Valproate induces DNA demethylation in nuclear extracts from adult mouse brain

Abstract

The methylation and demethylation of CpG dinucleotides that are embedded in promoters play an important role in controlling gene transcription. In the mammalian brain, CpG promoter methylation is a postreplicative process mediated by a group of DNA methyltransferases (DNMT), such as DNMT1 and DNMT3a, DNMT3b. Several studies demonstrate that in addition to DNMTs, promoter methylation in the brain can be regulated by a putative DNA demethylation process that specifically removes the methyl group from the carbon-5 of cytosines. To test the existence of a possible active DNA demethylation activity in postmitotic neuronal or glial cells, we incubated an SssI methylated mouse reelin (Reln) promoter fragment (-720 to +140) with nuclear extracts from the mouse frontal cortex (FC). We observed the presence of DNA demethylation activity, which was increased in FC nuclear extracts from mice treated with valproate (VPA, 2.2 mmol/kg, twice a day for 3 days). VPA not only reduces anxiety, and cognitive deficits, and other symptoms in bipolar disorder (BP) disorder and schizophrenia (SZ) patients but also upregulates Reln and glutamic acid decarboxylase 67 (Gad67) mRNA/protein expression by reducing the methylation of their promoters. We believe that the identification of an enzyme in brain that facilitates DNA-demethylation and an understanding of how drugs induce DNA demethylation are crucial to progress in a new line of pharmacological interventions to treat neurodevelopment, neuropsychiatric, and neurodegenerative diseases.

Epigenetic Mechanisms in Stroke and Epilepsy

“…Intriguingly, valproic acid, which is commonly prescribed as an anticonvulsant drug, was subsequently discovered to be an HDAC inhibitor (Gottlicher et al, 2001). In spite of their neuroprotective actions in epilepsy and stroke, valproic acid and other broad-spectrum HDAC inhibitors can cause global DNA demethylation (Dong et al, 2010) and histone acetylation (Eleuteri et al, 2009), resulting in cell death. These findings suggest that HDAC inhibitors are relevant and feasible targets for developing clinical drugs, but at the same time, point to the need to develop new HDAC inhibitors with greatly enhanced specificity and reduced toxicity.…”

Epigenetic Treatments for Cognitive Impairments

“…Interestingly, the anti-psychotic drugs clozapine and sulpiride, which are both used for schizophrenia treatment in clinical settings, have been found to demethylate the reelin gene in vivo (Dong et al, 2008). Likewise, a number of HDAC inhibitors are capable of inducing demethylation in the brain, and co-application of the HDAC inhibitor valproate along with clozapine and sulpiride dramatically enhances the ability of these drugs to reverse reelin methylation (Dong et al, 2008(Dong et al, , 2010Szyf, 2009). Thus, treatment with HDAC inhibitors may provide a new avenue of treatment for schizophrenia, whether alone or in combination with existing pharmacotherapies.…”

Prenatal antiepileptic exposure associates with neonatal DNA methylation differences

“…[19][20][21][22] These epigenetic mechanisms participate in fundamental developmental and regulatory processes. Thus, increasing attention has been focused on the epigenetic changes resulting from other commonly prescribed AEDs.…”