Oxidative glutamate toxicity can be a component of the excitotoxicity cascade.
Along with ionotropic and metabotropic glutamate receptors, the cystine/glutamate antiporter x(c)(-) may play a critical role in CNS pathology. High levels of extracellular glutamate inhibit the import of cystine, resulting in the depletion of glutathione and a form of cell injury called oxidative glutamate toxicity. Here we show that a portion of the cell death associated with NMDA receptor-initiated excitotoxicity can be caused by oxidative glutamate toxicity. In primary mouse cortical neurons the cell death resulting from the short-term application of 10 microm glutamate can be divided into NMDA and NMDA receptor-independent phases. The NMDA receptor-independent component is associated with high extracellular glutamate and is inhibited by a variety of reagents that block oxidative glutamate toxicity. These results suggest that oxidative glutamate toxicity toward neurons lacking functional NMDA receptors can be a component of the excitotoxicity-initiated cell death pathway.
Schubert
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Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. schubert@salk.edu
Piasecki
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D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D027182:Amino Acid Transport System y+; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000633:toxicity; D003553:Cystine / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
D027182:Amino Acid Transport System y+; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C492255:Slc7a11 protein, mouse; D018698:Glutamic Acid; D003553:Cystine; D015763:2-Amino-5-phosphonovalerate; D005978:Glutathione