Aurintricarboxylic acid (ATA), an inhibitor of
endonuclease activity and other
protein-
nucleic acid interactions, blocks apoptosis in several cell types and prevents delayed death of hippocampal pyramidal CA1 neurons induced by transient global
ischemia. Global
ischemia in rats and gerbils induces down-regulation of GluR2
mRNA and increased
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (
AMPA)-induced Ca2+ influx in CA1 before neurodegeneration. This result and neuroprotection by antagonists of
AMPA receptors suggests that formation of
AMPA receptors lacking GluR2, and therefore Ca2+ permeable, leads to excessive Ca2+ influx in response to endogenous
glutamate; the resulting delayed neuronal death in CA1 exhibits many characteristics of apoptosis. In this study, we examined the effects of ATA on expression of mRNAs encoding
glutamate receptor subunits in gerbil hippocampus after global
ischemia. Administration of ATA by injection into the right cerebral ventricle 1 h before (but not 6 h after) bilateral carotid occlusion prevented the
ischemia-induced decrease in GluR2
mRNA expression and the delayed neurodegeneration. These findings suggest that ATA is neuroprotective in
ischemia by blocking the transcriptional changes leading to down-regulation of GluR2, rather than by simply blocking
endonucleases, which presumably act later after Ca2+ influx initiates apoptosis. Maintaining formation of Ca2+ impermeable, GluR2 containing
AMPA receptors could prevent delayed death of CA1 neurons after transient global
ischemia, and block of GluR2 down-regulation may provide a further strategy for neuroprotection.