Valproic Acid Protects Primary Dopamine Neurons from MPP+-Induced Neurotoxicity: Involvement of GSK3β Phosphorylation by Akt and ERK through the Mitochondrial Intrinsic Apoptotic Pathway.

Chi Zhang,Zijin Zhao,Songlin Liu,Xiangyu Wang,Qing Liu,Jun Su,Haoyu Li,Zhongliang Hu,Yiwei Liao,Xianrui Yuan,Ming Wu,Jian Yuan

doi:10.1155/2017/8124501

Chi Zhang, Zijin Zhao + Show 10 more

Open Access

https://doi.org/10.1155/2017/8124501

Copy DOI

Abstract

Valproic acid (VPA), a drug widely used to treat manic disorder and epilepsy, has recently shown neuroprotective effects in several neurological diseases, particularly in Parkinson's disease (PD). The goal of the present study was to confirm VPA's dose-dependent neuroprotective propensities in the MPP+ model of PD in primary dopamine (DA) neurons and to investigate the underlying molecular mechanisms using specific mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase- (PI3K-) Akt signaling inhibitors. VPA reversed MPP+-induced mitochondrial apoptosis and counteracted MPP+-induced extracellular signal-regulated kinase (ERK) and Akt repression and inhibited glycogen synthase kinase 3β (GSK3β) activation through induction of GSK3β phosphorylation. Moreover, inhibitors of the PI3K and MAPK pathways abolished GSK3β phosphorylation and diminished the VPA-induced neuroprotective effect. These findings indicated that VPA's neuroprotective effect in the MPP+-model of PD is associated with GSK3β phosphorylation via Akt and ERK activation in the mitochondrial intrinsic apoptotic pathway. Thus, VPA may be a promising therapeutic candidate for clinical treatment of PD.

Highlights

Parkinson’s disease (PD) is a chronic and progressive disorder of the nervous system that affects nearly one million people and causes an economic burden of nearly $25 billion per year in the United States alone [1, 2]
Cell viability, [3H] DA uptake, tyrosine hydroxylase (TH) activity, and Transferase dUTP Nick end Labeling (TUNEL) staining assays were performed to inspect the neuroprotective effect of Valproic acid (VPA) on MPP+-induced neurotoxicity in DA neuronal cultures
A cell viability assay showed that MPP+ caused approximately 50% neuronal loss compared with the control group 48 h after treatment (Figure 1(a), P < 0.05). [3H] DA uptake and TH activity were reduced to about 32% of the original level (Figures 1(b)–1(d), P < 0.05)

Summary

Introduction

Parkinson’s disease (PD) is a chronic and progressive disorder of the nervous system that affects nearly one million people and causes an economic burden of nearly $25 billion per year in the United States alone [1, 2]. PD affects the patient’s movement with the cardinal motor symptoms of resting tremor, bradykinesia, freezing of gait, and rigidity [3]. The motor manifestations of PD are attributable to the degeneration and decrease in the number of dopamine-generating cells in the substantia nigra pars compacta (SNpc) [4]. Emerging evidence showed that apoptosis plays a fundamental role in PD’s pathology. Therapeutic strategies aimed at providing neuroprotective effects against apoptosis may be beneficial in the treatment of PD [7, 8]

Objectives

Methods

Results

Discussion

Conclusion