Valproate induces epigenetic modifications in lymphomonocytes from epileptic patients

Valproate (VPA) is an anti-epileptic and mood-stabilizing drug with a broad range of action and which mechanism of action still remains in part elusive. Recently the discovery that VPA modifies the epigenome increasing the transcriptional rate of target genes raises the issue of understanding the exact role of this mechanism. In this work we tested the possibility that VPA could modify the epigenome of lymphomonocytes (PBMC) obtained from epileptic patients chronically treated in monotherapy with VPA and phenobarbital. Acetyl-histone H3 expression was assessed by western blotting and global DNA methylation by incorporation of [(3)H]dCTP. A significant increase in histone acetylation and a correlated decrease of global DNA methylation were shown at VPA therapeutically relevant plasma concentrations. This effect was drug-related, since it was not demonstrated in PBMC obtained from phenobarbital-treated patients. Moreover, a VPA dose-response curve was performed on PBMC obtained from healthy controls, demonstrating an increase of acetyl-histone H3 content. We suggest that the epigenetic properties of VPA expressed on PBMC at these concentrations might be operative in different tissues, with possible implications for the field of neuropsychiatric disorders.