The broad goal of this research is to discover estrogenic steroids with neurotrophic activity that will promote the growth and survival of neurons derived from brain regions involved in cognitive function. Germination this proposal began when we discovered several estrogenic steroids that exhibit relatively low affinity for the uterine estrogen nuclear receptor (122-126), which could reduce the risk of breast and uterine cancer, but which exerted a neurotrophic effect similar to what we had observed for the endogenous human female estrogen, and beta-estradiol. (3) Of particular interest was the neurotrophic activity of the equine estrogen, equilin. Equilin is a major component of Premarin, a complex formulation of at least 10 different conjugated equine estrogens, that is currently the leading prescribed pharmaceutical for estrogen replacement therapy in postmenopausal women and is currently under study in 8,000 women participating in the multicenter Women's Health Initiative Memory Study. (59) The proposed studies are designed to test the overall hypothesis that steroids which are estrogenic in chemical structure will influence neuronal outgrowth and survival with varying efficacies depending on their molecular structure. Further, the basis for the different efficacies and potencies of estrogen steroids on neuronal outgrowth will be reflected in their ability to regulate receptor channel function. We further hypothesize that mechanisms that promote an increase in intracellular calcium will underlie estrogenic steroid-induced neurotropism. Lastly, we hypothesize that estrogenic steroids that exert a neurotrophic effect will also promote neuronal survival by enhancing viability and thereby will enhance the capacity of neurons to resist a oxidative stress by beta-amyloid peptide and other free radical generators. To test these hypotheses morphological analyses of dissociated cortical and hippocampal neurons in culture in response to estrogenic steroids and to pharmacological agents that block nuclear estrogen receptors, plasma membrane glutamatergic receptors and protein kinases will be conducted. In addition, whole cell recording will conducted in cultured neurons and slice preparations to analyze the electrophysiological effects of neurotrophic estrogens. Results of these studies will have a direct impact on the use and design of estrogen replacement therapy for the amelioration of cognitive deficits in postmenopausal women and for the prevention of Alzheimer's Disease in this population.
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