Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity

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 MeHginduced 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.

Diphenyl diselenide a janus-faced molecule

“…17 Similarly, the in vitro pro-oxidant activity of the environmental neuroxicant methylmercury 18 in brain cortical slices was blocked by diphenyl diselenide 19 and ebselen tentatively via degradation of hydrogen peroxide formed at the mitochondrial level. 18,19 The results obtained with brain slices clearly indicated that diphenyl diselenide can behave as a mimetic of GPx in biological systems in vitro. Furthermore, these results may suggest that the blockage of lipid peroxidation by diphenyl diselenide observed under different experimental Oxidation of thiol-containing enzymes by diphenyl deselenide (PhSeSePh).…”

“…Hg 2+ and methylmercury (MeHg) are the two most important forms of mercury found in the environment 7,18 and chemically they can be classified as soft acids (soft electrophiles) and will react preferentially with soft bases (soft nucleophiles). 50 In living cells, the most important nucleophile center is the sulfhydryl group (thiol/thiolate; Figure 2) found in proteins and GSH.…”

Toxicity of organic and inorganic mercury species in differentiated human neurons and human astrocytes

“…They ranged from 30 nM in rat cerebellar neurons (48 h incubation) to 5 M in mouse cerebellar neurons (15 min incubation) [9][10][11]. Since evidence exists that MeHg accumulates preferentially in astrocytes and neuronal dysfunction is secondary to disturbance of astrocytes, a central role for astrocytes in mediating Hg induced neurotoxicity has been proposed [12]. Pieper et al compared cytotoxic effects of MeHg, thiomersal and mercuric mercury on human astrocytes (CCF-STTG1) concluding an increased cytotoxic potential with rising alkylation level [13].…”

Characterization of methylmercury demethylation in the central nervous system.

“…This suggests that there may be a different mechanism for toxicity in neurons and glia. This is in agreement with in vitro tests which show different rates of accumulation and metabolism of neurons and astrocytes (Syversen et al, 2006;Aschner et al, 2007).…”