Delayed application of aurintricarboxylic acid reduces glutamate-induced cortical neuronal injury.
The non-specific endonuclease inhibitor, aurintricarboxylic acid (ATA), attenuated glutamate-induced destruction of cultured cortical neurons. In part, this protective effect likely reflected the ability of ATA to produce a slowly developing block of N-methyl-D-aspartate receptor-mediated inward whole cell current or increase in intracellular free Ca2+. However, ATA also attenuated a high K(+)-induced increase in intracellular free Ca2+ in the presence of D-amino-phosphonovalerate, suggesting that ATA may have a more general effect on Ca2+ homeostasis. In addition, ATA attenuated glutamate neurotoxicity even if added up to 2 hr after completion of glutamate exposure, a time when glutamate antagonists or lipid peroxidation inhibitors are no longer neuroprotective. Involvement of apoptosis in this excitotoxic death is unlikely, as Southern blotting of genomic DNA revealed no evidence of fragmentation, and death was not prevented by inhibitors of RNA or protein synthesis. Most likely, ATA interferes with some key downstream consequences of excitotoxic glutamate receptor overactivation.
Csernansky
C A
CA
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110.
Canzoniero
L M
LM
Sensi
S L
SL
Yu
S P
SP
Choi
D W
DW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D015139:Blotting, Southern; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates / Q000633:toxicity*; D018698:Glutamic Acid; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects*; D011188:Potassium / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D001312:Aurintricarboxylic Acid; D016202:N-Methylaspartate; D004247:DNA; D011188:Potassium; D002118:Calcium