Proestrus levels of estradiol during transient global cerebral ischemia improves the histological outcome of the hippocampal CA1 region: perfusion-dependent and-independent mechanisms.

We conducted this study to determine whether high physiological levels of estradiol (proestrus) could protect the hippocampal CA1 neurons following transient global ischemia. Ovariectomized or ovary-intact female rats were subjected to 20 min of ischemia and allowed to survive for 96 h. Estradiol was administered subcutaneously in a group of ovariectomized rats 24 h before ischemia induction. Ending serum estrogen levels were correlated to cerebral blood flow (CBF), histologic assessment and immunofluorescent caspase-3 active peptide (C-3AP) positive cell count. Estradiol administration significantly improved CBF in the hippocampus (compared with intact or ovariectomized rats) but not in the parietal cortex. No significant differences in CBF between intact or ovariectomized rats were noted. Estradiol administration maintained serum levels of the steroid in estradiol-treated rats-about 10 times that of intact animals and more than 20 times that of ovariectomized animals. Morphologically, live cell counts in estradiol-treated rats were significantly higher than in intact or ovariectomized rats. Live cell counts were also significantly higher in intact than ovariectomized rats. C-3AP positive cell counts were much higher in ovariectomized rats than in intact and estradiol-treated rats. In conclusion, proestrus levels of 17beta-estradiol protect hippocampal CA1 neurons against transient global ischemia, through mechanisms that appear to involve improvement of perfusion and inhibition of caspase-3 activity.