Global
ischemia arising during
cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons.
Phytoestrogens are naturally occurring
plant-derived compounds that are present in the human diet and are considered selective
estrogen receptor (ER) modulators. The
phytoestrogen coumestrol is a potent isoflavonoid, with binding affinities for both ER-α and ER-β that are comparable to those of 17 b-
estradiol. The present study examined the hypothesis that
coumestrol protects hippocampal neurons in ovariectomized rats in a model of cerebral global
ischemia. Ovariectomized rats were subjected to global
ischemia (10 min) or
sham surgery and received a single intracerebroventricular or peripheral infusion of 20 μg of
coumestrol, 20 μg of
estradiol or vehicle 1h before
ischemia or 0 h, 3h, 6h or 24h after reperfusion.
Estradiol and
coumestrol afforded significant neuroprotection in all times of administration, with the exception of
estradiol given 24h after the ischemic insult. Animals received icv infusion of the broad-spectrum ER antagonist
ICI 182,780 (50 μg) or vehicle into the lateral ventricle just before the E2 or
coumestrol administration. The ER antagonist abolished
estradiol protection, consistent with a role of classical ERs. In contrast,
ICI 182,780 effected only partial reversal of the neuroprotective actions of
coumestrol, suggesting that other cellular mediators in addition to classical ERs may be important. Additional research is needed to determine the molecular targets mediating the neuroprotective action of
coumestrol and the therapeutic potential of this
phytoestrogen in the mature nervous system.