AGING, HYPERTENSION AND ESTROGEN NEUROPROTECTION

衰老、高血压和雌激素神经保护

• 批准号: 6287577
• 负责人: SCOTT H CARLSON
• 金额: $ 7.6万
• 依托单位: LUTHER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6287577
• 关键词: aging; behavior test; behavioral /social science research tag; biological models; blood pressure; cerebral ischemia /hypoxia; cerebrovascular system; cognition disorders; disease /disorder model; estrogens; female; hormone regulation /control mechanism; hypertension; laboratory rat; model design /development; multiinfarct dementia; neural degeneration; neural plasticity; neuroprotectants; ovariectomy; pathologic process; postmenopause; statistics /biometry; ultrasound blood flow measurement; women's health

Following menopause many women experience progressive cognitive impairment and have a significantly higher risk of dementia. While the mechanisms which contribute to these progressive cognitive deficits are unknown, the loss of estrogen appears to be a major underlying factor. The loss of estrogen at menopause is also associated with an increased risk of hypertension which contributes to cognitive impairment. Previous work from our laboratory has shown that male spontaneously hypertensive rats (SHR) display age-related learning and memory impairments that are associated with neuronal remodeling in the retrosplenial cortex, an area that is important for spatial learning in rats and humans. While these deficits normally become apparent in aged (2 year-old) male Sprague-Dawley rats, they are first identifiable in male SHR at a significantly younger age (1 year-old). Chronic anti-hypertensive therapy (captopril) significantly delays both cognitive impairment and neuronal remodeling in SHR, suggesting that hypertension contributes to these changes. Few studies have examined the effects of hypertension and estrogen loss on cognitive function. We have established for the first time that elimination of both endogenous estrogen (ovariectomy) and exogenous estrogens (plant phytoestrogens in the diet) has a dramatic effect on arterial pressure control in female SHR, i.e., female SHR normally do not show an increase in arterial pressure when fed a high NaCl diet, but following elimination of both endogenous and exogenous estrogen, they respond to a high NaCl diet with a very large increase in arterial pressure (> 60 mm Hg). This provides a provocative model with which to test the hypothesis that both the loss of estrogen and hypertension can accelerate the age-related decline in cognitive ability and neuronal stability in female SHR. The proposed studies test the hypotheses that: Specific Aim 1. Estrogen depletion accelerates cognitive impairment and neuronal remodeling in the retrosplenial cortex, and that estrogen replacement protects against these changes. Specific Aim 2. Estrogen-depletion reduces cerebral blood flow in female SHR and estrogen replacement reverses these decreases. Specific Aim 3. Estrogen-depletion impairs vascular reactivity and causes arteriolar hypertrophy in female SHR, and that estrogen replacement reverses these effects.

绝经后，许多妇女经历进行性认知障碍，患痴呆症的风险明显较高。虽然导致这些进行性认知缺陷的机制尚不清楚，但雌激素的损失似乎是一个主要的潜在因素。绝经期雌激素的丧失也与高血压的风险增加有关，高血压会导致认知障碍。我们实验室以前的工作表明，雄性自发性高血压大鼠（SHR）显示出与年龄相关的学习和记忆障碍，这些障碍与压后皮质的神经元重塑有关，压后皮质是大鼠和人类空间学习的重要区域。虽然这些缺陷通常在老年（2岁）雄性Sprague-Dawley大鼠中变得明显，但它们首先在明显更年轻（1岁）的雄性SHR中被识别。慢性抗高血压治疗（卡托普利）显着延迟SHR的认知功能障碍和神经元重塑，表明高血压有助于这些变化。很少有研究检查高血压和雌激素损失对认知功能的影响。我们首次证实，消除内源性雌激素（卵巢切除术）和外源性雌激素（饮食中的植物雌激素）对雌性SHR的动脉压控制有显著影响，即，当喂食高NaCl饮食时，雌性SHR通常不显示动脉压的增加，但是在消除内源性和外源性雌激素之后，它们对高NaCl饮食的反应是动脉压非常大的增加（> 60 mm Hg）。这提供了一个挑衅性的模型，以测试的假设，即雌激素和高血压的损失可以加速与年龄相关的认知能力和神经元的稳定性下降，在女性SHR。这些研究的假设是：具体目标1。雌激素耗竭加速认知障碍和压后皮质神经元重塑，而雌激素替代可保护这些变化。具体目标2。雌激素耗竭会减少雌性SHR的脑血流量，而雌激素替代会逆转这些减少。具体目标3。雌激素缺乏会损害雌性SHR的血管反应性并导致小动脉肥大，而雌激素替代可逆转这些效应。