Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity

M Aschner,J.B.T Rocha,T Syversen,M Farina,D.O Souza

doi:10.1590/s0100-879x2007000300001

Abstract

This review addresses the mechanisms of methylmercury (MeHg)-induced neurotoxicity, specifically examining the role of oxidative stress in mediating neuronal damage. A number of critical findings point to a central role for astrocytes in mediating MeHg-induced neurotoxicity as evidenced by the following observations: a) MeHg preferentially accumulates in astrocytes; b) MeHg specifically inhibits glutamate uptake in astrocytes; c) neuronal dysfunction is secondary to disturbances in astrocytes. The generation of reactive oxygen species (ROS) by MeHg has been observed in various experimental paradigms. For example, MeHg enhances ROS formation both in vivo (rodent cerebellum) and in vitro (isolated rat brain synaptosomes), as well as in neuronal and mixed reaggregating cell cultures. Antioxidants, including selenocompounds, can rescue astrocytes from MeHg-induced cytotoxicity by reducing ROS formation. We emphasize that oxidative stress plays a significant role in mediating MeHg-induced neurotoxic damage with active involvement of the mitochondria in this process. Furthermore, we provide a mechanistic overview on oxidative stress induced by MeHg that is triggered by a series of molecular events such as activation of various kinases, stress proteins and other immediate early genes culminating in cell damage.

Highlights

Methylmercury (MeHg) is a major neurotoxicant that continues to pose appreciable risk to human health as evidenced by the tragic epidemics of MeHg poisoning in Japan and Iraq [1,2]
This review addresses the mechanisms of methylmercury (MeHg)induced neurotoxicity, examining the role of oxidative stress in mediating neuronal damage
A number of critical findings point to a central role for astrocytes in mediating MeHg-induced neurotoxicity as evidenced by the following observations: a) MeHg preferentially accumulates in astrocytes; b) MeHg inhibits glutamate uptake in astrocytes; c) neuronal dysfunction is secondary to disturbances in astrocytes

Summary

Introduction

Methylmercury (MeHg) is a major neurotoxicant that continues to pose appreciable risk to human health as evidenced by the tragic epidemics of MeHg poisoning in Japan and Iraq [1,2]. Recent studies in human populations support the earlier findings that maternal exposure to mercury during pregnancy is associated with neurological as well as neuropsychological deficits detectable in the child at 6 to 7 years of age [6,7]. Another recent study has pointed to the selective detrimental effects of MeHg on neurogenesis. The ultimate effects of MeHg in the human population remain unknown and clearly there is an urgent need to understand the mechanisms and consequences of MeHg exposure for CNS function. The current literature suggests that no single mechanism can explain the multitude of effects observed in MeHg-induced neurotoxicity

The role of astrocytes in brain function

Mechanisms of methylmercuryinduced neurotoxicity and glutamate

Though free radicals are known to play a

Findings

Cell damage