Female rodents producing endogenous estrogens are protected from stroke dam
age in comparison with male counterparts. This natural protection is lost a
fter ovariectomy or reproductive senescence. The aim of this study is to de
termine whether estrogen reduces early neuronal injury and cell loss after
ischemia by increasing the expression of Bcl-2. Male, intact female, ovarie
ctomized, and estrogen-repleted ovariectomized rats were subjected to middl
e cerebral artery occlusion, and 22 hr later the level and localization of
Bcl-2 mRNA and protein were determined. The levels of post-ischemic bcl-2 m
RNA and protein were increased exclusively in neurons within the peri-infar
ct region. Intact females and estrogen-treated castrates demonstrated incre
ased bcl-2 mRNA and protein expression compared with males and estrogen-def
icient females, accompanied by a decrease in infarct size. To test the hypo
thesis that the neuroprotective mechanism of estrogen functions via Bcl-2,
we compared ischemic outcome in male, female, and ovariectomized wild-type
mice and mice overexpressing Bcl-2 exclusively in neurons. Wild-type female
mice sustained smaller infarcts compared with males. Bcl-2 overexpression
reduced infarct size in males, but provided no added protection in the fema
le. Moreover, ovariectomy exacerbated infarction in wildtype females, but h
ad no effect in Bcl-2 overexpressors. These data indicate that overexpressi
on of Bcl-2 simulates the protection against ischemic injury conferred by e
ndogenous female sex steroids. We concluded that estrogen rescues neurons a
fter focal cerebral ischemia by increasing the level of Bcl-2 in peri-infar
ct regions and that estrogen-induced bcl-2 gene expression is an important
downstream component of neuronal protection in female stroke.