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女性患上卵巢癌的风险增加 与同龄女性相比，患有阿尔茨海默病 (AD) 等痴呆症的女性需要更多。 自然发病前保护认知功能的治疗选择。 更年期会导致雌激素的产生突然停止，从而导致循环水平下降 然而，关于雌激素替代品的危害与益处存在争议。 认知治疗 (ERT) 仍在继续 即使 ERT 被证明可以提供认知益处，但 ERT 仍然是无效的。 某些女性禁忌，而其他女性则可能因其他原因不选择 ERT。 血管紧张素系统为高血压患者提供了一种有前景的新治疗方法。 与年龄相关的认知能力下降和痴呆（包括 AD）的风险增加。 研究表明，不同类别的抗高血压药物保护认知功能的效果各不相同 多项临床研究表明，血管紧张素 1 与它们对血压 (BP) 的影响无关。 受体（AT1R）阻滞剂（ARB）在降低风险方面优于其他抗高血压药物 认知能力下降或痴呆（包括 AD）这些临床结果表明 ARB 可以预防认知能力下降。 以 BP 依赖性和非依赖性方式对雄性动物进行的衰退和转化为 AD 的研究。 支持 ARB 对认知发挥保护作用的临床发现，独立于其对认知的影响 BP 和研究表明 AT1R 在 AD 中更为活跃，但对于认知方面的影响却知之甚少。 ARB 对自然绝经年龄之前卵巢激素缺乏的女性的保护作用 迄今为止，尚未发表关于 ARB 对认知机制影响的基础科学研究 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。 雌激素损失对脑阻力小动脉和海马神经病理学内皮功能的影响 在目标 2 中，我们将确定与高血压和认知能力下降模型中的 AD 相关的作用。 神经元 AT1R 活性和血压对脑阻力血管、海马内皮功能的影响 RAS 活性与神经病理学和认知障碍作为卵巢切除术的功能。 为绝经前双侧绝经前妇女设计新疗法和干预试验提供信息 卵巢切除术，并为经历过卵巢切除术的女性提供保护认知功能的见解 卵巢早衰和绝经后妇女。 1