Animals subjected to sublethal transient global ischemia (ischemic preconditioning) exhibit neuroprotection against subsequent global ischemia-induced neuronal death in the hippocampal CA1 (ischemic tolerance). The molecular mechanisms underlying ischemic tolerance are unclear. Here we report that ischemic preconditioning induced a small, transient down-regulation of GluR2 mRNA expression and greatly attenuated subsequent ischemia-induced GluR2 mRNA and protein down-regulation and neuronal death. Ischemic preconditioning and GluR2 antisense knockdown acted synergistically to increase cell death. Sublethal antisense knockdown did not protect against subsequent ischemic insults or antisense knockdown. These findings indicate that ischemic preconditioning acts at step(s) upstream from suppression of GluR2 gene expression to afford neuroprotection and implicate transcriptional regulation of GluR2 expression in the adaptive mechanisms associated with ischemic tolerance
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