Semester

Fall

Date of Graduation

2020

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

James Simpkins

Committee Member

Candice Brown

Committee Member

Werner Geldenhuys

Committee Member

Marina Galvez-Peralta

Committee Member

Ann Hubbs

Abstract

Progestins are synthetic hormones that are designed to mimic the biological actions of progesterone. They, however, possess other pharmacological actions and properties, in addition to their progestational activities. Medroxyprogesterone Acetate (MPA) is a progestin used globally in the hormonal contraceptive, Depo Provera®, by women in their reproductive prime and is a major compound found in hormone therapy (HT) formulations used by menopausal women. MPA is used by approximately 1 in 5 adolescents and adult women in the United States who are sexually active. Globally, nearly 48 million women utilize injectable contraceptives to prevent pregnancy, with most users utilizing MPA as their hormone of choice. Despite the extensive use of hormonal methods as either contraception or menopausal HT, there is very little known about the potential effects of these compounds on the cellular processes of the brain. Additionally, MPA promotes changes in the circulating levels of matrix metalloproteinases (MMPs), such as MMP-9, in the endometrium, yet limited literature studying the effects of MPA on neurons and astroglia cells has been conducted. Furthermore, the dysregulation of MMPs has been implicated in the pathology of Alzheimer’s disease (AD), where inhibiting the secretion of MMP-9 from astroglia reduces the proteolytic degradation of amyloid beta.

The key objective for my dissertation work was to investigate the effects of acute and chronic administration of MPA on MMP-9 production and secretion, as well as AD-related pathology, by utilizing hormonal modulation of Aβ-degrading enzymes. Two sets of studies were designed to begin addressing some of the knowledge gaps associated with MPA and its potential effects on the brain. The hypothesis of these studies was that MPA alters the levels of MMP-9 secretion and enzymatic activity, in turn, negatively impacting the degradation of Aβ and cognitive function.

The first set of studies examined the outcomes of MPA on MMP-9 secretory, proteolytic, and Aβ-degrading activities. We found that MPA treatment inhibited transcription of MMP-9, which resulted in a subsequent decrease in the production and secretion of MMP-9 protein, in part through the glucocorticoid receptor. Additionally, we investigated the consequences on amyloid beta-degrading activity and found that MPA treatment decreased proteolytic degradation of amyloid beta. Our results suggest MPA suppresses amyloid beta degradation in an MMP-9-dependent manner, in vitro, and potentially compromises the clearance of amyloid beta in vivo.

The second set of studies was an in vivo assessment, evaluating the effects of chronic administration of exogenous progestins on cognitive function and MMP-9 expression. Our findings suggest that long-term, subcutaneous administration of MPA negatively impacts cognitive function, specifically memory consolidation, in wild-type (WT) mice, and enhances cognitive function, in a triple transgenic mouse model of AD (3xTg-AD), but causes a net increase MMP-9 expression in both mouse models.

Collectively, these two studies demonstrated that MPA’s actions on the brain need to be further investigated and more inclusive of non-menopausal and AD models. MPA elicits a differential effect in WT and AD animals, however, increases cortical MMP-9 expression in both phenotypes. Overall, these findings suggest that MPA has the potential to elicit differential effects on women in their reproductive prime and women with predispositions for AD and should encourage more elaborate investigations of its effects.

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