PHYTOESTROGENS IN THE BRAIN

Purpose: Soy is one of the top ten herbal supplements taken in the United States. It is generally marketed as a safe and natural way to improve a diverse array of disease conditions such as osteoporosis and to improve menopausal symptoms. Its efficacy, however, has not been completely validated. Genistein, which is a major constituent of soy, is a phytoestrogen, and is thought to elicit some of soy's beneficial effects through activation of estrogen receptors (ER). Despite its wide use, it is currently unclear how genistein might affect the brain. We hypothesize that like estrogen, genistein can be neuroprotective but its capacity to do so is dependent on the availability of "intact" ER-brain derived neurotrophic factor (BDNF) signaling. We have also tested the hypothesis that because ER expression may change as a function of age and sex, such changes may alter genistein's capacity to influence neuroprotective proteins such as BDNF. Methods: This hypothesis was tested using complementary in vitro and in vivo models. For our in vitro experiments we used mouse cerebral cortical explants. Genistein was applied to the cultures at ER activating concentrations. Glutamate was then applied as an excitotoxic insult to induce cell death. Cell death was quantified by measuring the amount of lactate dehydrogenase (LDH) released by the cells into the media. To corroborate our in vitro data, we assessed whether age related changes in ER expression affect genistein's ability to induce BDNF in male and female mice. Results: Our in vitro data indicate that genistein at 100nM significantly reduces the amount of cell death induced by glutamate in cortical explants which express both ERɑ and ERβ. Our in vivo data indicate that age does affect ER expression but it does so in a sex and brain region specific manner. Genistein's effect on BDNF levels were also age, sex, and brain region specific. Conclusions: Our results indicate that genistein can be protective, but its protective effects may be dependent on the expression of appropriate ERs and their capacity to influence BDNF signaling.