Valproate induces epigenetic modifications in lymphomonocytes from epileptic patients

Lucio Tremolizzo, Jacopo C. DiFrancesco, Virginia Rodriguez-Menendez, Chiara Riva, Elisa Conti, Gloria Galimberti, Claudio Ruffmann, Carlo Ferrarese

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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 [3H]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.

Original languageEnglish
Pages (from-to)47-51
Number of pages5
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume39
Issue number1
DOIs
Publication statusPublished - Oct 1 2012

Fingerprint

Valproic Acid
Epigenomics
Histones
DNA Methylation
Phenobarbital
Acetylation
Pharmaceutical Preparations
Western Blotting
Genes

Keywords

  • DNA methylation
  • Epimutations
  • Histone acetylation
  • Valproate

ASJC Scopus subject areas

  • Biological Psychiatry
  • Pharmacology

Cite this

Tremolizzo, L., DiFrancesco, J. C., Rodriguez-Menendez, V., Riva, C., Conti, E., Galimberti, G., ... Ferrarese, C. (2012). Valproate induces epigenetic modifications in lymphomonocytes from epileptic patients. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 39(1), 47-51. https://doi.org/10.1016/j.pnpbp.2012.04.016

Valproate induces epigenetic modifications in lymphomonocytes from epileptic patients. / Tremolizzo, Lucio; DiFrancesco, Jacopo C.; Rodriguez-Menendez, Virginia; Riva, Chiara; Conti, Elisa; Galimberti, Gloria; Ruffmann, Claudio; Ferrarese, Carlo.

In: Progress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 39, No. 1, 01.10.2012, p. 47-51.

Research output: Contribution to journalArticle

Tremolizzo, L, DiFrancesco, JC, Rodriguez-Menendez, V, Riva, C, Conti, E, Galimberti, G, Ruffmann, C & Ferrarese, C 2012, 'Valproate induces epigenetic modifications in lymphomonocytes from epileptic patients', Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 39, no. 1, pp. 47-51. https://doi.org/10.1016/j.pnpbp.2012.04.016
Tremolizzo, Lucio ; DiFrancesco, Jacopo C. ; Rodriguez-Menendez, Virginia ; Riva, Chiara ; Conti, Elisa ; Galimberti, Gloria ; Ruffmann, Claudio ; Ferrarese, Carlo. / Valproate induces epigenetic modifications in lymphomonocytes from epileptic patients. In: Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2012 ; Vol. 39, No. 1. pp. 47-51.
@article{054ea881c4774bed9a3b35efff09f993,
title = "Valproate induces epigenetic modifications in lymphomonocytes from epileptic patients",
abstract = "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 [3H]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.",
keywords = "DNA methylation, Epimutations, Histone acetylation, Valproate",
author = "Lucio Tremolizzo and DiFrancesco, {Jacopo C.} and Virginia Rodriguez-Menendez and Chiara Riva and Elisa Conti and Gloria Galimberti and Claudio Ruffmann and Carlo Ferrarese",
year = "2012",
month = "10",
day = "1",
doi = "10.1016/j.pnpbp.2012.04.016",
language = "English",
volume = "39",
pages = "47--51",
journal = "Progress in Neuro-Psychopharmacology and Biological Psychiatry",
issn = "0278-5846",
publisher = "Elsevier Inc.",
number = "1",

}

TY - JOUR

T1 - Valproate induces epigenetic modifications in lymphomonocytes from epileptic patients

AU - Tremolizzo, Lucio

AU - DiFrancesco, Jacopo C.

AU - Rodriguez-Menendez, Virginia

AU - Riva, Chiara

AU - Conti, Elisa

AU - Galimberti, Gloria

AU - Ruffmann, Claudio

AU - Ferrarese, Carlo

PY - 2012/10/1

Y1 - 2012/10/1

N2 - 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 [3H]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.

AB - 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 [3H]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.

KW - DNA methylation

KW - Epimutations

KW - Histone acetylation

KW - Valproate

UR - http://www.scopus.com/inward/record.url?scp=84864506892&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864506892&partnerID=8YFLogxK

U2 - 10.1016/j.pnpbp.2012.04.016

DO - 10.1016/j.pnpbp.2012.04.016

M3 - Article

C2 - 22584634

AN - SCOPUS:84864506892

VL - 39

SP - 47

EP - 51

JO - Progress in Neuro-Psychopharmacology and Biological Psychiatry

JF - Progress in Neuro-Psychopharmacology and Biological Psychiatry

SN - 0278-5846

IS - 1

ER -