Accumulation of extracellular glutamate and neuronal death in astrocyte-poor cortical cultures exposed to glutamine.
The function of astrocytes in cerebral cortex may be studied by comparing the properties of conventional, astrocyte-rich cultures with astrocyte-poor cultures in which astrocyte proliferation has been stringently suppressed. Exposure of astrocyte-poor, but not astrocyte-rich, cultures to fresh medium containing 2 mM glutamine resulted in the death of most neurons within 24 h. This study was undertaken to understand the basis for the apparent toxicity of glutamine in astrocyte-poor cultures. The toxicity of glutamine was found to be mediated by glutamate, which demonstrated an LD50 as a neurotoxin in astrocyte-poor cultures of 2 microM. Exposure of astrocyte-poor (but not astrocyte-rich) cultures to fresh medium containing glutamine for 17.5-24 h resulted in the accumulation of substantial quantities of glutamate (255 +/- 158 microM; mean +/- standard deviation) coincident with the death of neurons in the cultures. Exposure of astrocyte-poor cultures to glutamate in the absence of glutamine did not result in the accumulation of extracellular glutamate. Both the neuronal death and the extracellular glutamate accumulation in astrocyte-poor cultures exposed to glutamine could be blocked by N-methyl-D-aspartate (NMDA) antagonists. These observations suggest that astrocytes as well as glutamine may play an important role in the pathogenesis of glutamate neurotoxicity in the central nervous system.
Rosenberg
P A
PA
Department of Neurology, Children's Hospital, Boston, Massachusetts 02115.
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000818:Animals; D001253:Astrocytes / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D005110:Extracellular Space / Q000737:chemistry; D005971:Glutamates / Q000032:analysis* / Q000633:toxicity; D018698:Glutamic Acid; D005973:Glutamine / Q000494:pharmacology* / Q000633:toxicity; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010875:Pipecolic Acids / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D005971:Glutamates; D010875:Pipecolic Acids; D011810:Quinoxalines; D005973:Glutamine; D018698:Glutamic Acid; C053672:selfotel; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate