Original Article

Exp Neurobiol 2019; 28(4): 504-515

Published online August 31, 2019

© The Korean Society for Brain and Neural Sciences

HDAC Inhibition by Valproic Acid Induces Neuroprotection and Improvement of PD-like Behaviors in LRRK2 R1441G Transgenic Mice

Taewoo Kim, Seohoe Song, Yeongwon Park, Sinil Kang and Hyemyung Seo*

Correspondence to: *To whom correspondence should be addressed.
TEL: 82-31-400-5511, FAX: 82-31-419-1760

These authors contributed equally to this work.

Received: May 29, 2019; Revised: July 29, 2019; Accepted: July 30, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License( which permits unrestricted non-commercial use, distribution, andreproduction in any medium, provided the original work is properly cited.

Parkinson’s disease (PD) is one of the late-onset neurodegenerative movement disorder. Major pathological markers of PD include progressive loss of dopaminergic neurons, Lewy body formation, genetic mutations, and environmental factors. Epigenetic regulation of specific gene expression via impaired histone acetylation is associated with neuronal dysfunction in various neurodegenerative diseases. In this study, we hypothesized that histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can improve motor function by enhancing cell survival in PD genetic model mice with LRRK2 R1441G mutation. To address this question, we administered VPA in LRRK2 R1441G transgenic mice to determine whether VPA affects 1) histone acetylation and HDAC expression, 2) dopaminergic neuron survival, 3) inflammatory responses, 4) motor or non-motor symptoms. As results, VPA administration increased histone acetylation level and the number of tyrosine hydroxylase (TH) positive neurons in substantia nigra of LRRK2 R1441G mice. VPA reduced iba-1 positive activated microglia and the mRNA levels of pro-inflammatory marker genes in LRRK2 R1441G mice. In addition, VPA induced the improvement of PD-like motor and non-motor behavior in LRRK2 R1441G mice. These data suggest that the inhibition of HDAC can be further studied as potential future therapeutics for PD.

Graphical Abstract

Keywords: Parkinson&rsquo,s disease (PD), Histone deacetylase (HDAC), Valproic acid (VPA), Neuroprotection