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Ferulic Acid Ameliorates MPP+/MPTP-Induced Oxidative Stress via ERK1/2-Dependent Nrf2 Activation: Translational Implications for Parkinson Disease Treatment

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Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder closely associated with oxidative stress. The biochemical and cellular alterations that occur after cell and mouse treatment with the parkinsonism-inducing neurotoxin MPP+/MPTP are remarkably similar to those observed in idiopathic PD. Previously, we showed that ferulic acid (FA) has antioxidant properties and the ability to activate nuclear factor E2–related factor 2 (Nrf2). The present study tested the hypothesis that FA attenuates MPP+/MPTP-induced oxidative stress by regulating crosstalk between sirtuin 2 (SIRT2) and Nrf2 pathways. To test this hypothesis, we performed in vitro and in vivo studies using MPP+/MPTP-challenged SH-SY5Y cells or mice treated with or not with FA. FA marginally inhibited SIRT2 in parallel with α-synuclein at levels of transcription and translation in SH-SY5Y cells challenged with MPP+. Moreover, FA attenuated MPP+-induced oxidative stress, as indicated by reactive oxygen species, lipid hydroperoxides, GSH/GSSG ratio, and NAD+/NADH ratio. Mechanistically, FA strongly upregulated the glutamate cysteine ligase catalytic subunit and heme oxygenase-1 expression at the levels of transcription and translation. Interestingly, FA-mediated extracellular signal–regulated kinases 1 and 2 (ERK1/2) activation contributed to nuclear accumulation of Nrf2 via de novo synthesis, which was validated by the use of dominant negative ERK2. Surprisingly, activation of the ERK1/2 and inhibition of SIRT2 by FA are mediated by independent mechanisms. Furthermore, FA ameliorated motor deficits and oxidative stress in the ventral midbrain in MPTP-treated (25 mg/kg, i.p., daily for 5 days) wild-type mice and α-synuclein knockout mice, but not in Nrf2 knockout mice. Collectively, FA exerts antioxidant effects through ERK1/2-mediated activation of the Nrf2 pathway, and these results may have important translational value for the treatment of PD.

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Abbreviations

ARE:

Antioxidant response element

DCFH-DA:

2′,7′-Dichlorofluorescein-diacetate

DN:

Dominant negative

ERK:

Extracellular signal–regulated kinases

FA:

Ferulic acid

GCL:

Glutamate cysteine ligase

GSH:

Glutathione

HO-1:

Heme oxygenase-1

KO:

Knockout

LPO:

Lipid hydroperoxides

MAPK:

Mitogen-activated protein kinase

MDA:

Malondialdehyde

MPP+ :

1-Methyl-4-phenylpyridinium

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NADH:

Nicotinamide adenine dinucleotide

NQO1:

NAD(P) H quinone oxidoreductase 1

Nrf2:

Nuclear factor E2-related factor 2

PD:

Parkinson’s disease

ROS:

Reactive oxygen species

shRNA:

Short hairpin RNA

SIRT2:

Sirtuin 2

Trx1:

Thioredoxin 1

WT:

Wild-type

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Acknowledgments

We thank Yingcai Niu for valuable scientific discussion.

Funding

This research was supported by the National Natural Science Foundation of China (No. 81873133) to Dong MX.

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Author notes

  1. Xu Li and Jing Zhang contributed equally to this work.

Authors and Affiliations

  1. The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, JianHua District, Qiqihar, 161006, China

    Xu Li, Hua Rong, Xiaojie Zhang & Miaoxian Dong

  2. Department of Hematology, the First Affiliated Hospital, Harbin Medical University, Harbin, 150001, China

    Jing Zhang

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  1. Xu Li
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Contributions

M.D. and X.Z. designed and supervised the study. M.D. wrote the first draft of the manuscript. X.L., H.R., and J.Z. carried out experiments. J.Z. undertook the statistical analysis.

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Correspondence to Miaoxian Dong.

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Li, X., Zhang, J., Rong, H. et al. Ferulic Acid Ameliorates MPP+/MPTP-Induced Oxidative Stress via ERK1/2-Dependent Nrf2 Activation: Translational Implications for Parkinson Disease Treatment. Mol Neurobiol 57, 2981–2995 (2020). https://doi.org/10.1007/s12035-020-01934-1

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