Anti-inflammatory properties of estradiol during stroke

雌二醇在中风期间的抗炎特性

• 批准号: 7652502
• 负责人: Candice Brown
• 金额: $ 5.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652502
• 关键词: Adult; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Basic Science; Brain; Brain Injuries; Caspase; Cell Death; Cerebral Ischemia; Clinical; Complex; Data; Disease; Estradiol; Estrogens; Female; Gene Expression; In Situ Nick-End Labeling; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemic Penumbra; Ischemic Stroke; Knockout Mice; Lead; Long-Term Effects; Measures; Mediating; Menopause; Middle Cerebral Artery Occlusion; Modeling; Molecular Mechanisms of Action; Mus; Nerve Degeneration; Nervous System Trauma; Neuraxis; Neurodegenerative Disorders; Neuroprotective Agents; Pathway interactions; Pattern; Physiological; Postmenopause; Production; Property; Rate; Risk; Role; Signal Pathway; Staining method; Stains; Stimulus; Stroke; Testing; Therapeutic Effect; Woman; Women' s Health; Work; Writing; aging brain; caspase-8; caspase-9; chemokine; cytokine; human NOS2A protein; neuron apoptosis; older women; protein expression; reproductive; reproductive function

DESCRIPTION (provided by applicant): Menopause marks an important transition in females that affects both reproductive and non-reproductive function. The extended period of hypoestrogenicity in post-menopausal women profoundly affects the central nervous system by modifying multiple brain functions, increasing the incidence of neurodegenerative diseases, and increasing the risk of ischemic stroke in older women. Several studies have shown that physiological concentrations of 17beta-estradiol (E2) protect against delayed cell death in stroke models and serve an anti-inflammatory role in the central nervous system (CMS.) To further examine the dynamic and complex relationship between E2, inflammation, and apoptosis during stroke, this proposal will test the hypothesis that physiological concentrations of E2 decrease inflammation leading to apoptotic cell death. This hypothesis will be tested in ovariectomized (OVX) and OVX + E2 - treated C57BL/6J (WT) and inducible nitric oxide synthase knockout (iNOSKO) mice using a model of permanent middle cerebral artery occlusion. Three critical components of the ischemic inflammatory response, i.e. 1) microglial activation, 2) inducible nitric oxide synthase gene expression, and 3) production of cytokines and chemokines, will be measured to determine to determine their ability to potentiate two markers^of apoptosis, i.e. 1) TUNEL staining and 2) caspase-8 and caspase-9 activation. This set of studies will enable us to determine: 1) how these three components of inflammation contribute to apoptotic cell death, 2) whether the intrinsic or extrinsic caspase pathways are involved, and 3) the neuroprotective mechanisms utilized by E2 to preserve the ischemic penumbra during stroke. Taken together, these studies will deepen our understanding of the complex neurprotective mechanisms employed by E2 in the adult and aging brain. Lay Summary After menopuase, the brain is particularly vulnerable to the long-term effects of hypoestrogenicity, as several studies have shown that low, physiological levels of 17beta-estadiol are capable of protecting the brain from injury and disease. Using a model of middle cerebral artery occlusion, these studies will determine the therapeutic effects of low, physiological levels of estradiol as a neuroprotectant from the multiple inflammatory stimuli that lead to programmed cell death of neurons during stroke. Completion of these studies will enhance our understanding of the complex ways that 17beta-estradiol protects during neurological injury.

描述（由申请人提供）：更年期标志着女性的一个重要转变，影响生殖和非生殖功能。绝经后女性雌激素水平低下的时间延长，通过改变多种脑功能，增加神经退行性疾病的发病率，增加老年女性缺血性卒中的风险，深刻影响中枢神经系统。几项研究表明，生理浓度的17 β-雌二醇（E2）可防止中风模型中的延迟性细胞死亡，并在中枢神经系统（CMS）中发挥抗炎作用。为了进一步研究中风期间E2、炎症和细胞凋亡之间的动态和复杂关系，本提案将检验E2生理浓度降低炎症导致细胞凋亡的假设。将使用永久性大脑中动脉闭塞模型在卵巢切除（OVX）和OVX + E2处理的C57 BL/6 J（WT）和诱导型一氧化氮合酶敲除（iNOSKO）小鼠中检验该假设。将测量缺血性炎症反应的三个关键组分，即1）小胶质细胞活化，2）诱导型一氧化氮合酶基因表达，和3）细胞因子和趋化因子的产生，以确定它们增强细胞凋亡的两个标志物的能力，即1）TUNEL染色和2）半胱天冬酶-8和半胱天冬酶-9活化。这组研究将使我们能够确定：1）炎症的这三个组成部分如何促进凋亡细胞死亡，2）是否涉及内在或外在的caspase途径，以及3）E2用于保护中风期间缺血半暗带的神经保护机制。总之，这些研究将加深我们对E2在成人和衰老大脑中所采用的复杂神经保护机制的理解。服用雌二醇后，大脑特别容易受到低雌激素性的长期影响，因为几项研究表明，低生理水平的17 β-雌二醇能够保护大脑免受损伤和疾病的影响。使用大脑中动脉闭塞模型，这些研究将确定低生理水平的雌二醇作为神经保护剂对中风期间导致神经元程序性细胞死亡的多种炎症刺激的治疗效果。这些研究的完成将增强我们对17 β-雌二醇在神经损伤期间保护的复杂方式的理解。