Plasminogen activators and cerebral ischemic injury

婴儿在围产期经常因中风或中风而处于缺氧和缺血状态。 分娩或产后呼吸管理问题。新生儿中风发病率可高达 每 4000 名新生儿中就有 1 人。神经损伤的原因之一是脑血管功能障碍。唯一FDA 经批准的急性中风治疗方法是使用 tPA。尽管如此，在基础科学研究中，tPA 已观察到表现出双重有益/有害作用。除了它的有益作用之外 再灌注时，tPA 可能导致神经细胞死亡。 tPA 治疗的潜在解释 治疗悖论可能与 tPA 的血管活性（扩张）有关。术语神经血管单元（NVU） 重点关注脑血管和神经元之间的相互作用。有丝分裂原激活蛋白 脑缺血后激酶（MAPK）表达增强，可能是最远端的系统之一 影响脉管系统和基因组学。假设是纤溶酶原激活剂的产生 脑缺氧/缺血后会导致脑血流动力学受损和神经元细胞损失 发布侮辱。据推测，纤溶酶原激活剂会损害对血管刺激的反应性并产生 充血导致水肿，导致神经元细胞损失。脑血之间的动态相互作用 因此，血管和神经元对损伤产生综合反应，这与 NVU 概念一致。至 为了解决这一假设，我们将在新生猪身上追求三个具体目标： 1. 表征 缺氧/缺血后纤溶酶原激活剂与脑血流动力学的关系，2。 研究 MAPK 作为纤溶酶原激活剂控制大脑的机制的作用 损伤后的血流动力学； MAPK 亚型表达谱的变化导致大脑受损 血流动力学和神经元细胞损失。 3. 确定大脑受损之间的关联 损伤后的血流动力学和组织病理学。闭颅窗技术将用于测量 软脑膜动脉直径并通过 ELISA 测定脑脊液纤溶酶原激活剂浓度。 CBF 将 采用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 表达将用于实现完整的动物/分子整合 纤溶酶原激活剂、脑血流动力学和血流动力学之间关系的观点 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.