Anti-inflammatory properties of estradiol during stroke

描述(申请人提供)：更年期标志着女性的重要转变，影响生殖和非生殖功能。绝经后妇女雌激素低下的时间延长，通过改变多种大脑功能，增加神经退行性疾病的发生率，增加老年妇女缺血性中风的风险，从而深刻地影响中枢神经系统。几项研究表明，生理浓度的17β-雌二醇(E2)可以保护中风模型中延迟性细胞死亡，并在中枢神经系统(CMS)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而复杂的关系，这一建议将检验生理浓度的E2可以减少炎症导致细胞凋亡的假说。这一假设将在去卵巢(OVX)和OVX+E2处理的C57BL/6J(WT)和诱导型一氧化氮合酶基因敲除(INOSKO)小鼠中使用永久性大脑中动脉闭塞模型进行验证。缺血性炎症反应的三个关键成分，即1)小胶质细胞激活，2)诱导型一氧化氮合酶基因表达，以及3)细胞因子和趋化因子的产生，将被测量以确定它们增强两个凋亡标志物的能力，即1)TUNEL染色和2)caspase-8和caspase-9激活。这组研究将使我们能够确定：1)炎症的这三个组成部分是如何导致细胞凋亡的，2)是否涉及内在或外在的caspase途径，以及3)E2用来保护中风时缺血半暗带的神经保护机制。综上所述，这些研究将加深我们对E2在成人和衰老大脑中使用的复杂神经保护机制的理解。在更年期之后，大脑特别容易受到雌激素水平低下的长期影响，因为多项研究表明，低生理水平的17β-雌二醇能够保护大脑免受损伤和疾病。利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。这些研究的完成将加强我们对17β-雌二醇在神经损伤中保护作用的复杂方式的理解。

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.