The effects of 17β-estradiol, a potent estrogen, on ischemia-induced neuronal damage, membrane depolarization and changes in intracellular Ca2+ concentration were studied in gerbil hippocampi. The histological outcome evaluated seven days after 3 min of transient forebrain ischemia in hippocampal CA1 pyramidal cells was improved by high doses of 17β-estradiol (30 μg, i.c.v. and 4 mg/kg, i.p.), whereas low doses of 17β-estradiol (3 and 10 μg, i.c.v.) showed no protective effect. Administration of 17β- estradiol did not affect the changes in the direct current potential shift in ischemia in the hippocampal CA1 area at any dosage. A hypoxia-induced intracellular Ca2+ increase was evaluated by in vitro microfluorometry in gerbil hippocampal slices. Pretreatment of 17β-estradiol (4 mg/kg, injected i.p. 1 h before decapitation) suppressed the increase in the intracellular concentration of Ca2+ due to the in vitro hypoxia, affecting both the onset of the increase and the extent. The in vitro hypoxia in the Ca2+free condition induced an elevation of the intracellular concentration of Ca2+, although the increase was gradual. Pretreatment of 17β-estradiol (4 mg/kg, i.p.) also inhibited this elevation. These findings imply that high doses of 17β-estradiol protect the neurons from ischemia by inhibiting the release of Ca2+ from the intracellular Ca2+ stores, as well as by inhibiting the influx of Ca2+ from the extracellular space.
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