Objective:To investigate the changes of PERK-eIF2-ATF4 signaling pathway, pro-apoptosis CHOP, and JNK-c-Jun, as well as the effect of 17-estradiol (E2) following cerebral chronic hypoperfusion in the hippocampal CA1 region. Methods: Female rats were bilaterally ovariectomized, and 1 week later, chronic hypoperfusion was induced by occlusion bilateral common carotid arteries. The rats were randomly divided into the sham (14 d and 21 d)groups, the hypoperfusion (BCCAO 14 d, 21 d and 28 d) groups, the continuous physiological dose of E2 group, the JNK inhibitor SP600125 group and the solvent control group. GRP78, ATF4, CHOP, and phosphorylation levels of PERK, eIF2α, JNK and c-Jun were detected using Western blotting in the hippocampal CA1 region. Results: Compared to the sham 14 d group, phosphorylation levels of PERK and eIF2α, as well as ATF4 and CHOP expressions were significantly increased at 14 d, 21 d and 28 d after BCCAO, although there was no statistic difference in GRP78 protein expression. Furthermore, p-JNK and p-c-Jun significantly increased after BCCAO compared with the sham 14 d group. Either E2 or SP600125 not only significangly prevented the activation of JNK/c-Jun pathway, but also attenuated PERK-eIF2α-ATF4-CHOP stress signaling induced by BCCAO after 21 d in the hippocampal CA1 region. Conclusion: Chronic hypoperfusion induced by BCCAO could cause long term ER stress in the hippocampal CA1 region, which might include activation of JNK/c-Jun signaling pathway and CHOP transcriptional activity, and ultimately induce neuron damage. Continuously administration of physiological dose E2 could significantly prevent the damage.