CEREBRAL ISCHEMIA IN THE FEMALE

描述：在本动物研究方案中，研究人员建议 以确定脑血流量和代谢的影响， 在全球化期间和之后，假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、代谢影响 代谢和软脑膜血管反应性，与 他们的男性同行。 调查人员还将评估是否 女性荷尔蒙β-雌二醇在 缺血的恢复机制。 未经绝育的雄性也将 研究，以确定是否有重要的性别特异性恢复 缺血/再灌注期间的反应和任何治疗益处（如果有） 仅限于女性。 的 拟议的实验将探讨缺血性心脏病的两种具体机制， 体内损伤;具体来说，1）酸中毒导致恢复迟缓 能量代谢，pH调节的丧失，以及相关的铁催化 氧化损伤;和2）微血管内皮功能障碍。 研究 这些变量，研究人员将使用磁共振（MR） 光谱和活体显微镜检查，以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 具体目标#1，研究人员将测试假设， 女性缺血性酸中毒较少，因此更完全 与男性相比，脑能量磷酸盐的恢复; 雌激素治疗进一步改善缺血后能量恢复 具体目标#2将检查 缺血前的高血糖症以及随之而来的 酸中毒对代谢恢复的影响，检验抗- 雌二醇的氧化活性降低了对高血糖症的易感性， 介导的再灌注损伤。 活体显微镜将用于 具体目标#3，以确定缺血后软脑膜血管对 雌性动物的内皮依赖性药物受损， 雌二醇处理的动物。 最后，具体目标#4将测试 慢性雌二醇治疗增加脑cGMP、一氧化氮 一氧化氮合酶活性和软脑膜血管对NO介导的 以剂量依赖的方式。 从这些信息中获得的信息 实验应该有助于我们理解血管功能 在脑血管疾病风险降低的女性中， 雌激素作为潜在的神经保护治疗的作用 对于任何性别的患者。

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.