Plasminogen activators and cerebral ischemic injury

婴儿在围产期经常暴露于缺氧和缺血，原因是中风或 分娩或分娩后呼吸管理问题。新生儿中风的发病率可能会很高， 每4000个新生儿中就有一个。脑血管功能障碍是神经系统损伤的一个原因。唯一的FDA 批准的急性中风治疗是给予tPA。然而，在基础科学研究中，tPA 已经观察到显示出有益/有害的双重作用。除了它的有益作用， 再灌注后，tPA可能导致神经元细胞死亡。tPA治疗的一种可能解释 治疗矛盾可能与tPA的血管活性（扩张）有关。神经血管单位（NVU） 重点关注脑血管和神经元之间的相互作用。丝裂原活化蛋白 脑缺血后MAPK表达增强，可能是脑缺血后最远端的系统之一， 影响血管系统和基因组假设纤溶酶原激活物的产生 脑缺氧/缺血后导致脑血流动力学受损和神经元细胞丢失 后侮辱。假设纤溶酶原激活剂损害对血管刺激的反应性，并产生 充血导致水肿，引起神经元细胞损失。脑血流之间的动态相互作用 因此，血管和神经元导致对损伤的综合反应，这与NVU概念一致。到 为了解决这一假设，将在新生猪中追求三个具体目标：1.表征 纤溶酶原激活物与缺氧缺血后脑血流动力学的关系; 2. 探讨MAPK作为纤溶酶原激活剂调控脑缺血的机制 损伤后血流动力学; MAPK亚型表达谱的变化导致脑损伤 血液动力学和神经元细胞损失。3.确定受损的大脑 损伤后血液动力学和组织病理学。将使用闭合颅窗技术测量 软脑膜动脉直径，并通过ELISA测定CSF纤溶酶原激活物浓度。CBF将在 通过放射性标记微球法测定。免疫组织化学和检测技术 纤溶酶原激活剂和MAPK表达将用于实现整合的整个动物/分子生物学模型。 纤溶酶原激活物与脑血流动力学及脑血管病关系的研究进展 组织病理学

Babies are frequently exposed to hypoxia and ischemia during the perinatal period due to stroke or problems with delivery or respiratory management post delivery. Neonatal stroke incidence can be as high as 1 in 4000 births. One contributor to neurologic damage is cerebrovascular dysfunction. The only FDA approved treatment for acute stroke is the administration of tPA. Nonetheless, in basic science studies, tPA has been observed to exhibit a dual beneficial/deleterious effect. In addition to its salutary role in reperfusion, tPA may contribute to neuronal cell death. A potential explanation for the tPA therapeutic treatment paradox could relate to the vascular activity (dilation) of tPA. The term neurovascular unit (NVU) focuses attention on the interactions between cerebral blood vessels and neurons. Mitogen activated protein kinase (MAPK) expression is enhanced after cerebral ischemia and may be one of the most distal systems affecting both the vasculature and genomics. The hypothesis is that plasminogen activator production following cerebral hypoxia/ischemia contributes to impaired cerebral hemodynamics and neuronal cell loss post insult. Plasminogen activators are hypothesized to impair reactivity to vascular stimuli and produce hyperemia which results in edema causing neuronal cell loss. Dynamic interactions between cerebral blood vessels and neurons thus result in an integrated response to the insult, consistent with the NVU concept. To address this hypothesis, three specific aims will be pursued in newborn pigs: 1. Characterize the relationship between plasminogen activators and cerebral hemodynamics after hypoxia/ischemia, 2. Investigate the role of MAPK as the mechanism by which plasminogen activators control cerebral hemodynamics post insult; Changes in the MAPK isoform expression profile result in impaired cerebral hemodynamics and neuron cell loss. 3. Determine the association between impaired cerebral hemodynamics and histopathology post insult. The closed cranial window technique will be used to measure pial artery diameter and determine CSF plasminogen activator concentration via ELISA. CBF will be determined by the radiolabeled microsphere method. Immunohistochemistry and techniques for detection of plasminogen activator and MAPK expression will be used to achieve an integrated whole animal/molecular perspective on the relationship between plasminogen activators, cerebral hemodynamics, and histopathology.