HSP70 HEAT-SHOCK GENE-REGULATION DURING ISCHEMIA

The hsp70 gene is induced by denatured protein in injured cells and is an extremely sensitive and reliable marker of cells injured by ischemia, seizures, and toxins. Normal brains have little detectable hsp70 mRNA or HSP70 protein. After status epilepticus produced by systemic injections of kainic acid, however, HSP70 protein is induced in neurons but not glia in brain regions known to be injured by kainic acid. Global and focal ischemia also induce the hsp70 gene in brain. The induction of HSP70 protein in hippocampus following increasing durations of global ischemia correlates with the regional and cellular vulnerability to ischemia: CA1 neurons express HSP70 after the briefest periods of ischemia followed by CA4, CA3, dentate granule neurons, glia, and lastly, endothelial cells. Moreover, as the severity of ischemia worsens, a transcriptional and/or translational blockade of the hsp70 gene occurs in the same order so that moderate degrees of ischemia induce HSP70 in CA3 neurons and dentate granule neurons but not necrotic CA1 neurons, and severe ischemia induces HSP70 in capillary endothelial cells of hippocampus but not in any infarcted neurons or glia throughout the hippocampus. Brief periods of focal ischemia induce HSP70 primarily in neurons, suggesting that even focal ischemia can produce selective neuronal injury without infarction. In some instances, HSP70 immunoreactive astrocytes surround the HSP70 immunostained neurons. Focal ischemia that produces infarction induces HSP70 primarily in endothelial cells of cerebral blood vessels in the regions of infarction and in neurons and astrocytes on the perimeter or the penumbral area of infarction. Our studies of hsp70 mRNA during focal ischemia suggest that when blockade of translation occurs in a particular cell type, transcription of the hsp70 gene also appears to be blocked. For example, after focal infarction, hsp70 mRNA and HSP70 protein are localized to endothelial cells in infarcted regions, whereas hsp70 mRNA and HSP70 protein are localized to neurons and glia in the penumbra. Because N-methyl-D-aspartic acid antagonists are often used in ischemia research, it is notable that these drugs induce HSP70 in brain. MK-801 and ketamine induce HSP70 in injured posterior cingulate and other cortical neurons. Phencyclidine induces HSP70 in neurons in the posterior cingulate, neocortex, piriform cortex, amygdala, and possibly hippocampus. These drugs appear to denature proteins and thereby induce the hsp70 gene in these neurons, which are believed to survive this drug-induced injury.