Preservation of extracellular glutathione by an astrocyte derived factor with properties comparable to extracellular superoxide dismutase

Stewart, Victoria C.; Stone, Rebecca; Gegg, Matthew E.; Sharpe, Martyn A.; Hurst, Roger D.; Clark, John B.; Heales, Simon

doi:10.1046/j.1471-4159.2002.01216.x

Cited by 49 publications

(33 citation statements)

References 39 publications

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“…Previously we have shown that primary rat astrocytes and a human astrocytoma cell line are able to retard the loss of GSH in minimal media, partially through the secretion of 'guardian' molecules [14]. One of these molecules was provisionally identified as extracellular SOD (EC-SOD or SOD3) [14] and this identification has now been confirmed by western blotting (Unpublished data).…”

Section: Introductionmentioning

confidence: 76%

“…One of these molecules was provisionally identified as extracellular SOD (EC-SOD or SOD3) [14] and this identification has now been confirmed by western blotting (Unpublished data). Astrocytes also secrete the cytosolic form of SOD1 (Unpublished data and [27]).…”

Section: Introductionmentioning

confidence: 83%

“…Cultured astrocytes export GSH [12][13][14] and can maintain or increase intracellular levels of GSH in neurones in co-culture systems [8][9][10]. Co-culture of neurones with astrocytes, which have been depleted of GSH, leads to significantly lower neuronal GSH compared to neurones grown with control astrocytes and these 'low GSH' neurones are more susceptible to nitric oxide insult [10].…”

Section: Introductionmentioning

confidence: 99%

“…Glutathione and other thiols have been shown to be oxidised in cell culture media [14,19,20]. Free transition metal ions, such as iron (III) and copper (II) are thought to contribute to thiol oxidation.…”

Section: Introductionmentioning

confidence: 99%

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Astrocytes Protect Against Copper-Catalysed Loss of Extracellular Glutathione

2008

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Glutathione (GSH) is one of the major antioxidants in the brain. GSH is secreted by astrocytes and this extracellular GSH is used by neurones to maintain and increase their intracellular GSH levels. For efficient GSH trafficking between astrocytes and neurones, GSH needs to be maintained in the reduced form. In model systems, GSH trafficking has been shown to be essential for neuroprotection against a variety of stress conditions. Previously we and others have shown that GSH and thiols are unstable in cell culture media and are easily oxidised. In the present study it is shown that nanomolar concentrations of copper (II) ions can cause decay of GSH in cell culture media. Increased free or redox active copper has been implicated in a variety of diseases and degradation of extracellular GSH is a possible mechanism by which it exerts its harmful effects. Rat astrocytes, a human astrocytoma cell line and astrocyte-conditioned media, in the absence of cells, are able to retard this copper-catalysed decay of GSH and maintain GSH in its reduced form. The protective effect of astrocytes appears to be a combination of copper removing and antioxidant mechanisms. The importance of these protective mechanisms is discussed with regards to neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Astrocytes Protect Against Copper-Catalysed Loss of Extracellular Glutathione

2008

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“…Several groups have demonstrated that astrocytes export GSH to extracellular space; however, the transporter(s) involved in this process have not been identified yet [14][15][16][17][18]. Studies performed in cultured human retinal pigmented epithelial cells have demonstrated that GSH efflux could be mediated by two different mechanisms, one Na ?…”

Section: Introductionmentioning

confidence: 99%

Glutamate Induces Glutathione Efflux Mediated by Glutamate/Aspartate Transporter in Retinal Cell Cultures

et al. 2010

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This study was undertaken in order to characterize the role of the glutamate/aspartate transporter (GLAST) in the glutathione (GSH) efflux induced by glutamate. Our results demonstrated that retinal cell cultures exhibit two mechanisms of GSH release, one Na(+)-independent and other Na(+)-dependent. Glutamate and aspartate induced GSH efflux only in presence of Na(+). Treatment with PCD (L-trans-Pyrrolidine-2,4-dicarboxylate), a transportable glutamate uptake blocker, increased GSH release indicating that GSH can be carried by glutamate transporters in retinal cell cultures. Added to this, treatment with zinc ion cultures, a recognized inhibitor of GLAST blocked GSH efflux evoked by glutamate. Treatment with NMDA antagonist (MK-801) did not have any effect on the GSH release induced by glutamate. These results suggest that glutamate induces GLAST-mediated release of GSH from retinal cell cultures and this could represent an important mechanism of cellular protection against glutamate toxicity in the CNS.

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Dual pathways mediate β-amyloid stimulated glutathione release from astrocytes

Shen

Zhang

et al. 2015

Glia

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Oxidative stress plays an important role in the progression of Alzheimer's disease (AD) and other neurodegenerative conditions. Glutathione (GSH), the major antioxidant in the central nervous system, is primarily synthesized and released by astrocytes. We determined if β-amyloid (Aβ42), crucially involved in Alzheimer's disease, affected GSH release. Monomeric Aβ (mAβ) stimulated GSH release from cultured cortical astrocytes more effectively than oligomeric Aβ (oAβ) or fibrillary Aβ (fAβ). Monomeric Aβ increased the expression of the transporter ABCC1 (also referred to as MRP1) that is the main pathway for GSH release. GSH release from astrocytes, with or without mAβ stimulation, was reduced by pharmacological inhibition of ABCC1. Astrocytes robustly express connexin proteins, especially connexin43 (Cx43), and mAβ also stimulated Cx43 hemichannel-mediated glutamate and GSH release. Aβ-stimulation facilitated hemichannel opening in the presence of normal extracellular calcium by reducing astrocyte cholesterol level. Aβ treatment did not alter the intracellular concentration of reduced or oxidized glutathione. Using a mouse model of AD with early onset Aβ deposition (5xFAD), we found that cortical ABCC1 was significantly increased in temporal register with the surge of Aβ levels in these mice. ABCC1 levels remained elevated from 1.5 to 3.5 months of age in 5xFAD mice, before plunging to subcontrol levels when amyloid plaques appeared. Similarly, in cultured astrocytes, prolonged incubation with aggregated Aβ, but not mAβ, reduced induction of ABCC1 expression. These results support the hypothesis that in the early stage of AD pathogenesis, less aggregated Aβ increases GSH release from astrocytes (via ABCC1 transporters and Cx43 hemichannels) providing temporary protection from oxidative stress which promotes AD development.

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Preservation of extracellular glutathione by an astrocyte derived factor with properties comparable to extracellular superoxide dismutase

Cited by 49 publications

References 39 publications

Astrocytes Protect Against Copper-Catalysed Loss of Extracellular Glutathione

Astrocytes Protect Against Copper-Catalysed Loss of Extracellular Glutathione

Glutamate Induces Glutathione Efflux Mediated by Glutamate/Aspartate Transporter in Retinal Cell Cultures

Dual pathways mediate β-amyloid stimulated glutathione release from astrocytes

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