Stimulation of d-aspartate efflux by mercuric chloride from rat primary astrocyte cultures

Mullaney, K.J.; Vitarella, Domenico; Albrecht, Jan; Kimelberg, Harold K.; Aschner, Michael

doi:10.1016/0165-3806(93)90030-e

Cited by 21 publications

(5 citation statements)

References 30 publications

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“…The conjugated products can be transported out of the target cells by the MRPs (Konig et al, 1999), which substantially decrease the intracellular concentrations of mercurials and lower the toxicity. Previous studies have also 138 established the protective roles afforded by GSH in MeHginduced toxicity (Mullaney et al, 1993(Mullaney et al, , 1994. In the present study, we showed that MeHg exposure lead to a biphasic response in intracellular astrocytic GSH content (Figure 1), and the increase of GSH was associated with activation of Nrf2 (Figure 2).…”

Section: Discussionsupporting

confidence: 73%

Methylmercury Toxicity and Nrf2-dependent Detoxification in Astrocytes

Wang

Jiang

Yin³

et al. 2008

Toxicological Sciences

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Methylmercury (MeHg) is a potent neurotoxicant and preferentially induces oxidative injury in astrocytes. In neuronal tissues, nuclear factor erythroid 2-related factor 2 (Nrf2) is a key factor determining the protective antioxidant response against various environmental toxicants. Nrf2 is subjected to regulation by many other signaling pathways. The purpose of this study is to characterize its interaction with the phosphatidylinositol 3 (PI3) kinase in cultured rat neonatal primary astrocytes. The results showed that at pathologically relevant concentrations, exposure of primary astrocytes to MeHg led to Nrf2 activation and upregulation of its downstream antioxidant genes. Inhibition of the PI3 kinase resulted in decreased Nrf2 activity, decreased cellular glutathione, and increased cell death to high-dose MeHg. The functional interaction between the two signaling pathways underlined an important mechanism for astrocyte protection against MeHg toxicity. Modulation of Nrf2 by pharmacological modalities should afford a treatment to attenuate MeHg-induced neurotoxicity.

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Section: Discussionsupporting

confidence: 73%

Methylmercury Toxicity and Nrf2-dependent Detoxification in Astrocytes

Wang

Jiang

Yin³

et al. 2008

Toxicological Sciences

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“…11), the major molecule to maintain the normal cellular thiol status; and (iii) Nrf2 activation is regulated by oxidative modifications of its cysteine thiol groups, as well as by thiol oxidation in Keap1 (He and Ma,2009). The cytoprotective effect of GSH in MeHg‐induced toxicity is a well known phenomenon (Mullaney et al,1993,1994). GSH readily binds to MeHg via its sulfhydryl groups, and the conjugated products are actively pumped out of the cells by multi‐drug resistance proteins, leading to a decrease in intracellular MeHg and, by inference, its ensuing toxicity (Konig et al,1999).…”

Section: Discussionmentioning

confidence: 99%

Comparative study on the response of rat primary astrocytes and microglia to methylmercury toxicity

Yin

et al. 2011

Glia

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As the two major glial cell types in the brain, astrocytes and microglia play pivotal but different roles in maintaining optimal brain function. Although both cell types have been implicated as major targets of methylmercury (MeHg), their sensitivities and adaptive responses to this metal can vary given their distinctive properties and physiological functions. This study was carried out to compare the responses of astrocytes and microglia following MeHg treatment, specifically addressing the effects of MeHg on cell viability, reactive oxygen species (ROS) generation and glutathione (GSH) levels, as well as mercury (Hg) uptake and the expression of NF-E2-related factor 2 (Nrf2). Results showed that microglia are more sensitive to MeHg than astrocytes, a finding that is consistent with their higher Hg uptake and lower basal GSH levels. Microglia also demonstrated higher ROS generation compared to astrocytes. Nrf2 and its downstream genes were upregulated in both cell types, but with different kinetics (much faster in microglia). In summary, microglia and astrocytes each exhibit a distinct sensitivity to MeHg, resulting in their differential temporal adaptive responses. These unique sensitivities appear to be dependent on the cellular thiol status of the particular cell type.

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“…5). Previous studies have established the cytoprotective effects of GSH in MeHg-induced toxicity (Mullaney et al, 1993(Mullaney et al, , 1994). GSH binds to Hg compounds via its sulfhydryl groups, and the conjugated products are actively pumped out of the cells by multidrug resistance proteins, leading to the decrease in intracellular Hg and its toxicity (Konig et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Methylmercury Induces Acute Oxidative Stress, Altering Nrf2 Protein Level in Primary Microglial Cells

Ni¹,

Li²,

Yin

et al. 2010

Toxicological Sciences

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The neurotoxicity of methylmercury (MeHg) is well documented in both humans and animals. MeHg causes acute and chronic damage to multiple organs, most profoundly the central nervous system (CNS). Microglial cells are derived from macrophage cell lineage, making up approximately 12% of cells in the CNS, yet their role in MeHg-induced neurotoxicity is not well defined. The purpose of the present study was to characterize microglial vulnerability to MeHg and their potential adaptive response to acute MeHg exposure. We examined the effects of MeHg on microglial viability, reactive oxygen species (ROS) generation, glutathione (GSH) level, redox homeostasis, and Nrf2 protein expression. Our data showed that MeHg (1-5 microM) treatment caused a rapid (within 1 min) concentration- and time-dependent increase in ROS generation, accompanied by a statistically significant decrease in the ratio of GSH and its oxidized form glutathione disulfide (GSSG) (GSH:GSSG ratio). MeHg increased the cytosolic Nrf2 protein level within 1 min of exposure, followed by its nuclear translocation after 10 min of treatment. Consistent with the nuclear translocation of Nrf2, quantitative real-time PCR revealed a concentration-dependent increase in the messenger RNA level of Ho-1, Nqo1, and xCT 30 min post MeHg exposure, whereas Nrf2 knockdown greatly reduced the upregulation of these genes. Furthermore, we observed increased microglial death upon Nrf2 knockdown by the small hairpin RNA approach. Taken together, our study has demonstrated that microglial cells are exquisitely sensitive to MeHg and respond rapidly to MeHg by upregulating the Nrf2-mediated antioxidant response.

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Stimulation of d-aspartate efflux by mercuric chloride from rat primary astrocyte cultures

Cited by 21 publications

References 30 publications

Methylmercury Toxicity and Nrf2-dependent Detoxification in Astrocytes

Methylmercury Toxicity and Nrf2-dependent Detoxification in Astrocytes

Comparative study on the response of rat primary astrocytes and microglia to methylmercury toxicity

Methylmercury Induces Acute Oxidative Stress, Altering Nrf2 Protein Level in Primary Microglial Cells

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