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.