Browsing by Subject "menopause"
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Item A Novel Prodrug Approach for Central Nervous System-Selective Estrogen Therapy(MDPI, 2019-11-19) Prokai-Tatrai, Katalin; Prokai, LaszloBeneficial effects of estrogens in the central nervous system (CNS) results from the synergistic combination of their well-orchestrated genomic and non-genomic actions, making them potential broad-spectrum neurotherapeutic agents. However, owing to unwanted peripheral hormonal burdens by any currently known non-invasive drug administrations, the development of estrogens as safe pharmacotherapeutic modalities cannot be realized until they are confined specifically and selectively to the site of action. We have developed small-molecule bioprecursor prodrugs carrying the para-quinol scaffold on the steroidal A-ring that are preferentially metabolized in the CNS to the corresponding estrogens. Here, we give an overview of our discovery of these prodrugs. Selected examples are shown to illustrate that, independently of the route of administrations and duration of treatments, these agents produce high concentration of estrogens only in the CNS without peripheral hormonal liability. 10beta,17beta-Dihydroxyestra-1,4-dien-3-one (DHED) has been the best-studied representative of this novel type of prodrugs for brain and retina health. Specific applications in preclinical animal models of centrally-regulated and estrogen-responsive human diseases, including neurodegeneration, menopausal symptoms, cognitive decline and depression, are discussed to demonstrate the translational potential of our prodrug approach for CNS-selective and gender-independent estrogen therapy with inherent therapeutic safety.Item Neuroprotective properties of Phytoestrogens(2012-12-01) Brock, Courtney Anne; Singh, MeharvanWomen make up nearly two thirds of total Alzheimer’s cases in the United States. It has been speculated that the loss of endogenous estradiol during menopause is, at least in part, what renders the post-menopausal brain more vulnerable to the effects of aging and Alzheimer’s Disease. While hormone therapy can potentially thwart some of the undesirable consequences and increased risks associated with menopause, women are increasingly rejecting hormone therapy and seeking alternative therapy. There is a strong in interest in phytoestrogens as an alternative to traditional hormone therapy. Phytoestrogens are naturally occurring estrogen like compounds derived from plants which have been shown to have a variety of health benefits. Their effects in the brain however are not fully understood. It was my goal to evaluate the effect of phytoestrogens on brain cells as it relates to neuroprotection. We initially assessed the ability of genistein, the most abundant phytoestrogen found in soy, to protect brain cells against age-associated insults in vitro using the hippocampal cell line (HT22 cells), a cortical cell line (HCN-1A cells), and primary slice cultures of the cerebral cortex. The results of these experiments were such that genistein was protective in the explant model and HCN-1A cells, but not in the HT22 cells suggesting that certain key players must be present for genistein to elicit neuroprotective effects. Based on the known estrogen receptor (ER) profiles for the models used in our study, we hypothesized that ER profiles may dictate the effects of phytoestrogens on brain cells. As such, we evaluated male and female C57/Bl6 mice at 3 different ages for ER expression profile and the effects that a phytoestrogen diet had on BDNF, used in this study as a surrogate marker of neuroprotection. Results showed that phytoestrogens’ effects on the brain differ between the cortex and the hippocampus and are dependent upon the sex of the animal and age at which the diet was initiated. From our results we have proposed a mechanism by which phytoestrogens differentially elicit their effects in the brain. The data presented herein provides valuable insight into phytoestrogens’ effects on the brain.Item The impact of 17beta-estradiol on the estrogen-deficient female brain: from mechanisms to therapy with hot flushes as target symptoms(Frontiers Media S.A., 2024-01-23) Prokai-Tatrai, Katalin; Prokai, LaszloSex steroids are essential for whole body development and functions. Among these steroids, 17beta-estradiol (E2) has been known as the principal female" hormone. However, E2's actions are not restricted to reproduction, as it plays a myriad of important roles throughout the body including the brain. In fact, this hormone also has profound effects on the female brain throughout the life span. The brain receives this gonadal hormone from the circulation, and local formation of E2 from testosterone via aromatase has been shown. Therefore, the brain appears to be not only a target but also a producer of this steroid. The beneficial broad actions of the hormone in the brain are the end result of well-orchestrated delayed genomic and rapid non-genomic responses. A drastic and steady decline in circulating E2 in a female occurs naturally over an extended period of time starting with the perimenopausal transition, as ovarian functions are gradually declining until the complete cessation of the menstrual cycle. The waning of endogenous E2 in the blood leads to an estrogen-deficient brain. This adversely impacts neural and behavioral functions and may lead to a constellation of maladies such as vasomotor symptoms with varying severity among women and, also, over time within an individual. Vasomotor symptoms triggered apparently by estrogen deficiency are related to abnormal changes in the hypothalamus particularly involving its preoptic and anterior areas. However, conventional hormone therapies to "re-estrogenize" the brain carry risks due to multiple confounding factors including unwanted hormonal exposure of the periphery. In this review, we focus on hot flushes as the archetypic manifestation of estrogen deprivation in the brain. Beyond our current mechanistic understanding of the symptoms, we highlight the arduous process and various obstacles of developing effective and safe therapies for hot flushes using E2. We discuss our preclinical efforts to constrain E2's beneficial actions to the brain by the DHED prodrug our laboratory developed to treat maladies associated with the hypoestrogenic brain."