BLOOD TO BRAIN SODIUM TRANSPORT IN ISCHEMIC BRAIN EDEMA

缺血性脑水肿中钠的血脑转运

• 批准号: 2264971
• 负责人: A LORRIS BETZ
• 金额: $ 20.15万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2264971
• 关键词: blood brain barrier; brain circulation; brain edema; cerebral ischemia /hypoxia; cerebrovascular occlusions; disease /disorder model; inhibitor /antagonist; ion transport; laboratory rat; membrane transport proteins; nonhuman therapy evaluation; protein isoforms; sodium; sodium channel; sodium potassium exchanging ATPase

DESCRIPTION (Investigator's Abstract): Despite the major clinical importance of brain edema, most treatments remain non-specific and directed at reducing elevated lntracranial pressure rather than inhibiting edema formation. Our long-term goal is to better understand the mechanisms of brain edema formation so that specific therapy can be developed. We have chosen to study edema during cerebral ischemia because the two primary types of brain edema, cytotoxic and vasogenic, occur during ischemia. Using animal models of focal ischemia, we have demonstrated that the development. of edema is closely related to the movement of sodium and chloride from the blood to the brain. Based upon these findings, we hypothesize that brain edema formation can be controlled by blocKing the influx of sodium from blood to brain. When the blood-brain barrier (BBB) is intact, sodium enters brain via specific transport pathways in the brain capillary endothelial cell and, therefore, it should be possible to reduce sodium influx into brain by inhibiting these transport systems. However, once the BBB opens, sodium is free to diffuse from the blood to the brain. The treatment of brain edema in this vasogenic phase must focus on preventing. BBB opening so that transport inhibitors can be effective. In support of the hypothesis, our preliminary studies show that treatment with dimethylamiloride, an inhibitor of the BBB Na/H exchanger, and benzamil, an inhibitor of the BBB-Na channel, reduce edema formation during early focal ischemia. Tee specific aims of this proposal are to 1) identify the transport pathways that mediate BBB sodium and chloride transport and determine how they are regulated, 2) identify the mechanisms that produce BBB opening in ischemia, and 3) determine whether the formation of ischemic brain edema can be reduced by inhibition of BBB sodium transporters and/or by inhibiting breakdown of the BBB. We will study the mechanisms- of BBB ion transport using in situ perfusion of the rat brain and identification of transporter isoforms in isolated brain capillaries by protein and mRNA analysis. The mechanisms of BBB opening will be studied using pharmacologic agents to attenuate BBB disruption following middle cerebral artery occlusion in rats. Finally, the effect on brain edema formation of transport inhibitors and agents that prevent BBB opening will be determined also in the middle cerebral artery occlusion model. By better understanding the mechanisms of BBB ion transport and BBB disruption, we believe that it will be possible to develop effective therapies that limit the formation of brain edema during ischemia and following other types of brain injuries.

描述（研究者的摘要）：尽管有主要的临床 大脑水肿的重要性，大多数疗法仍然非特异性，并且 针对降低升高的lntracranial压力而不是 抑制水肿形成。我们的长期目标是更好地了解 脑水肿形成的机制，以便特定的疗法可以是 发达。我们选择在脑缺血期间研究水肿 因为两种主要类型的脑水肿，细胞毒性和血管生成 在缺血期间发生。使用局灶性缺血的动物模型，我们有 证明了这一发展。水肿与 钠和氯化物从血液到大脑的运动。 基于这些发现，我们假设脑水肿的形成可以 通过阻止钠从血向大脑的流入来控制。什么时候 血脑屏障（BBB）完好无损，钠通过 脑毛细管内皮细胞中的特定运输途径，并 因此，应该可以通过 抑制这些运输系统。但是，一旦BBB打开，钠 可以自由从血液到大脑扩散。大脑的治疗 在这个血管生成阶段的水肿必须集中于预防。 BBB开放 该运输抑制剂可以有效。支持 假设，我们的初步研究表明 Dimethylamiloride，BBB Na/H交换器的抑制剂和苯甲甲中的抑制剂， BBB-NA通道的抑制剂，早期减少水肿的形成 局灶性缺血。 该提案的特定目标是1）确定运输 介导BBB钠和氯化物转运并确定的途径 2）确定产生BBB的机制 在缺血中开放，3）确定缺血的形成是否形成 通过抑制BBB钠转运蛋白可以减少脑水肿 和/或通过抑制BBB的崩溃。我们将研究机制 - 使用大鼠大脑的原位灌注的BBB离子运输和 通过鉴定分离的脑毛细血管中的转运蛋白同工型 蛋白质和mRNA分析。将研究BBB开放的机制 使用药理剂来减弱中间后的BBB破坏 大鼠的脑动脉阻塞。最后，对脑水肿的影响 抑制剂和阻止BBB开放的转运抑制剂和试剂的形成 也将在大脑中部动脉闭塞模型中确定。 通过更好地了解BBB离子运输和BBB的机制 干扰，我们认为有可能发展有效 限制缺血期间脑水肿形成的疗法 遵循其他类型的脑损伤。