Effects of dopamine on the glutathione metabolism of cultured astroglial cells: implications for Parkinson's disease.
To investigate the effects of dopamine (DA) on the release of glutathione (GSH) from astrocytes, we used astroglia-rich primary cultures from the brains of newborn rats. In the absence of DA, GSH accumulated in the medium of these cultures with a constant rate. In contrast, during incubation of the cells with 50 micro m DA extracellular GSH was not detectable anymore. This disappearance of extracellular GSH was prevented by superoxide dismutase, indicating that DA does not affect GSH release but rather reacts with the released GSH in a superoxide-dependent reaction. Incubation of astroglial cultures with 0.5 and 1 mm DA established almost constant extracellular concentrations of H2O2 of 5 microm and 15 microm, respectively. Under these conditions astroglial cultures release glutathione disulphide (GSSG). This GSSG export was blocked by catalase and by MK571, an inhibitor of the multidrug resistance protein 1. The effects of DA on the extracellular accumulations of GSH and GSSG were not modulated by inhibitors of DA receptors, DA transport, and monoamine oxidases. The other catecholamines adrenaline and noradrenaline showed similar effects on the accumulation of GSH and GSSG in the medium compared with those obtained for DA. In conclusion, the data presented demonstrate that DA affects astroglial GSH metabolism by two mechanisms: (i) directly by chemical reaction with extracellular GSH, and (ii) indirectly by generation of hydrogen peroxide that leads to the efflux of GSSG from astroglial cells. These observations are discussed in the context of the brain's GSH metabolism in Parkinson's disease.
Hirrlinger
Johannes
J
Physiologisch-chemisches Institut der Universität, Tübingen, Germany.
Schulz
Jörg B
JB
Dringen
Ralf
R
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D002374:Catalase / Q000494:pharmacology; D002395:Catecholamines / Q000494:pharmacology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000032:analysis / Q000378:metabolism; D016877:Oxidants / Q000032:analysis / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000494:pharmacology
D000975:Antioxidants; D002395:Catecholamines; D017077:Culture Media, Conditioned; D016877:Oxidants; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione; D019803:Glutathione Disulfide; D004298:Dopamine