There are 750,000 new cases of stroke each year in the United States, and brain damage from stroke leads to high health care costs and disabilities. Needed, but currently not available, are therapies that can be administered prior to, during, or after cerebral ischemia that reduce or eliminate neuronal damage from stroke. To address this issue, we began to assess the neuroprotective effects of estrogens and related compounds in stroke neuroprotection to determine whether these compounds had potential for clinical application. First, we demonstrated that 17 beta-estradiol (E2) pretreatment exerted potent neuroprotection of the cerebral cortex over a wide dose range and pretreatment interval. Thereafter, we assessed the ability of a variety of non-feminizing estrogens to protect brain tissue from stroke. We observed that pretreatment with 17 alpha-estradiol, the complete enantiomer of E2 (ENT-E2), 2-adamantylestrone, and the enantiomer of 17-desoxyestradiol, were as effective as E2 in pretreatment protection from stroke damage. These data suggest that non-estrogen receptor mechanisms are involved in brain neuroprotection under our treatment conditions. We then determined whether the observed E2 protection could be extended to times after the onset of the cerebral ischemic event. Using a formulation of E2 that rapidly delivers the steroid, a necessary condition for acute therapy of an ongoing stroke, we demonstrated that 100 mg E2/kg could protect brain tissue for up to 3 h after the onset of the stroke. To determine whether this therapeutic window could be extended with higher doses of the steroid, we conducted a dose-response assessment of E2 when administered at 6 h after the onset of the ischemic event. While the effectiveness of the 100 micro g E2/kg was reduced at this time interval, higher doses of E2 were effective. E2, at doses of 500 and 1000 micro g/kg, reduced infarct volume by more than 50%, even with this 6-h delay in treatment. Collectively, these data indicate that estrogens could prove to be useful therapies in preventing brain damage from strokes.