Variations in Hormone Therapy: Effects on Cognition and Markers of Brain Aging

激素疗法的变化：对认知和大脑衰老标志的影响

• 批准号: 7931530
• 负责人: HEATHER A. BIMONTE-NELSON
• 金额: $ 7.85万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931530
• 关键词: Acetylcholine; Address; Affect; Age; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease risk; Animal Experimentation; Animals; Attenuated; Basic Science; Brain; Brain region; Clinic; Clinical Research; Clinical Trials; Cognition; Cognitive; Cognitive aging; Combined Modality Therapy; Conjugated Equine Estrogens; Conjugated Estrogens; Controlled Clinical Trials; Data; Dendritic Spines; Deterioration; Dose; Drug Formulations; Endometrial Carcinoma; Estradiol; Estriol; Estrogen Replacements; Estrogen Therapy; Estrogens; Evaluation; Event; Female; Goals; Growth Factor; Health; Hippocampus (Brain); Hormone replacement therapy; Hormones; Human; Impaired cognition; In Vitro; Learning; Life; Link; Mediating; Medroxyprogesterone; Memory; Menopausal Symptom; Menopause; Modeling; Negative Finding; Neuraxis; Neurobiology; Norethisterone Acetate; Outcome; Ovarian hormone; Prempro; Preparation; Progesterone; Progestins; Pyramidal Cells; Rattus; Replacement Therapy; Research; Research Personnel; Risk; Risk Factors; Rodent; Rodent Model; Staging; Sum; Supplementation; Synaptic plasticity; System; Testing; Treatment Protocols; Uterus; Variant; Woman; Women' s Health; Work; age related; aged; aging brain; animal data; attenuation; base; clinically relevant; cognitive function; evaluation/testing; gamma-Aminobutyric Acid; hormone therapy; middle age; neuropathology; neurotrophic factor; pre-clinical; programs; receptor; research study

DESCRIPTION (provided by applicant): The broad goal of this application is to determine which variables influence whether hormone therapy acts as a protectant or a risk factor for cognitive functioning and brain aging. Ovarian hormone loss due to menopause has been linked with cognitive decline and increased risk of Alzheimer's disease. While there is evidence that hormone replacement decreases such effects, recent clinical trials failed to find positive effects, and some found detrimental effects. However, abundant basic science evidence suggests that estrogens exert beneficial effects on cognition and neurobiological variables related to memory. Hence, despite the null and negative findings in some clinical trials, the numerous animal and clinical studies showing positive effects of hormone treatment begs the question of what factors determine whether hormone therapy acts as a protectant or a risk factor for brain functioning and brain aging. We will use the rat model to systematically evaluate variations in current hormone therapies, testing whether they are beneficial or detrimental to cognition, neurotrophins, and markers of synaptic plasticity. Based on prior research, what factors might influence the outcome of estrogen replacement? 1. Dose and type of estrogen. Specific Aim I compares the dose-specific effects of three estrogen preparations: the most commonly used estrogen in animal studies (estradiol), the most commonly used estrogen therapy in the clinic (Premarin, or conjugated equine estrogens), and a promising estrogen therapy that has positive effects on menopausal symptoms (estriol). Neither Premarin nor estriol have been tested for cognitive effects in the rodent. 2. Unopposed vs. opposed estrogen treatment. We recently found that progesterone, given alone, is detrimental to spatial memory, and that tonic estradiol replacement enhances memory and alters neurotrophins in cognitive brain regions in aged rats. When progesterone was added to estradiol treatment, the cognitive and neurotrophin alterations due to estradiol were completely reversed. Specific Aim 2 tests whether the three most common clinically-used progestins alter cognition and the brain when given alone, and counteract estrogen-induced alterations when given as part of combination hormone therapy. Further, we will also test a mechanism of progesterone's effects on cognition. Some metabolites of progesterone have effects on the GABAA receptor. We hypothesize that progesterone is impairing memory by increasing GABAA stimulation, in turn resulting in greater hippocampal inhibition thereby impairing memory. By using GABAA antagonists and agonists as well as metabolites of progesterone that mediate the actions of GAB A on the GABAA receptor, Specific Aim 3 will test whether progesterone's negative effects on cognition, when given alone and concurrently with estradiol, are due to effects mediated by the GABAA system. In each study, rats will be tested on a battery of spatial and non-spatial working and reference memory tests, followed by evaluations of neurotrophin levels and markers of synaptic plasticity in cognitive brain regions. These studies will help elucidate which variations in hormone therapy attenuate or exacerbate age-related changes in cognition and the brain, as well as the mechanism of progesterone's effects when given alone and with estrogen.

描述（由申请人提供）：本申请的广泛目标是确定哪些变量影响激素治疗是否作为认知功能和脑老化的保护剂或风险因素。更年期引起的卵巢激素减少与认知能力下降和阿尔茨海默病风险增加有关。虽然有证据表明激素替代疗法可以减少这种影响，但最近的临床试验未能发现积极的影响，有些人发现了有害的影响。然而，大量的基础科学证据表明，雌激素对认知和与记忆相关的神经生物学变量产生有益的影响。因此，尽管在一些临床试验中发现了无效和负面的结果，但大量的动物和临床研究显示激素治疗的积极作用，这就引出了一个问题，即哪些因素决定激素治疗是作为大脑功能和大脑衰老的保护剂还是风险因素。我们将使用大鼠模型来系统地评估当前激素疗法的变化，测试它们对认知、神经营养因子和突触可塑性标志物是否有益或有害。根据先前的研究，哪些因素可能影响雌激素替代治疗的结果？1.雌激素的剂量和类型。具体目标我比较了三种雌激素制剂的剂量特异性效应：动物研究中最常用的雌激素（雌二醇），临床上最常用的雌激素治疗（倍美力，或共轭马雌激素），以及对更年期症状有积极作用的有前途的雌激素治疗（雌三醇）。倍美力和雌三醇都没有在啮齿动物中测试过对认知的影响。2.不反对与反对雌激素治疗。我们最近发现，孕酮，单独给予，是有害的空间记忆，和补充雌二醇增强记忆和改变神经营养因子在认知大脑区域的老年大鼠。当孕酮加入雌二醇治疗，认知和神经营养因子的改变，由于雌二醇被完全逆转。具体目标2测试三种最常见的临床使用的孕激素单独给药时是否会改变认知和大脑，以及作为联合激素治疗的一部分时是否会抵消雌激素诱导的改变。此外，我们还将测试孕酮对认知的影响机制。孕酮的一些代谢产物对GABAA受体有影响。我们假设孕酮通过增加GABAA刺激损害记忆，反过来导致更大的海马抑制，从而损害记忆。通过使用GABAA拮抗剂和激动剂以及介导GABA对GABAA受体的作用的孕酮代谢物，具体目标3将测试孕酮在单独给药和与雌二醇同时给药时对认知的负面作用是否是由于GABAA系统介导的作用。在每项研究中，将对大鼠进行一系列空间和非空间工作记忆和参考记忆测试，然后评价神经营养因子水平和认知脑区突触可塑性标志物。这些研究将有助于阐明激素治疗的哪些变化会减弱或加剧认知和大脑中与年龄相关的变化，以及单独和与雌激素一起使用时孕酮的作用机制。