Excitatory amino acid-induced cytotoxicity in primary cultures of mouse cerebellar granule cells correlates with elevated, sustained c-fos proto-oncogene expression.
An elevated, sustained expression of c-fos mRNA was found in primary cultures of mouse cerebellar granule cells following exposure to toxic concentrations of the excitatory amino acids, L-glutamate, L-homocysteate, S-sulpho-L-cysteine and N-methyl-D-aspartate (NMDA), using leakage of lactate dehydrogenase (LDH) as an indicator of cytotoxicity. In contrast, when used at non-toxic concentrations these compounds induced a rapid and transient increase in c-fos mRNA levels. Both LDH release and elevated, sustained c-fos mRNA induction were blocked (in the case of L-homocysteate) or reduced (in the case of L-glutamate and S-sulpho-L-cysteine) by the selective NMDA receptor antagonist (DL(+/-)-2-amino- 5-phosphonopentanoic acid) whereas 6-cyano-7-nitroquinoxaline-2,3-dione (a selective antagonist at non-NMDA ionotropic receptors) had no effect. These data suggest a role for altered c-fos mRNA expression in excitotoxic mechanisms.
Gorman
A M
AM
Division of Cell and Molecular Biology, School of Biological and Medical Sciences, University of St. Andrews, Fife, UK.
Scott
M P
MP
Rumsby
P C
PC
Meredith
C
C
Griffiths
R
R
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D007770:L-Lactate Dehydrogenase