AURINTRICARBOXYLIC ACID PREVENTS GLUR2 MESSENGER-RNA DOWN-REGULATION AND DELAYED NEURODEGENERATION IN HIPPOCAMPAL CA1 NEURONS OF GERBIL AFTER GLOBALISCHEMIA

Aurintricarboxylic acid (ATA), an inhibitor of endonuclease activity a nd other protein-nucleic acid interactions, blocks apoptosis in severa l cell types and prevents delayed death of hippocampal pyramidal CA1 n eurons induced by transient global ischemia, Global ischemia in rats a nd gerbils induces down-regulation of GluR2 mRNA and increased lpha-am ino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced Ca2+ i nflux in CA1 before neurodegeneration, This result and neuroprotection by antagonists of AMPA receptors suggests that formation of AMPA rece ptors 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 enco ding glutamate receptor subunits in gerbil hippocampus after global is chemia, Administration of ATA by injection into the right cerebral ven tricle 1 h before (but not 6 h after) bilateral carotid occlusion prev ented the ischemia-induced decrease in GluR2 mRNA expression and the d elayed neurodegeneration, These findings suggest that ATA is neuroprot ective 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, Ma intaining formation of Ca2+ impermeable, GluR2 containing AMPA recepto rs could prevent delayed death of CA1 neurons after transient global i schemia, and block of GluR2, down-regulation may provide a further str ategy for neuroprotection.