Our goal is to understand mechanisms by which estrogens affect the brain and cognitive performance. Estrogens have many beneficial effects in the brain;however, the mechanisms by which estrogens mediate these effects are in many ways unknown. We hypothesize that these effects reflect in large part effects on multiple interacting neurotransmitter pathways in specific brain regions. In particular, we hypothesize that loss of ovarian function results in multiple and simultaneous decreases in specific monoaminergic pathways in the brain, and that selective agonists acting at specific estrogen receptors can reverse these effects and restore the neurotransmitter pathways to a physiologically normal state. Over the past decade, Dr. Yao's (co-PI) laboratory has focused on developing technologies to quantify multiple low-molecular weight redox-active compounds (e.g., monoamines, monoamine metabolites, amino acids, markers of oxidative stress, etc...) in biological tissues. This is accomplished using state-of-the-art high-pressure liquid chromatography coupled with a 16-channel Coulometric Multi-Electrode Array System (HPLC-CMEAS) and capillary gas chromatography with a flame-ionization detector (GC-FID). The power of this technology is the ability to assess multiple metabolites from different biochemical pathways simultaneously in the picomol range. Using animal models of both surgical and natural menopause, we will apply this technology to evaluate the effects of 'menopause'and treatment with selective estrogen receptor agonists on multiple neurotransmitter pathways within specific brain regions. Models of menopause will include ovariectomy (a model of surgical menopause), and treatment with 4-vinylcyclohexene diepoxide (VCD;a model of natural menopause). Estrogen treatments will include 17ss-estradiol (E2), G-1 (a selective GPR30 agonist), PPT (a selective ER? agonist) and DPN (a selective ERss agonist) administered continuously sc. at 5 ?g/day for 1 week or six weeks following loss of ovarian function. Tissues from the hippocampus, frontal cortex, and striatum will be dissected and analyzed for levels of monoamines, monoamine metabolites, amino acid neurotransmitters, and choline acetyltransferase (a marker of cholinergic neurons). This study will provide a detailed description of the changes in neurochemically relevant compounds that occur in specific regions of the brain, in two models of menopause, in response to selective hormone treatments. The studies also will be the first to evaluate the effects of a selective GPR30 agonist on these targets and to compare them with the effects of selective ER? and ERss agonists. The findings will provide a much clearer understanding of the neurochemical changes associated with different types of menopause and will lead to better strategies for approaching estrogen therapy in women.

Public Health Relevance

Estrogens have many beneficial effects in the brain;however, the mechanisms by which estrogen mediate these effects are in many ways unknown. Identifying a network of multiple interacting neurochemical pathways that account for the constellation of clinical and biological features would advance our understanding of estrogen effects in the brain tremendously. For the past decade, the PIs'laboratories have studied estrogen effects on the brain and most recently have developed technologies to obtain a three-dimensional metabolic profile by applying high-pressure liquid chromatography coupled with a Coulometric Multi-Electrode Array System (HPLC-CMEAS) and capillary gas chromatography with a flame-ionization detector (GC-FID) to quantify multiple low-molecular weight redox-active compounds (e.g., monoamine metabolites and amino acids) in biological tissues. This project will take advantage of these approaches to evaluate the effects of selective estrogen receptor agonists on multiple neurotransmitter pathways in the brain, and will compare effects associated with two different and important models of menopause. This targeted metabolomics approach will greatly increase our understanding of the neurochemical changes associated with two clinically relevant models of menopause, as well as the potential of specific estrogen receptor agonists to reverse the effects of menopause on monoaminergic pathways that are critical for normal brain function and cognitive performance.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG043817-02
Application #
8705338
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Mackiewicz, Miroslaw
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213