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

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 alpha-synuclein decreased, in its native form, in substantia nigra and striatum of rotenone-treated rats, while monoubiquitinated alpha-synuclein increased in the same regions. VPA treatment counteracted both these alpha-synuclein alterations. Furthermore, monoubiquitinated alpha-synuclein increased its localization in nuclei isolated from substantia nigra of rotenone-treated rats, an effect also prevented by VPA treatment. Nuclear localization of alpha-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.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Indeed, in Drosophila, toxic nuclear aggregates of α-synuclein interact with histone H3 and promote its deacetylation, possibly through a histone-"masking" mechanism [104]. Consistent with this result, several studies targeting HDAC members through sodium butyrate or valproic acid have shown an increase in histone acetylation, associated with prosurvival and anti-inflammatory effects, and decreased neurotoxicity markers [105][106][107][108][109][110].…”

Using iPSC‐derived human DA neurons from opioid‐dependent subjects to study dopamine dynamics

“…In addition, VPA is neuroprotective in several models of neurodegenerative diseases (Monti et al. 2009, 2010; Chiu et al. 2011).…”

Protective effect of Bu-7, a flavonoid extracted from Clausena lansium, against rotenone injury in PC12 cells

“…Observations have shown that a defect in mitochondrial complex I activity may induce the apoptosis of dopaminergic cells, which may contribute to the neurodegenerative process in PD [9] . Administration of rotenone has been used extensively to create PD models to screen for neuroprotective agents both in vivo [10,11] and in vitro [12,13] .…”