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Ferulic Acid Protects Against Lead Acetate-Induced Inhibition of Neurite Outgrowth by Upregulating HO-1 in PC12 Cells: Involvement of ERK1/2-Nrf2 Pathway

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Abstract

Prenatal lead exposure is associated with poor intellectual development in children. However, there are few breakthroughs in therapeutic intervention of developmental lead neurotoxicity. The aim of this study is to evaluate the hypothesis that ferulic acid-mediated promotion of neurite outgrowth following lead exposure might mainly result from its antioxidant capability by extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Exposure of PC12 cells to lead acetate inhibits neurite outgrowth and causes oxidative stress as measured by ROS, LPO, GSH/GSSG, and NAD+/NADH. FA treatment significantly, although not completely, protected the cells against lead acetate-induced neurite outgrowth inhibition. The effects of FA could be blocked by PD98059, zinc protoporphyrin (Zn-PP), and Nrf2 shRNA. In addition, FA induced heme oxygenase 1 (HO-1) gene expression, enhanced antioxidant response element (ARE) promoter activity, promoted ERK1/2 phosphorylation, and Nrf2 translocation in PC12 cells exposed to lead acetate. ERK1/2 locate upstream of Nrf2 and regulate Nrf2-dependent HO-1 expression in antioxidative effects of FA. Our results suggest that FA is a promising candidate for treatment of developmental lead neurotoxicity. These promising findings warrant future investigation evaluating the FA-mediated potentiation of neurite outgrowth following lead exposure in vivo.

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Abbreviations

DCFH-DA:

2′,7′-Dichlorodihydrofluorescin diacetate

ARE:

Antioxidant response element

DPI:

Diphenyleneiodonium chloride

ERK1/2:

Extracellular signal-regulated kinases 1 and 2

FA:

Ferulic acid

HO-1:

Heme oxygenase 1

LPO:

Lipid hydroperoxides

MAPKs:

Mitogen-activated protein kinases

NGF:

Nerve growth factor

NADH:

Nicotinamide adenine dinucleotide diaphorase

Nrf2:

Nuclear factor erythroid 2-related factor 2

ANOVA:

One-way analysis of variance

GSSG:

Oxidized glutathione

PI3K:

Phosphatidylinositol-3 kinase

PCR:

Polymerase chain reaction

PKC:

Protein kinase C

ROS:

Reactive oxygen species

GSH:

Reduced glutathione

SD:

Standard deviation

SNK:

Student-Newman-Keuls

Zn-PP:

Zinc protoporphyrin

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Acknowledgments

This research was supported by the National Natural Science Foundation of China (no. 81273640) to Niu YC. We thank Zhi Pan for valuable scientific discussion.

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

    Chun-Lei Yu, Xue-Mei Zhao & Ying-Cai Niu

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Correspondence to Ying-Cai Niu.

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Yu, CL., Zhao, XM. & Niu, YC. Ferulic Acid Protects Against Lead Acetate-Induced Inhibition of Neurite Outgrowth by Upregulating HO-1 in PC12 Cells: Involvement of ERK1/2-Nrf2 Pathway. Mol Neurobiol 53, 6489–6500 (2016). https://doi.org/10.1007/s12035-015-9555-x

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