Alpha-Lipoic Acid Mediates Clearance of Iron Accumulation by Regulating Iron Metabolism in a Parkinson's Disease Model Induced by 6-OHDA.

Shengyan Tai,Ting Cai,Chunlin Zhang,Li Xu,Suzhen Zhai,Qian Zheng,Ling Jiao,Lizhu Yang

doi:10.3389/fnins.2020.00612

Abstract

The disruption of neuronal iron homeostasis and oxidative stress are related to the pathogenesis of Parkinson’s disease (PD). Alpha-lipoic acid (ALA) is a naturally occurring enzyme cofactor with antioxidant and iron chelator properties and has many known effects. ALA has neuroprotective effects on PD. However, its underlying mechanism remains unclear. In the present study, we established PD models induced by 6-hydroxydopamine (6-OHDA) to explore the neuroprotective ability of ALA and its underlying mechanism in vivo and in vitro. Our results showed that ALA could provide significant protection from 6-OHDA-induced cell damage in vitro by decreasing the levels of intracellular reactive oxygen species and iron. ALA significantly promoted the survival of the dopaminergic neuron in the 6-OHDA-induced PD rat model and remarkably ameliorated motor deficits by dramatically inhibiting the decrease in tyrosine hydroxylase expression and superoxide dismutase activity in the substantia nigra. Interestingly, ALA attenuated 6-OHDA-induced iron accumulation both in vivo and in vitro by antagonizing the 6-OHDA-induced upregulation of iron regulatory protein 2 and divalent metal transporter 1. These results indicated that the neuroprotective mechanism of ALA against neurological injury induced by 6-OHDA may be related to the regulation of iron homeostasis and reduced oxidative stress levels. Therefore, ALA may provide neuroprotective therapy for PD and other diseases related to iron metabolism disorder.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disorder with a significant prevalence in elderly people
Apomorphine-Induced Rotation Behavior To screen for PD model rats, we analyzed the rats by apomorphine-induced rotation test at 4 weeks after 6-OHDA
The results showed that the number of body rotations in the PD group was increased drastically compared with the sham group

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder with a significant prevalence in elderly people It is associated with the loss of striatal dopamine (DA) and degeneration of dopaminergic neurons in the substantia nigra (SN) (Angelini, 2017). Oxidative stress, resulting from increased brain iron levels, and possibly from defects in antioxidant defense mechanisms, is widely believed to be associated with neuronal death in these disorders (Berg et al, 2006). IRP2 is an RNA-binding protein that can regulate intracellular iron homeostasis by binding iron responsive elements (IREs) of DMT1. Iron accumulation in PD is caused by IRP2, which increases iron uptake by regulating DMT1 (Jiang et al, 2017)

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Results

Conclusion