Astrocyte-mediated enhancement of neuronal survival is abolished by glutathione deficiency

Drukarch, Benjamin; Schepens, Erik; Jongenelen, Cornelis A.M.; Stoof, Johannes C.; Langeveld, Cornelis H.

doi:10.1016/s0006-8993(97)00790-7

Cited by 106 publications

(54 citation statements)

References 48 publications

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“…tial because depletion of GSH with BSO abolishes astrocytemediated neuroprotection (Drukarch et al, 1997;Chen et al, 2001). One mechanism underlying this protection is the continuous glial delivery of GSH and/or GSH precursors to neurons for GSH synthesis (Yudkoff et al, 1990;Sagara et al, 1993a,b;Dringen et al, 1999Dringen et al, , 2000.…”

Section: Discussionmentioning

confidence: 99%

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

Johnson²,

et al. 2003

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Astrocytes have a higher antioxidant potential in comparison to neurons. Pathways associated with this selective advantage include the transcriptional regulation of antioxidant enzymes via the action of the Cap'n'Collar transcription factor Nrf2 at the antioxidant response element (ARE). Here we show that Nrf2 overexpression can reengineer neurons to express this glial pathway and enhance antioxidant gene expression. However, Nrf2-mediated protection from oxidative stress is conferred primarily by glia in mixed cultures. The antioxidant properties of Nrf2-overexpressing glia are more pronounced than those of neurons, and a relatively small number of these glia (Ͻ 1% of total cell number added) could protect fully cocultured naive neurons from oxidative glutamate toxicity associated with glutathione (GSH) depletion. Microarray and biochemical analyses indicate a coordinated upregulation of enzymes involved in GSH biosynthesis (xCT cystine antiporter, ␥-glutamylcysteine synthetase, and GSH synthase), use (glutathione S-transferase and glutathione reductase), and export (multidrug resistance protein 1) with Nrf2 overexpression, leading to an increase in both media and intracellular GSH. Selective inhibition of glial GSH synthesis and the supplementation of media GSH indicated that an Nrf2-dependent increase in glial GSH synthesis was both necessary and sufficient for the protection of neurons, respectively. Neuroprotection was not limited to overexpression of Nrf2, because activation of endogenous glial Nrf2 by the small molecule ARE inducer, tert-butylhydroquinone, also protected against oxidative glutamate toxicity.

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Section: Discussionmentioning

confidence: 99%

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

Johnson²,

et al. 2003

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“…Astrocytes are integrally involved in metabolic and ionic homeostasis, inflammatory responses, and control of extracellular glutamate levels (Aas et al, 1993;Hertz and Zielke, 2004;Hertz et al, 1999;Storm-Mathisen et al, 1992;Torp et al, 1994). Astrocytes also produce neurotrophic factors that promote neuronal survival and provide neurons with precursors for glutathione biosyn-thesis, which is necessary to combat oxidative stress (Dringen, 2000;Drukarch et al, 1997;Makarov et al, 2002). Moreover, astrocytes release lactate, which is then used by neighboring neurons as fuel for aerobic energy metabolism (Dienel and Hertz, 2001) particularly following cerebral ischemia (Schurr, 2002;Pellerin et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Hyperoxia promotes astrocyte cell death after oxygen and glucose deprivation

Danilov

Fiskum

2008

Glia

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Astrocyte dysfunction and death accompany cerebral ischemia/reperfusion and possibly compromise neuronal survival. Animal studies indicate that neuronal death, neurologic injury, and oxidative molecular modifications are worse in animals exposed to hyperoxic compared to normoxic ventilation during reperfusion after global cerebral ischemia. It is unknown, however, whether ambient O 2 affects brain cell survival using in vitro ischemia paradigms where mechanisms of injury to specific cell types can be more thoroughly investigated. This study tested the hypothesis that compared with the supraphysiological level of 20% O 2 normally used in cell culture, lower, more physiological O 2 levels protect astrocytes from death following oxygen and glucose deprivation. Primary rat cortical astrocytes were cultured under either 7 or 20% O 2 , exposed to O 2 , and glucose deprivation for 4 h, and then exposed to normal medium under either 7 or 20% O 2 . Cell death and 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine immunoreactivities were assessed at different periods of reoxygenation. Astrocytes exposed to low levels of O 2 during reoxygenation undergo less death and exhibit lower levels of protein nitration and nucleic acid oxidation when compared with those under high levels of O 2 during reoxygenation. These results support the hypothesis that the 20% O 2 normally used in cell culture exacerbates astrocyte death and oxidative stress in an in vitro ischemia/reperfusion model compared to levels that more closely approximate those that exist in vivo.

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“…Neuronal antioxidant defenses rely mainly on the cellular levels of reduced glutathione (GSH) (15,28). Elevated GSH levels in hippocampus and midbrain were reported in AD (1), an indication that AD neurons may be over-reacting to an oxidative load.…”

Section: Glutathione: the Main Antioxidant Molecule In Neuronsmentioning

confidence: 99%

Iron and glutathione at the crossroad of redox metabolism in neurons

et al. 2006

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Neurons, as non-dividing cells, encounter a myriad of stressful conditions throughout their lifespan. In particular, there is increasing evidence that iron progressively accumulates in the brain with age and that ironinduced oxidative stress is the cause of several forms of neurodegeneration. Here, we review recent evidence that gives support to the following notions: 1) neuronal iron accumulation leads to oxidative stress and cell death; 2) neuronal survival to iron accumulation associates with decreased expression of the iron import transporter DMT1 and increased expression of the efflux transporter IREG1; and 3) the adaptive process of neurons towards iron-induced oxidative stress includes a marked increase in both the expression of the catalytic subunit of gamma glutamate-cysteine ligase and glutathione. These findings may help to understand aging-related neurodegeneration hallmarks: oxidative damage, functional impairment and cell death.

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Astrocyte-mediated enhancement of neuronal survival is abolished by glutathione deficiency

Cited by 106 publications

References 48 publications

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

Hyperoxia promotes astrocyte cell death after oxygen and glucose deprivation

Iron and glutathione at the crossroad of redox metabolism in neurons

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