Modification of glutamate-induced oxidative stress by lead: the role of extracellular calcium.
The role of extracellular calcium in glutamate-induced oxidative stress, and the role of glutamatergic neuronal stimulation and oxidative stress in lead neurotoxicity were explored in mouse hypothalamic GT1-7 cells. Glutamate increased the production of reactive oxygen species (ROS) whether or not extracellular calcium was present. Glutamate-induced ROS production was amplified by lead acetate (PbAc), but only in the absence of extracellular calcium. However, PbAc on its own did not increase the production of ROS. A PKC inhibitor (Ro 31-8220) and superoxide dismutase (SOD) abolished the amplification of glutamate-induced production of ROS by PbAc, but did not inhibit ROS production induced by glutamate alone. Both glutamate and PbAc decreased the levels of intracellular glutathione (GSH), and amplified each other's effect on GSH depletion. Glutamate did not decrease cell viability, whereas the cytotoxicity of PbAc was amplified by glutamate. Extracellular calcium, a PKC inhibitor, or SOD did not modify the effects of glutamate, PbAc or their combination on the levels of GSH or cell viability. These data indicate that in GT1-7 cells extracellular calcium is not essential for glutamate-induced ROS production, which is amplified by PbAc, but only without extracellular calcium. The joint cytotoxicity of glutamate and PbAc is mainly induced by PbAc, preferentially through mechanisms other than ROS production.
Loikkanen
J J
JJ
Department of Pharmacology and Toxicology, University of Kuopio, Finland.
Naarala
J
J
Savolainen
K M
KM
D000818:Animals; D002118:Calcium / Q000494:pharmacology / Q000502:physiology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D009942:Organometallic Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007211:Indoles; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D013482:Superoxide Dismutase; D011493:Protein Kinase C; D005978:Glutathione; C008261:lead acetate; D002118:Calcium; C064758:Ro 31-8220