Estrogen is a powerful neuroprotective hormone that is particularly effective in reducing cerebral ischemic damage in stroke. Endogenous and exogenous estrogen is also associated with protection from neurodegenerative disease in humans. However, the benefits of estrogen are mitigated by recent clinical results suggesting that hormone replacement therapy (HRT) has health consequences. Concerns about hormone dependent cancer will continue to deter women from taking replacement therapy. Pharmacological selective estrogen receptor modulators (SERMs) show promise in preserving the beneficial effects of estrogen without increasing cancer risk. However, many women are already opting for """"""""natural"""""""" SERMs such as plant derivatives containing soy and other phytoestrogens with the presumption that such therapies are both effective and safer than HRT. Epidemiological and experimental data suggest that diets high in soy phytoestrogens provide many of the same benefits as estrogen with the potential for decreased negative side effects seen with traditional HRT. Nevertheless, very little is known about the effects of dietary soy phytoestrogens in the brain. In vitro, soy phytoestrogens can mimic some of estrogen's neuroprotective actions, but these same compounds have also been shown to inhibit some estrogen actions in the brain. The present proposal seeks to determine the whether of soy phytoestrogens protect neurons from ischemic damage in vitro and in vivo. We hypothesize that physiologically relevant doses of soy phytoestrogens are neuroprotective by mimicking both genomic and non-genomic actions of estrogen.
Aim 1 will test the hypothesis that the soy phytoestrogens genestein, daidzein, and equol inhibit apoptotic cell death in neuronal cell line models of cerebral ischemia in an estrogen receptor-dependent manner.
Aim 2 will test the hypothesis that in the absence of endogenous estrogen a high soy diet will decrease infarct size and cell death associated with middle cerebral artery occlusion in rats.
Aim 3 will test the hypothesis that in the absence of endogenous estrogen, ingestion of a high soy diet will induce the expression of the neuroprotective genes BDNF, NGF, Bcl-2, BCl-xL, and TrkB and reduce expression of the pro-apoptotic p75 NTR in brain regions damaged by middle cerebral artery occlusion. This proposal seeks to provide critical new information about the ability of phytoestrogens to protect the brain from focal cerebral ischemia.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
5R01AT001882-04
Application #
7173879
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Khalsa, Partap Singh
Project Start
2004-02-15
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2009-01-31
Support Year
4
Fiscal Year
2007
Total Cost
$276,486
Indirect Cost
Name
Georgia Regents University
Department
Physiology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Schreihofer, Derek A; Deutsch, Christian; Lovekamp-Swan, Tara et al. (2010) Effect of high soy diet on the cerebrovasculature and endothelial nitric oxide synthase in the ovariectomized rat. Vascul Pharmacol 52:236-42
Schreihofer, D A; Redmond, L (2009) Soy phytoestrogens are neuroprotective against stroke-like injury in vitro. Neuroscience 158:602-9
Glendenning, Michele L; Lovekamp-Swan, Tara; Schreihofer, Derek A (2008) Protective effect of estrogen in endothelin-induced middle cerebral artery occlusion in female rats. Neurosci Lett 445:188-92
Lovekamp-Swan, Tara; Glendenning, Michele L; Schreihofer, Derek A (2007) A high soy diet enhances neurotropin receptor and Bcl-XL gene expression in the brains of ovariectomized female rats. Brain Res 1159:54-66
Lovekamp-Swan, T; Glendenning, M; Schreihofer, D A (2007) A high soy diet reduces programmed cell death and enhances bcl-xL expression in experimental stroke. Neuroscience 148:644-52
Schreihofer, Derek A; Do, Khoi D; Schreihofer, Ann M (2005) High-soy diet decreases infarct size after permanent middle cerebral artery occlusion in female rats. Am J Physiol Regul Integr Comp Physiol 289:R103-8