Estrogen can ameliorate brain damage in experimental models of focal cerebral ischemia., estrogen increases levels of apolipoprotein E (apoE), which also has neuroprotective effects in brain injury. The authors tested the hypotheses that physiologically relevant levels of 17beta-estradiol are neuroprotective in global cerebral ischemia and that neuroprotection is mediated via apoE. In the first study, subcutaneous implants of 17beta-estradiol were tested in female C57Bl/6J mice (ovariectomized and nonovariectomized) and plasma levels measured by radioimmunoassay to validate that physiologically relevant levels could be achieved. In the second study, female C57Bl/6J and apoE-deficient mice were ovariectomized and implanted with 17beta-estradiol or placebo pellet. Two weeks later, transient global ischemia was induced by bilateral carotid artery occlusion and the mice killed after 72 hours. Ischemic and normal neurons were counted in the caudate nucleus and CA1 pyramidal cell layer and the percentage of neuronal damage was compared between the treated groups. In C57Bl/6J mice, there was less neuronal damage in the 17beta-estradiol-treated group compared with placebo group in the caudate nucleus (15 +/- 20% versus 39 +/- 27%, = 0.02) and in the CA1 pyramidal cell layer (1.8 +/- 2% versus 10 +/- 14%, = 0.08). In contrast, neuronal damage was not significantly different between the 17beta-estradiol and placebo groups in apoE-deficient mice in the caudate nucleus (47 +/- 35% versus 53 +/- 29%, = 0.7) or in the CA1 pyramidal cell layer (24 +/- 19% versus 24 +/- 19%, = 1.0). The data indicate a neuroprotective role for estrogen in global ischemia, the mechanism of which is apoE-dependent.