DNA methylation and demethylation as targets for antipsychotic therapy

Schizophrenia (SZ) and bipolar disorder (BPD) patients show a downregulation of GAD67, reelin (RELN), brain-derived neurotrophic factor (BDNF), and other genes expressed in telencephalic GABAergic and glutamatergic neurons. This downregulation is associated with the enrichment of 5-methylcytosine an...

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Bibliographic Details
Published in:Dialogues in clinical neuroscience 2014-09, Vol.16 (3), p.419-429
Main Authors: Guidotti, Alessandro, Grayson, Dennis R.
Format: Article
Language:English
Subjects:
Animals
Antipsychotic Agents - pharmacology
Antipsychotic Agents - therapeutic use
Biological and medical sciences
bipolar
Chromatin Assembly and Disassembly - drug effects
chromatin remodeling
clozapine epigenetics
DNA Methylation - drug effects
Down-Regulation - drug effects
histone deacetylase inhibitor
Humans
Medical sciences
Mental Disorders - drug therapy
Mental Disorders - enzymology
Mental Disorders - genetics
neuroleptic
Neuropharmacology
Pharmacological Aspects
Pharmacology. Drug treatments
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)
Psycholeptics: tranquillizer, neuroleptic
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
psychosis
schizophrenia
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Summary:Schizophrenia (SZ) and bipolar disorder (BPD) patients show a downregulation of GAD67, reelin (RELN), brain-derived neurotrophic factor (BDNF), and other genes expressed in telencephalic GABAergic and glutamatergic neurons. This downregulation is associated with the enrichment of 5-methylcytosine and 5-hydroxymethylcytosine proximally at gene regulatory domains at the respective genes. A pharmacological strategy to reduce promoter hypermethylation and to induce a more permissive chromatin conformation is to administer drugs, such as the histone deacetylase (HDAC) inhibitor valproate (VPA), that facilitate chromatin remodeling. Studies in mouse models of SZ indicate that clozapine induces DNA demethylation at relevant promoters, and that this action is potentiated by VPA. By activating DNA demethylation, clozapine or its derivatives with VPA or other more potent and selective HDAC inhibitors may be a promising treatment strategy to correct the gene expression deficits detected in postmortem brain of SZ and BPD patients.
ISSN:1294-8322
1958-5969
1958-5969
DOI:10.31887/DCNS.2014.16.3/aguidotti