, was ‘present’ for 3 of 3 replicates for like treatment and tissue groups.

Project description:BACKGROUND:The poly ADP ribose polymerase (PARP) inhibitor olaparib has been approved for treating prostate cancer (PCa) with BRCA mutations, and veliparib, another PARP inhibitor, is being tested in clinical trials. However, veliparib only showed a moderate anticancer effect, and combination therapy is required for PCa patients. Histone deacetylase (HDAC) inhibitors have been tested to improve the anticancer efficacy of PARP inhibitors for PCa cells, but the exact mechanisms are still elusive. METHODS:Several types of PCa cells and prostate epithelial cell line RWPE-1 were treated with veliparib or SAHA alone or in combination. Cell viability or clonogenicity was tested with violet crystal assay; cell apoptosis was detected with Annexin V-FITC/PI staining and flow cytometry, and the cleaved PARP was tested with western blot; DNA damage was evaluated by staining the cells with ?H2AX antibody, and the DNA damage foci were observed with a fluorescent microscopy, and the level of ?H2AX was tested with western blot; the protein levels of UHRF1 and BRCA1 were measured with western blot or cell immunofluorescent staining, and the interaction of UHRF1 and BRCA1 proteins was detected with co-immunoprecipitation when cells were treated with drugs. The antitumor effect of combinational therapy was validated in DU145 xenograft models. RESULTS:PCa cells showed different sensitivity to veliparib or SAHA. Co-administration of both drugs synergistically decreased cell viability and clonogenicity, and synergistically induced cell apoptosis and DNA damage, while had no detectable toxicity to normal prostate epithelial cells. Mechanistically, veliparib or SAHA alone reduced BRCA1 or UHRF1 protein levels, co-treatment with veliparib and SAHA synergistically reduced BRCA1 protein levels by targeting the UHRF1/BRCA1 protein complex, the depletion of UHRF1 resulted in the degradation of BRCA1 protein, while the elevation of UHRF1 impaired co-treatment-reduced BRCA1 protein levels. Co-administration of both drugs synergistically decreased the growth of xenografts. CONCLUSIONS:Our studies revealed that the synergistic lethality of HDAC and PARP inhibitors resulted from promoting DNA damage and inhibiting HR DNA damage repair pathways, in particular targeting the UHRF1/BRCA1 protein complex. The synergistic lethality of veliparib and SAHA shows great potential for future PCa clinical trials.

Dataset Information

HDAC2-dependent Antipsychotic-like Effects of Chronic Treatment with the HDAC Inhibitor SAHA in Mice.

Publications

HDAC2-dependent Antipsychotic-like Effects of Chronic Treatment with the HDAC Inhibitor SAHA in Mice.

Similar Datasets

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