Browsing by Subject "Genistein"
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Item PHYTOESTROGENS IN THE BRAIN(2013-04-12) Brock, CourtneyPurpose: 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.Item The role of aging and length of hypogonadism on the neuroprotective effects of dietary genistein following focal cerebral ischemia(2021-05) Oppong-Gyebi, Anthony; Schreihofer, Derek A.; Singh, Meharvan; Sumien, Nathalie; Yang, Shaohua; Shi, XiangrongThe risk of ischemic stroke increases with increasing age. Women beyond menopause have an exponential increase in stroke risk with worse post-stroke prognosis and mortalities compared to men of similar ages. One of the key reasons for this discrepancy is the sudden and drastic drop in the levels of the circulating principal female sex hormones estrogen and progesterone after menopause. Both sex hormones have been shown in several studies to provide neuroprotection against ischemic insults in stroke models and other disease models including Alzheimer's Disease and Parkinson's Disease. However, from clinical studies, neither estrogen nor progesterone alone or in combination has met clinical needs for the prevention of chronic cardiovascular diseases. These clinical failures were mainly evidenced by the absence of benefits in the human population or an increased predisposition to adverse side effects. Reports from studies including the Women's Health Initiative and Nurse's Health Study showed that the timing of initiation and age of recipients significantly influence the outcome of estrogen therapy. In this dissertation project, we investigated the plant-based estrogenic compound genistein as a possible alternative to estrogen therapy. It was hypothesized that the neuroprotective benefits of genistein will be less sensitive to the length of hypogonadism and age under experimental ischemic conditions. We used a rodent model of transient middle cerebral artery occlusion under varied lengths of estrogen deprivation and age to test the neuroprotection of dietary genistein. Findings from this dissertation show that early initiation of dietary genistein after hypogonadism improves aspects of cognition, an effect that is diminished following the long absence of circulating estrogen. Furthermore, pre-treatment with dietary genistein improves age-associated locomotor deficits after long-term hypogonadism after stroke. This dissertation, therefore, provides new considerations on the time-dependent sensitivity of the brain to genistein's effect as a potential therapeutic option to improve aspects of cognition and reduce the severity of stroke in the target population with low circulating estrogens.