Abstract
Diets high in soy are neuroprotective in experimental stroke. This protective effect is hypothesized to be mediated by phytoestrogens contained in soy, because some of these compounds have neuroprotective effects in in vitro models of cell death. We tested the ability of the soy phytoestrogens genistein, daidzein, and the daidzein metabolite equol to protect embryonic rat primary cortical neurons from ischemic-like injury in vitro at doses typical of circulating concentrations in human populations (0.1-1 microM). All three phytoestrogens inhibited lactate dehydrogenase (LDH) release from cells exposed to glutamate toxicity or the calcium-ATPase inhibitor, thapsigargin. In cells exposed to hypoxia or oxygen-glucose deprivation (OGD), pretreatment with the phytoestrogens inhibited cell death in an estrogen receptor (ER) dependent manner. Although OGD results in multiple modes of cell death, examination of alpha-spectrin cleavage and caspase-3 activation revealed that the phytoestrogens were able to inhibit apoptotic cell death in this model. In addition, blockade of phosphoinositide 3-kinase prevented the protective effects of genistein and daidzein, and blockade of mitogen-activated protein kinase prevented genistein-dependent neuroprotection. These results suggest that pretreatment with dietary levels of soy phytoestrogens can mimic neuroprotective effects observed with estrogen and appear to use the same ER-kinase pathways to inhibit apoptotic cell death.