Riluzole-triggered GSH synthesis via activation of glutamate transporters to antagonize methylmercury-induced oxidative stress in rat cerebral cortex.

Yu Deng,Yan-Gang Wei,Hai-Bo Yang,Zhao-Fa Xu,Bin Xu,Wei Liu

doi:10.1155/2012/534705

Abstract

Objective. This study was to evaluate the effect of riluzole on methylmercury- (MeHg-) induced oxidative stress, through promotion of glutathione (GSH) synthesis by activating of glutamate transporters (GluTs) in rat cerebral cortex. Methods. Eighty rats were randomly assigned to four groups, control group, riluzole alone group, MeHg alone group, and riluzole + MeHg group. The neurotoxicity of MeHg was observed by measuring mercury (Hg) absorption, pathological changes, and cell apoptosis of cortex. Oxidative stress was evaluated via determining reactive oxygen species (ROS), 8-hydroxy-2-deoxyguanosine (8-OHdG), malondialdehyde (MDAs), carbonyl, sulfydryl, and GSH in cortex. Glutamate (Glu) transport was studied by measuring Glu, glutamine (Gln), mRNA, and protein of glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1). Result. (1) MeHg induced Hg accumulation, pathological injury, and apoptosis of cortex; (2) MeHg increased ROS, 8-OHdG, MDA, and carbonyl, and inhibited sulfydryl and GSH; (3) MeHg elevated Glu, decreased Gln, and downregulated GLAST and GLT-1 mRNA expression and protein levels; (4) riluzole antagonized MeHg-induced downregulation of GLAST and GLT-1 function and expression, GSH depletion, oxidative stress, pathological injury, and apoptosis obviously. Conclusion. Data indicate that MeHg administration induced oxidative stress in cortex and that riluzole could antagonize this situation through elevation of GSH synthesis by activating of GluTs.

Highlights

Methylmercury (MeHg) is a well-recognized environmental contaminant with established health risk to human beings by fish and marine mammal consumption [1]
Comparing with the control group, there was no significant difference of Hg concentration absorbed in cerebral cortex in the riluzole alone group; elevation of Hg levels in cerebral cortex was found in both MeHg alone and riluzole + MeHg groups; when compared with MeHg alone group, there was no obvious difference of Hg concentration in riluzole + MeHg group (Table 1)
To observe apoptosis caused by MeHg exposure and riluzole preventive effects, single-cell suspensions of cerebral cortex were made and flow cytometer (FCM) analysis was used to quantify the rates of cell apoptosis through double staining of Annexin V-FITC and propidium iodide (PI)

Summary

Introduction

Methylmercury (MeHg) is a well-recognized environmental contaminant with established health risk to human beings by fish and marine mammal consumption [1]. MeHg can cross the blood-brain barriers and cause central nervous system (CNS) damage. The mechanism underlying MeHg neurotoxicity is not fully understood. The situation of imbalance between the generation and the elimination of reactive oxygen species (ROS) named oxidative stress, which is characterized by oxidizing biological macromolecules including lipoid, cellular protein, and nucleic acid [2]. There is growing evidence indicated that oxidative stress plays a critical role in the pathogenesis of MeHg neurotoxicity both in vivo and in vitro [3, 4]. Cultured microglial cells, astrocytes, and neurons exposed to MeHg and striatal synaptosomes prepared from rats injected with MeHg, demonstrate oxidative stress [5]

Methods

Results

Conclusion