CEREBRAL ISCHEMIA IN THE FEMALE

女性脑缺血

• 批准号: 2333011
• 负责人: PATRICIA D. HURN
• 金额: $ 16.14万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2333011
• 关键词: acidity /alkalinity; acidosis; antioxidants; bioenergetics; brain disorder chemotherapy; cerebral ischemia /hypoxia; enzyme activity; estradiol; female; gender difference; hormone regulation /control mechanism; hormone therapy; hyperglycemia; intravital microscopy; laboratory rabbit; microcirculation; neuroprotectants; nitric oxide; nitric oxide synthase; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; oxidative stress; pia mater; reperfusion; vascular endothelium

DESCRIPTION: In this animal research protocol, the investigators propose to ascertain the cerebral blood flow and metabolic effects of the presumed neuroprotective female hormones during and following global cerebral ischemia. Specifically, the proposed study will determine the effect of global cerebral ischemia on cerebral blood flow (CBF), energy metabolism, and pial vessel reactivity in female animals compared to their male counterparts. The investigators also will evaluate whether or not the female hormone, beta- estradiol, plays an important role in recovery mechanisms from ischemia. Un- neutered males also will be studied to determine if there are important gender-specific recovery responses during ischemia/reperfusion and if any therapeutic benefit from reproductive steroid administration is limited to females. The proposed experiments will explore two specific mechanisms of ischemic injury in vivo; specifically, 1) acidosis leading to depressed recovery of energy metabolism, loss of pH regulation, and related iron- catalyzed oxidant injury; and 2) microvascular endothelial dysfunction. To study these variables, the investigators will use magnetic resonance (MR) spectroscopy and intravital microscopy to determine if estradiol acts via specific cellular mechanisms. Four Specific Aims are presented. In Specific Aim #1, the investigators will test the hypothesis that ischemic acidosis is less in females, with consequently more complete recovery of brain energy phosphates compared to males; and that chronic estrogen therapy further improves post-ischemic recovery of energy metabolism and intracellular pH. Specific Aim #2 will examine the effect of pre-ischemic hyperglycemia and its consequent exaggerated tissue acidosis on metabolic recovery, testing the hypothesis that the anti- oxidant activity of estradiol decreases vulnerability to hyperglycemia- mediated reperfusion injury. Intravital microscopy will be employed in Specific Aim #3 to determine if post-ischemic pial vessel reactivity to endothelium-dependent pharmacologic agents is impaired in females and estradiol-treated animals. Finally, Specific Aim #4 will test the hypothesis that chronic estradiol therapy increases brain cGMP, nitric oxide synthase activity and pial vessel responsivity to NO-mediated agents in a dose-dependent manner. The information derived from these experiments should contribute to our understanding of vascular function in females at decreased risk for cerebrovascular disease relative to males and of the role of estrogen as potential neuroprotective therapy for patients of either sex.

描述：在这项动物研究方案中，研究人员提出 以确定脑血流量和代谢的影响 在全球范围内和之后推定的神经保护性女性激素 脑缺血。具体而言，拟议的研究将确定 全脑缺血对脑血流量、能量的影响 雌性动物的代谢和软脑膜血管反应性 他们的男性同行。调查人员还将评估 无论女性荷尔蒙是不是，β-雌二醇在 脑缺血的恢复机制。未绝育的男性也将 研究以确定是否存在重要的针对性别的恢复 缺血/再灌流期间的反应以及是否有任何治疗益处 生殖类固醇的使用仅限于女性。这个 拟议的实验将探索脑缺血的两个具体机制 体内损伤；具体地说，1)酸中毒导致恢复功能低下 能量代谢，失去pH调节，以及相关的铁催化 氧化损伤；2)微血管内皮细胞功能障碍。学习 对于这些变量，研究人员将使用磁共振(MR) 光谱学和活体显微镜来确定雌二醇是否通过 特定的细胞机制。提出了四个具体目标。在……里面 具体目标1，调查人员将检验假设 女性的缺血性酸中毒较少，因此更完全。 与男性相比，脑部能量磷酸盐的恢复；以及慢性 雌激素治疗进一步改善缺血后能量恢复 代谢和细胞内pH。具体目标#2将检查效果 缺血前高血糖及其导致的组织夸大 酸中毒对代谢恢复的影响，验证了抗酸中毒的假说 雌二醇的氧化活性降低了对高血糖的易感性- 介导性再灌注损伤。活体显微镜将被应用于 具体目标#3确定脑缺血后软脑膜血管的反应性 内皮依赖性药物在女性和女性患者中受损 雌二醇组动物。最后，具体目标#4将测试 慢性雌激素治疗增加脑内cGMP、NO的假说 一氧化氮合酶活性与软脑膜血管对一氧化氮的反应性 药物以剂量依赖的方式。从这些信息中得出的信息 实验应该有助于我们对血管功能的理解 与患脑血管疾病风险较低的女性相比 男性和雌激素作为潜在的神经保护疗法的作用 对男女患者都适用。