title: Glutamate induces release of glutathione from cultured rat astrocytes--a possible neuroprotective mechanism?
abstract: Glutamate is the major excitatory amino acid of the mammalian brain but can be toxic to neurones if its extracellular levels are not tightly controlled. Astrocytes have a key role in the protection of neurones from glutamate toxicity, through regulation of extracellular glutamate levels via glutamate transporters and metabolic and antioxidant support. In this study, we report that cultures of rat astrocytes incubated with high extracellular glutamate (5 mM) exhibit a twofold increase in the extracellular concentration of the tripeptide antioxidant glutathione (GSH) over 4 h. Incubation with glutamate did not result in an increased release of lactate dehydrogenase, indicating that the rise in GSH was not because of membrane damage and leakage of intracellular pools. Glutamate-induced increase in extracellular GSH was also independent of de novo GSH synthesis, activation of NMDA and non-NMDA glutamate receptors or inhibition of extracellular GSH breakdown. Dose-response curves indicate that GSH release from rat astrocytes is significantly stimulated even at 0.1 mM glutamate. The ability of astrocytes to increase GSH release in the presence of extracellular glutamate could be an important neuroprotective mechanism enabling neurones to maintain levels of the key antioxidant, GSH, under conditions of glutamate toxicity.
authors.affiliation: Centre for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Frade
authors.forename: Simon
authors.initials: S
authors.lastname: Pope
authors.forename: Maike
authors.initials: M
authors.lastname: Schmidt
authors.forename: Ralf
authors.initials: R
authors.lastname: Dringen
authors.forename: Rui
authors.initials: R
authors.lastname: Barbosa
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pocock
authors.forename: João
authors.initials: J
authors.lastname: Laranjinha
authors.forename: Simon
authors.initials: S
authors.lastname: Heales
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018696:Neuroprotective Agents; D018698:Glutamic Acid; D005978:Glutathione