The importance of
hormone therapy in affording protection against the sequelae of global
ischemia in postmenopausal women remains controversial. Global
ischemia arising during
cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Exogenous
estradiol ameliorates global
ischemia-induced neuronal death and
cognitive impairment in male and female rodents. However, the molecular mechanisms by which
estrogens intervene in global
ischemia-induced apoptotic cell death are unclear. Here we show that
estradiol acts via the classical
estrogen receptors, the
IGF-I receptor, and the ERK/MAPK signaling cascade to protect CA1 neurons in ovariectomized female rats and gerbils. We demonstrate that global
ischemia promotes early dephosphorylation and inactivation of ERK1 and the
transcription factor cAMP-response element binding protein (CREB), subsequent down-regulation of the antiapoptotic
protein Bcl-2, a known gene target of
estradiol and CREB, and activation of
caspase-3.
Estradiol treatment increases basal phosphorylation of both ERK1 and ERK2 in hippocampal CA1 and prevents
ischemia-induced dephosphorylation and inactivation of ERK1 and CREB, down-regulation of Bcl-2 and activation of the
caspase death cascade. Whereas ERK/MAPK signaling is critical to CREB activation and neuronal survival, the impact of
estradiol on Bcl-2 levels is ERK independent. These findings support a model whereby
estradiol acts via the classical
estrogen receptors and
IGF-I receptors, which converge on activation of ERK/MAPK signaling and CREB to promote neuronal survival in the face of global
ischemia.