Targeting angiotensin II in cognitive impairment associated with ovarian hormone loss

靶向血管紧张素 II 治疗与卵巢激素丧失相关的认知障碍

• 批准号: 9751159
• 负责人: Kathryn L Sandberg
• 金额: $ 19.13万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751159
• 关键词: Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensins; Animal Model; Animals; Antihypertensive Agents; Attenuated; Basic Science; Benign; Bilateral oophorectomy; Blood Pressure; Cerebrum; Clinic; Clinical; Clinical Research; Cognition; Cognitive; Cognitive Therapy; Cohort Studies; Dementia; Disease; Dose; Drops; Effectiveness; Endothelium; Estradiol; Estrogen Replacement Therapy; Estrogens; Female; Hippocampus (Brain); Historical Cohort Studies; Hypertension; Impaired cognition; Impairment; Individual; Intervention Trial; Longterm Follow-up; Malignant Neoplasms; Memory impairment; Menopause; Mesentery; Modeling; Neurons; Observational Study; Operative Surgical Procedures; Ovarian; Ovarian hormone; Ovariectomy; Pathology; Postmenopause; Premature Ovarian Failure; Premenopause; Production; Progestins; Prophylactic treatment; Public Health; Publishing; Rattus; Receptor, Angiotensin, Type 1; Recording of previous events; Renin-Angiotensin System; Research; Resistance; Risk; Role; Testing; Therapeutic; Therapeutic Trials; Thrombosis; Time; United States; Woman; Women' s Health; arteriole; cognitive benefits; cognitive function; cohort; dementia risk; design; endometriosis; endothelial dysfunction; experience; hormone deficiency; improved; inhibitor/antagonist; insight; male; malignant breast neoplasm; neuropathology; novel therapeutic intervention; novel therapeutics; post-operative cognitive dysfunction; protective effect; therapy design

Women who have undergone bilateral oophorectomy prior to natural menopause are at increased risk of developing dementia including Alzheimer's disease (AD) than age-matched women. There is a need for more therapeutic options to protect cognitive function. Bilateral oophorectomy before the onset of natural menopause causes an abrupt cessation of estrogen production with a consequent drop in circulating levels of estrogen (primarily 17-estradiol). Controversy, however, over the harm vs. benefit of estrogen replacement therapy (ERT) for cognition continues. Even if ERT is proven to provide cognitive benefits, ERT is contraindicated in some women and others may not elect ERT for other reasons. Targeting the renin angiotensin system offers a promising new therapeutic approach. Individuals with hypertension are at increased risk of age-associated cognitive decline and dementia including AD. Clinical studies with different classes of anti-hypertensive drugs have shown that effectiveness for protecting cognitive function varies independently of their effect on blood pressure (BP). Several clinical studies showed angiotensin type 1 receptor (AT1R) blockers (ARBs) to be superior to other antihypertensive drugs at reducing the risk of cognitive decline or dementia including AD. These clinical findings suggest that ARBs protect against cognitive decline and conversion to AD in both a BP-dependent and -independent manner. Studies in male animals support the clinical findings of ARBs exerting protective effects on cognition independently of their effects on BP and studies suggest AT1Rs are more active in AD; however, little is known regarding the cognitive protective effects of ARBs in women who are ovarian hormone deficient prior to the natural age of menopause and no basic science research has been published to date on the effects of ARBs on mechanisms of cognition in a female model of premenopausal ovarian hormone deficiency. In Aim 1, we will determine the role of age and estrogen loss on endothelial function in cerebral resistance arterioles and hippocampus neuropathology associated with AD in a model of hypertension and cognitive decline. In Aim 2, we will determine the role of neuronal AT1R activity and blood pressure on endothelial function in cerebral resistance vessels, hippocampus RAS activity and neuropathology and cognitive impairment as a function of ovariectomy. This research may inform the design of new therapeutics and intervention trials for women who undergo premenopausal bilateral oophorectomy as well as provide insights into protection of cognitive function for women who experience premature ovarian failure and post-menopausal women. 1

在自然绝经前接受双侧卵巢切除术的妇女， 患痴呆症包括阿尔茨海默氏病（AD）比年龄匹配的妇女。需要更多 保护认知功能的治疗选择。自然发病前双侧卵巢切除术 绝经会导致雌激素分泌突然停止，从而导致循环中的 雌激素（主要是17 β-雌二醇）。然而，关于雌激素替代疗法的利弊， 认知治疗（ERT）仍在继续。即使ERT被证明可以提供认知益处， 某些女性禁用ERT，其他女性可能因其他原因而不选择ERT。靶向肾素 血管紧张素系统提供了一种有前途的新的治疗方法。患有高血压的人在 与年龄相关的认知能力下降和痴呆症（包括AD）的风险增加。不同临床研究 抗高血压药物的种类表明，保护认知功能的有效性各不相同， 独立于其对血压（BP）的影响。几项临床研究表明，1型血管紧张素 受体（AT 1 R）阻滞剂（ARB）在降低高血压风险方面上级其他抗高血压药物， 认知衰退或痴呆，包括AD。这些临床研究结果表明，ARB可以防止认知障碍， 以BP依赖性和非依赖性的方式下降并转化为AD。雄性动物研究 支持ARB对认知产生保护作用的临床研究结果， BP和研究表明，AT 1 R在AD中更活跃;然而，关于认知功能知之甚少。 ARB对自然绝经年龄前卵巢激素缺乏妇女的保护作用 到目前为止，还没有关于ARB对认知机制影响的基础科学研究发表 在绝经前卵巢激素缺乏的女性模型中。在目标1中，我们将确定年龄的作用 雌激素缺乏对脑阻力小动脉内皮功能和海马神经病理学的影响 在高血压和认知能力下降模型中与AD相关。在目标2中，我们将确定 神经元AT 1 R活性和血压对海马脑阻力血管内皮功能的影响 卵巢切除术对RAS活性、神经病理学和认知障碍的影响。这项研究可能 为绝经前双侧乳腺癌患者设计新的治疗和干预试验提供信息。 卵巢切除术，并提供深入了解保护认知功能的妇女谁经历 卵巢早衰和绝经后妇女。 1