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Exploring Cross-Talk Between Oxidative Damage and Excitotoxicity and the Effects of Riluzole in the Rat Cortex After Exposure to Methylmercury

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Abstract

Methylmercury (MeHg) is a ubiquitous environmental toxin that causes neurologic and developmental diseases. Oxidative damage and excitotoxicity are putative mechanisms, which underlie MeHg-induced neurotoxicity. In this study, the cross-talk between the oxidative damage and excitotoxicity pathways and the protective effects of riluzole in the rat cortex were explored. Rats were injected with MeHg and/or riluzole, and cold vapor atomic fluorescence spectrometry, hematoxylin and eosin staining, flow cytometry, fluorescence assays, spectrophotometry, real-time PCR, and Western blotting were used to evaluate neurotoxicity. The present study showed that (1) MeHg accumulated in the cerebral cortex and caused pathology. (2) MeHg caused oxidative damage by inducing glutathione (GSH) depletion, reactive oxygen species (ROS) production, inhibition of antioxidant enzyme activity, and alteration of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. (3) MeHg disrupted the glutamate transporters (GluTs), glutamate–glutamine cycle, and N-methyl-d-aspartate receptor expression and induced excitotoxicity. (4) Excitotoxicity resulted in disruption of GSH synthesis, calcium overloading, oxidative damage, and excessive ROS production. (5) Pretreatment with riluzole antagonized MeHg neurotoxicity by down regulating cross-talk between the oxidative damage and excitotoxicity pathways. In conclusion, the cross-talk between the oxidative damage and excitotoxicity pathways caused by MeHg exposure was linked by GluTs and calcium and inhibited by riluzole treatment.

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Abbreviations

MeHg:

Methylmercury

CNS:

Central nervous system

GSH:

Glutathione

ROS:

Reactive oxygen species

Nrf2:

Nuclear factor erythroid 2-related factor 2

CNC:

Cap-n-collar

bZIP:

Basic region leucine zipper

AREs:

Antioxidant response elements

HO-1:

Heme oxygenase 1

γ-GCS:

γ-Glutamylcysteine synthetase

GPx-1:

Glutathione peroxidase 1

Glu:

Glutamate

NMDA:

N-methyl-d-aspartate

Gln:

Glutamine

PAG:

Phosphate activated glutaminase

GluTs:

Glutamate transporters

GLAST:

Glutamate/aspartate transporter

GLT-1:

Glutamate transporter-1

GS:

Glutamine synthetase

H2O2 :

Hydrogen peroxide

ONOO− :

Peroxynitrite

ALS:

Amyotrophic lateral sclerosis

SOD:

Superoxide dismutase

GSH-Px:

Glutathione peroxidase

DCFH-DA:

2, 7-Dichlorofluorescin-diacetate

BSA:

Bovine serum albumin

CVAFS:

Cold vapor atomic fluorescence spectrometry

HE:

Hematoxylin and eosin

DTNB:

1, 2-Dithio-bis nitro benzoic acid

PVDF:

Polyvinylidene difluoride

ANOVA:

One-way analysis of variance

BBB:

Blood–brain barrier

LAT:

L-type neutral amino acid carrier transport

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Acknowledgments

A grant from the National Natural Science Foundation of China (No. 81172631) supported this work.

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Authors and Affiliations

  1. Department of Environmental Health, School of Public Health, China Medical University, North 2nd Road 92, Heping Ward, Shenyang, 110001, Liaoning, People’s Republic of China

    Yu Deng, Zhaofa Xu, Bin Xu, Wei Liu, Yangang Wei, Yuehui Li, Shu Feng & Tianyao Yang

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  1. Yu Deng
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  2. Zhaofa Xu
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  3. Bin Xu
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  4. Wei Liu
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  7. Shu Feng
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Correspondence to Zhaofa Xu.

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Deng, Y., Xu, Z., Xu, B. et al. Exploring Cross-Talk Between Oxidative Damage and Excitotoxicity and the Effects of Riluzole in the Rat Cortex After Exposure to Methylmercury. Neurotox Res 26, 40–51 (2014). https://doi.org/10.1007/s12640-013-9448-6

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  • DOI: https://doi.org/10.1007/s12640-013-9448-6

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