Neurotoxicity Research

, Volume 17, Issue 2, pp 130–141

Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein

  • Barbara Monti
  • Valentina Gatta
  • Francesca Piretti
  • Simonetta S. Raffaelli
  • Marco Virgili
  • Antonio Contestabile
Article

DOI: 10.1007/s12640-009-9090-5

Cite this article as:
Monti, B., Gatta, V., Piretti, F. et al. Neurotox Res (2010) 17: 130. doi:10.1007/s12640-009-9090-5

Abstract

Valproic acid (VPA), an established antiepileptic and antimanic drug, has recently emerged as a promising neuroprotective agent. Among its many cellular targets, VPA has been recently demonstrated to be an effective inhibitor of histone deacetylases. Accordingly, we have adopted a schedule of dietary administration (2% VPA added to the chow) that results in a significant inhibition of histone deacetylase activity and in an increase of histone H3 acetylation in brain tissues of 4 weeks-treated rats. We have tested this schedule of VPA treatment in an animal model of Parkinson’s disease (PD), in which degeneration of nigro-striatal dopaminergic neurons is obtained through sub-chronic administration of the mitochondrial toxin, rotenone, via osmotic mini pumps implanted to rats. The decrease of the dopaminergic marker tyrosine hydroxylase in substantia nigra and striatum caused by 7 days toxin administration was prevented in VPA-fed rats. VPA treatment also significantly counteracted the death of nigral neurons and the 50% drop of striatal dopamine levels caused by rotenone administration. The PD-marker protein α-synuclein decreased, in its native form, in substantia nigra and striatum of rotenone-treated rats, while monoubiquitinated α-synuclein increased in the same regions. VPA treatment counteracted both these α-synuclein alterations. Furthermore, monoubiquitinated α-synuclein increased its localization in nuclei isolated from substantia nigra of rotenone-treated rats, an effect also prevented by VPA treatment. Nuclear localization of α-synuclein has been recently described in some models of PD and its neurodegenerative effect has been ascribed to histone acetylation inhibition. Thus, the ability of VPA to increase histone acetylation is a novel candidate mechanism for its neuroprotective action.

Keywords

Neurodegeneration Neuroprotection Nigro-striatal neurons Rotenone Valproic acid α-Synuclein 

Abbreviations

VPA

Valproic acid

PD

Parkinson’s disease

TH

Tyrosine hydroxylase

HDAC

Histone deacetylase

MPP+

1-Methyl-phenylpyridinium

6-OHDA

6-Hydrohydopamine

DMSO

Dimethylsulfoxide

PEG

Polyethylene-glycol

DOPAC

Dihydroxyphenyl acetic acid

HVA

Homovanillic acid

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Barbara Monti
    • 1
  • Valentina Gatta
    • 1
  • Francesca Piretti
    • 1
  • Simonetta S. Raffaelli
    • 2
  • Marco Virgili
    • 1
  • Antonio Contestabile
    • 1
  1. 1.Department of BiologyUniversity of BolognaBolognaItaly
  2. 2.Laboratorio Centralizzato, Policlinico S.Orsola-MalpighiBolognaItaly

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