Oxidative stress in MeHg-induced neurotoxicity - PubMed (original) (raw)

Review

Oxidative stress in MeHg-induced neurotoxicity

Marcelo Farina et al. Toxicol Appl Pharmacol. 2011.

Abstract

Methylmercury (MeHg) is an environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. Although the molecular mechanisms mediating MeHg-induced neurotoxicity are not completely understood, several lines of evidence indicate that oxidative stress represents a critical event related to the neurotoxic effects elicited by this toxicant. The objective of this review is to summarize and discuss data from experimental and epidemiological studies that have been important in clarifying the molecular events which mediate MeHg-induced oxidative damage and, consequently, toxicity. Although unanswered questions remain, the electrophilic properties of MeHg and its ability to oxidize thiols have been reported to play decisive roles to the oxidative consequences observed after MeHg exposure. However, a close examination of the relationship between low levels of MeHg necessary to induce oxidative stress and the high amounts of sulfhydryl-containing antioxidants in mammalian cells (e.g., glutathione) have led to the hypothesis that nucleophilic groups with extremely high affinities for MeHg (e.g., selenols) might represent primary targets in MeHg-induced oxidative stress. Indeed, the inhibition of antioxidant selenoproteins during MeHg poisoning in experimental animals has corroborated this hypothesis. The levels of different reactive species (superoxide anion, hydrogen peroxide and nitric oxide) have been reported to be increased in MeHg-exposed systems, and the mechanisms concerning these increments seem to involve a complex sequence of cascading molecular events, such as mitochondrial dysfunction, excitotoxicity, intracellular calcium dyshomeostasis and decreased antioxidant capacity. This review also discusses potential therapeutic strategies to counteract MeHg-induced toxicity and oxidative stress, emphasizing the use of organic selenocompounds, which generally present higher affinity for MeHg when compared to the classically studied agents.

Copyright © 2011 Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1. Interaction of MeHg or RSHgMe (a complex of MeHg with a low weight molecular thiol, e.g., cysteine or glutathione) with target cell proteins via exchange reactions

The first event can be of three types: A) MeHg (free MeHg) can react with a target protein (Tg 1) to oxidize it; B) the low-molecular weight complex of MeHg with a thiol-containing molecule (cysteine or small peptides derived from MeHg contaminated fish muscle proteins) can participate in an exchange reaction with the target protein 1 (Tg 1), oxidizing the Tg 1 and regenerating the free thiol molecule; and C) the complex MeHg-cysteine (MeHgSR) can be transported as a mimetic of methionine. The second event can be of two types: A) the MeHg bound to target protein 1 (Tg 1-HgMe complex) can participate in an exchange reaction with a second target protein (Tg 2) to oxidize it and release the free Tg 1; or B) the exchange can occur with intracellular low-molecular- weight thiols (e.g., cysteine or GSH) to form the MeHgSG or MeHgSCys complex and release the free Tg 1. The third event is similar to that described in the second event (i.e., an exchange reaction between a target protein with a different target protein or with intracellular low-molecular thiols). The fourth event represents the tentative unidirectional (indicated by the broken arrows) reactions of intracellular low-molecular MeHg-thiol complexes (RSHgMe) or of a target protein (Tg 3) with a target selenoprotein (Tg 4). In these cases, the selenocysteyl residue of the Tg 4 selenoprotein is oxidized by MeHg and hypothetically cannot participate in an exchange reaction due to the higher affinity of a selenol group for MeHg than that of a thiol group. The aforementioned events (1–4) are represented as numbers (or numbers plus letters) in parentheses (e.g., 1A).

Figure 2

Figure 2. Reactive species as mediators of MeHg induced neurotoxicity

MeHg leads to increased extracellular glutamate (GLU) levels through the inhibition of astrocytic glutamate uptake (event 1), the stimulation of glutamate release from presynaptic terminals (event 2) and the inhibition of vesicular glutamate uptake (event 3). Increased extracellular glutamate levels overactivate _N_-methyl D-aspartate (NMDA)-type glutamate receptors, increasing calcium influx into neurons (event 4). Increased levels of intracellular calcium, which can lead to mitochondrial collapse (event 5), activate neuronal nitric oxide synthase (nNOS) (event 6), thus increasing nitric oxide (NO) formation. MeHg affects the mitochondrial electron transfer chain (mainly at the level of complex II-III) (event 7), leading to the increased formation of superoxide anion (O2•−) and hydrogen peroxide (H2O2). H2O2 can produce hydroxyl radical anion (•OH) via Fenton’s Reaction (event 8). MeHg-induced increases in H2O2 levels might be a consequence of decreased glutathione peroxidase (GPx) activity (event 9) and glutathione (GSH) depletion (event 10).

Scheme 1

Scheme 1

Reaction of MeHg (CH3Hg+) with its two main cellular high-molecular generic targets, i.e., thiol- and selenol-containing proteins (PSH and PSeH, respectively).

Scheme 2

Scheme 2

Exchange reaction of MeHg from one type of thiol-containing molecule to another class of molecule. R1 and R2 can be either a low- or a high-molecular-weight thiol molecule.

Scheme 3

Scheme 3

Exchange reaction of MeHg between two molecules of the same chemical structure, representing the exchange of MeHg between two thiol-containing glutathione, i.e., a reduced glutathione displaces MeHg from a second GS-HgMe complex. Chemically, this reaction indicates a shift of MeHg from one GSH to another GSH molecule. Biologically, this type of exchange reaction is expected to have little significance.

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