Browsing by Subject "Estrogens"
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ItemRETINA-TARGETED ESTROGEN PRODRUG: A NEW CONCEPT FOR RETINAL PROTECTION(2022-05) Lal, Kevin; Wu, Hongli; Prokai-Tatrai, Katalin; Liu, YangRetinal injury due to excessive light exposure during military duties often results in serious vision damage to soldiers including irreversible loss of visual function. However, therapeutic interventions that can promote retinal protection or reverse retinal damage are very limited. This unmet clinical need also persists in the public when strong lasers, light, or fire cause trauma in ocular tissues. It is well known that estrogen has been shown to exhibit various beneficial actions in the central nervous system, including positively affecting mood and protecting the neuronal cells against neurodegenerative diseases. Despite estrogen's potential, its detrimental side effects prevent its clinical uses for neurotherapy. To overcome this challenge, a bioprecursor prodrug was developed, called 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), that is selectively converted to E2 only in the neuronal cells, including retinal cells. To determine if treatment with DHED can sufficiently protect the photoreceptor cells from light-induced damage, male C57BL/6J mice were injected with or without 100 μg/kg DHED (n=15), 200 μg/kg DHED (n=15), 400 μg/kg DHED (n=15) and 200 μg/kg E2 (n=15) for 10 days before the light injury. Seven days after the light exposure, the visual function and retinal structure were examined by the spectral-domain optical coherence tomography (SD-OCT) and electroretinogram (ERG). After light exposure, we found massive photoreceptor loss as indicated by thinning of the outer nuclear layer (ONL) in groups that received no treatment. However, DHED treatment significantly prevented light-induced retinal structural changes and light-induced a- and b-wave reduction. Additionally, photoreceptor loss was decreased as indicated by increased outer nucellar layer thickness and SD-OCT data. The photoreceptor protective effects upon DHED-derived E2 treatment are stronger than that of the direct E2 treatment, consistent with our earlier observation that targeted E2 delivery via DHED prodrug produces more robust neuroprotection than direct administration of E2. In conclusion, our study supported our hypothesis that DHED is an efficacious and safe site-specific delivery agent to produce robust estrogen-mediated retinal neuroprotection. ItemThe 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." ItemThe Phenotype of Cells Expressing Estrogen Receptor Alpha in the Nucleus of the Solitary Tract(2018-05) Horn, Christopher L.; Mifflin, Steve W.; Schreihofer, Ann M.; Cunningham, J. Thomas; Phillips, Nicole R.Estrogen protects females from hypertension. The nucleus tractus solitarius (NTS) is a hindbrain site involved in the regulation of blood pressure, however little is known about estrogen receptors within the NTS. The purpose of these studies was to determine the phenotype of the cells expressing estrogen alpha receptors in the nucleus tractus solitarius. Four female Sprague-Dawley rats were transcardially perfused with 4% paraformaldehyde and hindbrains harvested. In coronal sections containing the NTS (40μm thick), immunohistochemistry was performed to determine which type of cells were expressed with estrogen receptor alpha (ERα) expressing cells. We used the anti-ERα antibody with an antibody for each protein of interest: anti-tyrosine hydroxylase (TH), anti-glial fibrillary acidic protein (GFAP), anti-NeuN, and anti-Iba-1. Sections were captured using an Olympus BX41 Fluorescence Microscope and analyzed using ImageJ. The NTS was divided into 2 regions: sections caudal to the area postrema (caudal) and sections lying below the area postrema (sub-postrema, SP) and the number of immunoreactive neurons in each region counted and expressed as an average number of labeled neurons per section±SEM. The number of sections analyzed ranged from 5-10 per individual in caudal and 2-4 per individual in SP. At sacrifice, females were in estrus (1), diestrus (2) or proestrus (3). NeuN in SP NTS (n=4) was observed in 151±53 and ERα in 50±21 neurons per section. Colocalization of ERα and NeuN in SP NTS was observed in 11±6 neurons per section (about 7%). NeuN in caudal NTS was observed in 59±7 and ERα 27±3 neurons per section. Colocalization of ERα and NeuN in caudal NTS was observed in 4±1 neurons per section (about 7%). TH in SP NTS (n=6) was observed in 49±8 and ERα in 51±12 neurons per section. Colocalization of ERα and TH in SP NTS was observed in 26±4 neurons per section (about 53%). TH in caudal NTS was observed in 26±6 and ERα 29±7 neurons per section. Colocalization of ERα and TH in caudal NTS was observed in 17±4 neurons per section (about 51%). Due to the quantity and shape of GFAP immunoreactive cells in the NTS (n=4), we were not able to count the number cells. Colocalization of ERα and GFAP expressing cells were not observed in our study. Cells expressing Iba1 were not observed in the later trials of our study (n=4). ERα is expressed on a subset of catecholaminergic NTS neurons, as well as non-catecholaminergic neurons. Since the NTS catecholaminergic neurons contribute to responses to stress (e.g., hypoxia), this finding could provide a substrate for estrogen-mediated cardiovascular protection in females.