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EFFECTS OF ESTRADIOL AND SELECTIVE ESTROGEN RECEPTOR AGONISTS ON BIOCHEMICAL ENDPOINTS IN THE BRAIN: A COMPARISON BETWEEN TRANSITIONAL AND SURGICAL MENOPAUSE RAT MODELS

KIRSHNER, ZIV Z. (2019) EFFECTS OF ESTRADIOL AND SELECTIVE ESTROGEN RECEPTOR AGONISTS ON BIOCHEMICAL ENDPOINTS IN THE BRAIN: A COMPARISON BETWEEN TRANSITIONAL AND SURGICAL MENOPAUSE RAT MODELS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Women spend the last third of their lifetime postmenopause, with cessation of ovarian activity and diminished production of systemic estrogen. The loss of ovarian estrogen production is correlated with age-related cognitive decline, dementia and a shift in brain metabolism from glucose to ketone bodies. Estrogen treatment may prevent or reverse these changes. Our goal is to understand how the loss of ovarian function and estrogen replacement therapy affect metabolism and function of brain regions that are involved in cognitive functions. In this study, we evaluated the differences between surgical (ovariectomized, OVX) to transitional (ovatotoxin-treated, 4-vinylcyclohexene diepoxide, VCD) menopause rat models in comparison to normally cycling rats and with agonists treatments for the selective activation of estrogen receptor α (ERα), ERβ and G-protein coupled estrogen receptor 1 (GPER-1). Our endpoints were chosen to represent pivotal targets in major metabolic, energy, cytoskletal and neurological pathways which are modulated by estrogens with corresponding effects on neuronal or cognitive functions. Overall these studies established a highly reliable method to relatively quantify proteins in brain homogenates, a direct comparison of metabolic endpoints between OVX, VCD and cycling animals as well as the effects of ER agonists between OVX and VCD rats in two time points of continuous treatment (1- and 6- weeks) and three brain regions: hippocampus (HPC), frontal cortex (FCX) and striatum (STR). These studies illustrates that type and onset of menopause have versatile impact on brain metabolism, glucose utilization, cytoskeletal and cholinergic endpoints. We also demonstrated the differences in response to selective activation of different estrogen receptors and provided an insight into changes that occur in across duration of treatment, menopause models and treatments with selective estrogen receptor agonists. These can serve as a pre-clinical map for the development of more selective estrogen replacement therapy for postmenopausal women.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
KIRSHNER, ZIV Z.ziv.kirshner@gmail.comzzk20000-0002-6570-4602
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGibbs, Robert B.gibbsr@pitt.edugibbsr
Committee MemberVollmer, Regis R.vollm@pitt.eduvollm
Committee MemberDeFranco, Donalddod1@pitt.edudod1
Committee MemberXie, Wenwex6@pitt.eduwex6
Date: 27 November 2019
Date Type: Publication
Defense Date: 29 October 2019
Approval Date: 27 November 2019
Submission Date: 25 November 2019
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 180
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Hormone Replacement Therapy, HRT, Personalized Medicine, Selective Estrogen Receptor Agonist, SERM
Date Deposited: 27 Nov 2019 17:05
Last Modified: 27 Nov 2019 17:05
URI: http://d-scholarship.pitt.edu/id/eprint/37889

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  • EFFECTS OF ESTRADIOL AND SELECTIVE ESTROGEN RECEPTOR AGONISTS ON BIOCHEMICAL ENDPOINTS IN THE BRAIN: A COMPARISON BETWEEN TRANSITIONAL AND SURGICAL MENOPAUSE RAT MODELS. (deposited 27 Nov 2019 17:05) [Currently Displayed]

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