ALTERATIONS IN GENE-EXPRESSION AS AN INDEX OF NEURONAL INJURY - HEAT-SHOCK AND THE IMMEDIATE-EARLY GENE RESPONSE

The c-fos immediate early gene is induced by normal stimuli including light, stress, hyperosmolar solutions, and hormones. Ischemia, hypoxia, seizures, cortical injury, nerve section and other pathological stimuli can also induce c-fos. The induction can occur via increases in intracellular calcium that act through a Ca2+/cAMP element on its promoter, or via trophic and other factors that act through a serum response element (SRE) on its promoter. Several studies show that calcium entry via voltage sensitive calcium channels (VSCCs) is important for inducing c-fos. We have shown that calcium entry via the NMDA receptor is important for induction of c-fos mRNA by glutamate and cAMP in cultured cortical neurons. Moreover, the NMDA receptor appears to regulate translation of c-fos mRNA to Fos protein when cells are stimulated with other types of stimuli including vasoactive intestinal peptide, zinc, and fibroblast growth factor. These results suggest that toxins that elevate intracellular calcium will likely induce the c-fos gene in brain. The heat shock or stress genes are induced by a wide variety of stimuli including heavy metals, heat, oxidative and ischemic stress, prolonged seizures, hypoglycemia, calcium ionophores, and certain toxins. It is believed that denatured proteins stimulate heat shock factors to bind to heat shock elements on the promoters of all heat shock gen es to induce gene transcription. We and others have shown that global and focal ischemia induce the hsp70 heat shock gene in brain. Mild ischemia induces hsp70 mRNA and HSP70 protein in neurons only. Moderate ischemia induces the gene in glia surrounding the neurons, and may produce a translation block in hippocampal pyramidal neurons. Prolonged ischemia resulting in infarction induces hsp70 in endothelial cells and not in neurons or glia, suggesting that there is a transcriptional and translational block in the neurons and glia, but that the capillary endothelial cells are still alive and can synthesize stress genes. Recent work has also shown that the drugs phencyclidine (PCP), Ketamine, amd MK801 all induce the hsp70 heat shock gene. The induction is dose dependent, occurs in layer 3 cingulate neurons and layer 3,5, and 6 cortical neurons, lasts 1-2 weeks, and occurs in 30 day and older animals but not in 0-30 day old rats. This drug induced brain injury can be prevented by prior administration of the antipsychotic drug, haloperidol. This work shows that a variety of injurious stimuli can induce the hsp70 gene in brain, and that this gene induction can be used to mark injured cells and to determine whether a particular treatment is useful or not. (C) 1994 Intox Press, Inc.