Characterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling
Abstract
Recent advances in schizophrenia (SZ) research indicate that the telencephalic gamma-aminobutyric acid (GABA)ergic neurotransmission deficit associated with this psychiatric disorder probably is mediated by the hypermethylation of the glutamic acid decarboxylase 67 (GAD(67)), reelin and other GABAergic promoters. A pharmacological strategy to reduce the hypermethylation of GABAergic promoters is to induce a DNA-cytosine demethylation by altering the chromatin remodeling with valproate (VPA). When co-administered with VPA, the clinical efficacy of atypical antipsychotics is enhanced. This prompted us to investigate whether this increase in drug efficacy is related to a modification of GABAergic-promoter methylation via chromatin remodeling. Our previous and present results strongly indicate that VPA facilitates chromatin remodeling when it is associated with clozapine or sulpiride but not with haloperidol or olanzapine. This remodeling might contribute to reelin- and GAD(67)-promoter demethylation and might reverse the GABAergic-gene-expression downregulation associated with SZ morbidity.
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HDAC inhibitors may augment the efficacy of antipsychotic medications when coadministered.
“The therapeutic potential of HDAC inhibitors (HDACis) is suggested because HDACis may augment the efficacy of antipsychotic medications on coadministration.403,404”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [403]
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- Authors
- Guidotti, A., Dong, E., Kundakovic, M., Satta, R., Grayson, D. R., & Costa, E.
- Affiliations
- University of Illinois Chicago (US)
- Corresponding author
- Guidotti, Alessandro
- Venue
- Trends in Pharmacological Sciences
- Publisher
- Elsevier BV
- Published
- 2009-02
- Volume
- 30
- Issue
- 2
- Pages
- 55-60
- ISSN
- 0165-6147 (ISSN-L)
- OpenAlex
- W2125214478
- Cited by
- 130
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 1 · 2016: 9 · 2015: 9 · 2014: 22 · 2013: 7 · 2012: 15
- FWCI
- 1.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Pharmacological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH071667, MH070855, MH 62682, R01MH071667, R01MH070855, R01MH062682)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- valproic acid, chromatin remodeling, antipsychotic drugs, schizophrenia, GABAergic neurotransmission, DNA methylation, promoter demethylation, GAD67, reelin, clozapine, sulpiride, haloperidol, olanzapine, atypical antipsychotics, gene expression
- MeSH terms
- Reelin Protein, Animals, Cytosine, Drug Synergism, Drug Therapy, Combination, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Histones, Humans, Nerve Tissue Proteins, Neurons, Receptors, Nicotinic, Repressor Proteins, Schizophrenia, Serine Endopeptidases, Antipsychotic Agents, Valproic Acid, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Nicotinic Agonists, DNA Methylation, Genetic Predisposition to Disease, Chromatin Assembly and Disassembly, Epigenesis, Genetic, Histone Deacetylase Inhibitors
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