MODULATION OF CNS FUNCTION USING A NOVEL SELECTIVE ESTROGEN (SERM)

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our ongoing rhesus macaque studies confirm clinical observations that female aging is associated with decreased cognitive function, loss of white matter in the CNS and perturbed sleep-wake cycles. Moreover, these changes are closely associated with a marked attenuation of the circulating levels of estradiol as well as DHEA and DHEA sulfate (DHEAS), two adrenal steroids. It appears that the primate CNS expresses genes that encode key enzymes in the conversion of DHEA/DHEAS to estradiol and that these too show age-related alterations. Hence, a primary goal of our research program is to establish the efficacy of DHEA replacement as a potential therapy for age-associated impairments of the CNS, and importantly, one with less risk of causing cancer in peripheral tissues. In this related pilot study, our goal is to explore an alternate strategy. Namely, to use STX (a novel centrally-acting selectively active estrogen receptor modulator) to overcome age-related, sex-steroid dependent changes within the macaque CNS. This research has the potential to identify a novel hormone replacement therapy (HRT) for use in postmenopausal women - one that has the advantage of acting centrally and without causing unwanted peripheral side-effects. So far, we have found STX to be as effective as estradiol at suppressing core body temperature. Ongoing molecular biology studies are using Affymetrix gene arrays and RT-PCR to elucidate the underlying neural mechanism.