Astrocytes as Mediators of Methylmercury Neurotoxicity: Effects on D-Aspartate and Serotonin Uptake

Dave, Vijendra; Mullaney, K.J.; Goderie, Susan K.; Kimelberg, Harold K.; Aschner, Michael

doi:10.1159/000112110

Cited by 43 publications

(14 citation statements)

References 28 publications

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“…However, astrocyte nuclei labelled with the TUNEL technique were still visualized on these sections. This suggests that 1) either the mercuryinduced glial dysfunction lead indirectly to neuronal death, as it has been proposed by several authors (Largo et al, 1996;Aschner et al, 1995;Dave et al, 1994), or 2) at this high concentration, mercury induced directly a general cytotoxicity of neurons.…”

Section: Induction Of Apoptosis By Mercurymentioning

confidence: 58%

Induction of apoptosis by mercury compounds depends on maturation and is not associated with microglial activation

Monnet‐Tschudi

1998

J. Neurosci. Res.

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The earliest sign of neurotoxicity observed after exposure of three-dimensional brain cell cultures to low concentrations of mercury compounds is a microglial reaction. We hypothesized that an induction of apoptosis by mercury compounds could be an activating signal of the microglial reaction. Aggregating brain cell cultures of fetal rat telencephalon were treated for 10 days with either mercury chloride or monomethylmercury chloride at noncytotoxic concentrations during two developmental periods: from day 5 to 15, corresponding to an immature stage, and from day 25 to 35 corresponding to a mature stage. Apoptosis was evaluated by the TUNEL technique. It was found that both mercury compounds caused a significant increase in the number of apoptotic cells, but exclusively in immature cultures exhibiting also spontaneous apoptosis. Double staining by the TUNEL technique combined with either neuronal or astroglial markers revealed that the proportion of cells undergoing apoptosis was highest for astrocytes. Furthermore neither an association nor a colocalization was found between apoptotic cells and microglial cells. In conclusion, it appears that the induction of apoptosis by mercury compounds in immature cells is only an acceleration of a spontaneously occurring process, and that it is not a directly related to the early microglial reaction.

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Section: Induction Of Apoptosis By Mercurymentioning

confidence: 58%

Induction of apoptosis by mercury compounds depends on maturation and is not associated with microglial activation

Monnet‐Tschudi

1998

J. Neurosci. Res.

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“…Although not the only cell type to be adversely affected by MeHg, a number of studies have established a key role for astrocytes in mediating MeHg neurotoxicity: a) astrocytes represent a preferential cellular site for MeHg accumulation (13-16); b) MeHg selectively inhibits astrocytic transport of cystine and cysteine (Figure 1), thereby adversely affecting their redox status and attenuating glutathione (GSH) content (17-21); c) MeHg inhibits astrocytic glutamate (and aspartate) uptake ( Figure 1) and stimulates its efflux, thereby increasing glutamate concentrations in the extracellular fluid and sensitizing neurons to excitotoxic injury (17,18,(22)(23)(24); d) MeHg-induced neuronal dysfunction is secondary to disturbances in astrocytes (25), and the in vitro coapplication of non-toxic concentrations of mercury with glutamate results in the appearance of typical neuronal lesions found with excitotoxic stimulation (26); e) MeHg causes the activation of cytosolic phospholipase A 2 leading to arachidonic acid release and further inhibition of the glutamate transporter (Figure 1), setting in motion an unimpeded cytotoxic cycle (27,28).…”

Section: Mechanisms Of Methylmercuryinduced Neurotoxicity and Glutamatementioning

confidence: 99%

Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity

Aschner

Syversen

Souza

et al. 2007

Braz J Med Biol Res

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254

155

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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.

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“…While MeHg can directly cause damage to neurons, numerous studies have established a prominent role for astrocytes in mediating MeHg neurotoxicity [23,36]. The evidence includes observations that MeHg preferentially accumulate in astrocytes [5,18,34] and inhibits uptake systems for glutamate and cysteine transport, both of which will compromise glutathione (GSH) synthesis and redox status in astrocytes [2,16,30,61,62,63]. Furthermore, MeHg causes the activation of cytosolic phospholipase A 2 (cPLA 2 ), leading to arachidonic acid release and further inhibition of glutamate transporters and neuronal dysfunction [6,8].…”

Section: Introductionmentioning

confidence: 99%

Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes

Yin¹,

Milatović²,

Aschner³

et al. 2007

Brain Research

162

100

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The neurotoxicity of high levels of methylmercury (MeHg) is well established both in humans and experimental animals. Astrocytes accumulate MeHg and play a prominent role in mediating MeHg toxicity in the central nervous system (CNS). Although the precise mechanisms of MeHg neurotoxicity are ill-defined, oxidative stress and altered mitochondrial and cell membrane permeability appear to be critical factors in its pathogenesis. The present study examined the effects of MeHg treatment on oxidative injury, mitochondrial inner membrane potential, glutamine uptake and expression of glutamine transporters in primary astrocyte cultures. MeHg caused a significant increase in F 2 -isoprostanes (F 2 -IsoPs), lipid peroxidation biomarkers of oxidative damage, in astrocyte cultures treated with 5 or 10 μ M MeHg for 1 or 6 hours. Consistent with this observation, MeHg induced a concentration-dependant reduction in the inner mitochondrial membrane potential (ΔΨm), as assessed by the potentiometric dye, tetramethylrhodamine ethyl ester (TMRE). Our results demonstrate that ΔΨ m is a very sensitive endpoint for MeHg toxicity, since significant reductions were observed after only 1 h exposure to concentrations of MeHg as low as 1 μ M. MeHg pretreatment (1, 5 and 10 μ M) for 30 min also inhibited the net uptake of glutamine ( 3 H-glutamine) measured at 1 min and 5 min. Expression of the mRNA coding the glutamine transporters, SNAT3/SN1 and ASCT2, was inhibited only at the highest (10 μ M) MeHg concentration, suggesting that the reduction in glutamine uptake observed after 30 min treatment with lower concentrations of MeHg (1 and 5 μ M) was not due to inhibition of transcription. Taken together, these studies demonstrate that MeHg exposure is associated with increased mitochondrial membrane permeability, alterations in glutamine/glutamate cycling, increased ROS formation and consequent oxidative injury. Ultimately, MeHg initiates multiple additive or synergistic disruptive mechanisms that lead to cellular dysfunction and cell death.Please send request for reprints to Michael Aschner, Ph.D.,

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Astrocytes as Mediators of Methylmercury Neurotoxicity: Effects on D-Aspartate and Serotonin Uptake

Cited by 43 publications

References 28 publications

Induction of apoptosis by mercury compounds depends on maturation and is not associated with microglial activation

Induction of apoptosis by mercury compounds depends on maturation and is not associated with microglial activation

Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity

Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes

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