Perioperative Stroke and Cerebral Conditioning in the Female

女性围术期卒中和脑调理

• 批准号: 7635803
• 负责人: Stephanie J Murphy
• 金额: $ 33.65万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7635803
• 关键词: Accounting; Affect; Agonist; Anesthesia procedures; Anesthetics; Animals; Attenuated; Basic Science; Behavioral; Brain; Cardiovascular system; Carotid Endarterectomy; Cell Death; Cells; Cessation of life; Coronary Artery Bypass; Data; Estradiol; Estrogen Receptor alpha; Female; Functional disorder; Gender; Gene Expression; Gonadal Steroid Hormones; Hormone replacement therapy; Incidence; Infarction; Injury; Ischemic Brain Injury; Ischemic Preconditioning; Isoflurane; Knockout Mice; Lead; Mediating; Middle Cerebral Artery Occlusion; Modeling; Mus; Nervous System Trauma; Neuraxis; Neurologic; Neurons; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase Type I; Outcome; Pathway interactions; Patients; Perioperative; Perioperative complication; Peroxonitrite; Procedures; Reaction; Regulation; Risk; Role; Sex Characteristics; Stroke; Superoxides; Testing; Therapeutic; Woman; base; cardiovascular risk factor; conditioning; experience; functional outcomes; male; men; neuronal cell death inducible putative kinase; neuroprotection; novel; preconditioning; prevent; prospective; response

DESCRIPTION (provided by applicant): Women undergoing cardiovascular procedures have a greater perioperative stroke risk than men. Anesthesia for such cardiovascular procedures is an important consideration since anesthetic agents affect ischemic outcome in experimental stroke and may attenuate perioperative stroke incidence. Such anesthetic preconditioning (ARC) may therefore prevent or even delay neurological complications from perioperative stroke. Our preliminary data suggests that the ARC neuroprotection observed in male animals does not occur in females and that ARC in females actually enhances ischemic damage after middle cerebral artery occlusion. This application will focus on how female gender and estradiol-specific effects lead to a detrimental response in ARC female ischemic brain using a mouse isoflurane preconditioning (IsoPC) model. In Aim 1, we will examine the effects of gender and estradiol on ischemic histological and functional outcomes in IsoPC brain. In Aim 2, we will determine if IsoPC neuroprotection in males is mediated by Akt activation and if estradiol increases expression of neuronal cell death-inducible putative kinase (NIPK), a negative modulator of Akt, thus leading to decreased Akt activation in IsoPC females. These novel studies will yield new information about Akt regulation in IsoPC brain. In Aim 3, we will utilize female estrogen receptor (ER) alpha knockout mice and a selective ER alpha agonist to determine if estradiol acts via an ER alpha-dependent mechanism to attenuate Akt activation and increase NIPK gene expression in IsoPC mouse brain, thus leading to increased ischemic damage. In Aim 4, we hypothesize that IsoPC suppresses neuronal nitric oxide synthase (nNOS) activity and consequent peroxynitrite (ONOO) formation, and that the sexually dimorphic response to nNOS-derived nitric oxide cell-mediated death results in reduced infarct injury in IsoPC males and enhanced ischemic damage in IsoPC females. We will also demonstrate that loss of nNOS and reduced ONOO formation leads to greater superoxide-mediated injury in IsoPC female brain. Our findings will elucidate the mechanisms by which female stroke outcomes are worsened by preischemic isoflurane exposure.

描述（由申请人提供）：接受心血管手术的妇女的围手术期风险比男性更大。这种心血管手术的麻醉是一个重要的考虑因素，因为麻醉剂会影响实验性中风的缺血结果，并可能衰减围手术期的中风发生率。因此，这种麻醉预处理（ARC）可能会预防围手术期中风的神经系统并发症。我们的初步数据表明，在雄性动物中观察到的弧神经保护作用不会发生在女性中，而女性中的弧实际上会增强脑动脉闭塞后缺血性损害。该应用将重点介绍女性性别和雌二醇特异性效应如何使用小鼠异氟烷预处理（ISOPC）模型导致弧雌性缺血大脑的有害反应。在AIM 1中，我们将检查性别和雌二醇对ISOPC大脑缺血性组织学和功能结果的影响。在AIM 2中，我们将确定雄性中的ISOPC神经保护是否是通过AKT激活介导的，并且雌二醇是否会增加神经元细胞死亡可诱导的假定激酶（NIPK）的表达，AKT的负调节剂，因此导致ISOPC女性的Akt激活降低。这些新的研究将产生有关ISOPC大脑中AKT调节的新信息。在AIM 3中，我们将利用女性雌激素受体（ER）α基因敲除小鼠和选择性ERα激动剂来确定雌二醇是否通过ERα依赖性机制起作用，以减弱Akt激活并增加ISOPC小鼠中NIPK基因表达，从而导致缺血性损害增加。在AIM 4中，我们假设ISOPC抑制神经元氧化物合酶（NNOS）活性以及随之而来的过氧亚硝酸盐（ONOO）形成，并且对NNOS衍生的一氧化氮细胞细胞介导的死亡导致ISOPC MALES降低的ISOPC损害的疾病损伤和增强ISCC损害ISOPC的性损伤。我们还将证明，NNOS的丧失和减少的ONOO形成会导致ISOPC女性大脑的超氧化物介导的损伤更大。我们的发现将阐明通过前异氟烷暴露使女性中风结局恶化的机制。