Estrogen replacement therapy is thought to attenuate the incidence of
Alzheimer's disease in women and enhance cognitive functions. In rodents,
estrogen protects cerebral cortical neurons from ischemic injury and cultured neurons from a variety of perturbations. Because few nuclear
estrogen receptors have been detected in the dorsal hippocampus, the present studies used a global
ischemia model to evaluate the neuroprotective actions of
estrogen in this region. Ovariectomized gerbils were treated with placebo, 0.5 mg or 1 mg pellets of
estradiol for 13 days. On day 7, the common carotid arteries were occluded for 5 min and on day 13 the animals were killed. Analysis of
neurogranin mRNA, a marker of hippocampal neurons, with in situ hybridization revealed a dramatic and selective loss of CA1 neurons in the placebo-treated ovariectomized gerbils, whereas both 0.5 mg and 1 mg pellets of 17beta-estradiol prevented cell loss. Subsequent studies showed that a variety of
estrogens, including
diethylstilbestrol,
estrone and 17alpha-estradiol as well as
vitamin E, also protected CA1 neurons from ischemic injury in ovariectomized gerbils, whereas treatment with the
estrogen antagonist
tamoxifen was ineffective. The results of in vivo binding studies with 17alpha-iodovinyl-11beta-methoxyestradiol revealed a concentration of nuclear
estrogen binding sites in the CA1 region of the ovariectomized gerbil brain, whereas binding in other hippocampal regions was limited. Moreover, the binding studies revealed that the regional pattern of binding was not altered after ischemic injury, with the exception of the hippocampus, where the binding sites were attenuated in ovariectomized animals with time after ischemic injury. Together, these data demonstrate that a variety of steroidal and
non-steroidal estrogens are potent
neuroprotective agents in an animal model of global
ischemia, agents that protect neurons critical for learning and memory and susceptible to
neurodegenerative diseases.