To evaluate the mechanism of tolerance to ischemia, inductions of heat shock protein (HSP) 70 and heat shock cognate protein (HSC) 70 mRNAs in gerbil hippocampus were compared with in situ hybridization between cases of a single 3.5-min period of forebrain ischemia and a 3.5-min period of ischemia 2 days after 2-min pretreatment with ischemia. Immunohistochemistry for HSP70 protein and morphological studies were also performed in the same brains up to 7 days after the reperfusion. Following a single 3.5-min period of ischemia, HSP70 and HSC70 mRNAs were induced in all hippocampal cells. However, the hippocampal CA1 cells produced only a minimum of HSP70 protein, and the cells were almost lost by 7 days. Following 3.5 min of ischemia after 2-min pretreatment, large populations of the CA1 cells survived at 7 days. The peak time of the HSP70 and HSC70 mRNA induction shifted to an earlier period of reperfusion in all hippocampal cells as compared with the case of a single episode of ischemia. The peak of HSP70 and HSC70 mRNA induction shifted from 1 day to 3 h in the CA1 cells. The CA1 cells produced strongly immunoreactive HSP70 from 3 hr to 2 days. These results suggest that pretreatment with an initial period of ischemia (for 2 min) accelerated HSP70 and HSC70 gene expression at the transcriptional level, ameliorated the translational disturbance of HSP70 mRNA to protein, and saved the CA1 cells from subsequent lethal ischemia (for 3.5 min). These changes of heat shock gene expression might play important roles in the acquisition of ischemic tolerance of hippocampal CA1 neurons.