BLOOD-BRAIN BARRIER TRANSPORT AND ISCHEMIC BRAIN INJURY

血脑屏障运输和缺血性脑损伤

• 批准号: 6393753
• 负责人: Richard F Keep
• 金额: $ 18.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-25 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6393753
• 关键词: P glycoprotein; aminoacid transport; autoradiography; bilirubin; bioenergetics; biological fluid transport; blood brain barrier; brain circulation; cardiovascular pharmacology; cerebral ischemia /hypoxia; cerebrospinal fluid; choroid plexus; gene targeting; gerbil /jird; glutamine; laboratory mouse; laboratory rat; neurotoxins; pathologic process; taurine; vascular endothelium

DESCRIPTION: (adapted from applicant's abstract) Because of its juxtaposition to blood, the cerebral endothelium (which forms the blood-brain barrier, BBB) has been thought to be relatively resistant to the effects of cerebral ischemia. However, examination of taurine, glutamine and myo-inositol influx into brain (all Na+-dependent processes) indicate a marked early (<1 hour) reduction in transport during focal cerebral ischemia suggesting that endothelial cell injury could play a role in primary, rather than secondary, ischemic brain damage. This may be particularly the case if efflux from as well as influx into brain are affected since those efflux systems are involved in controlling the concentration of potentially toxic factors in the brain extracelluar space. This proposal, therefore, has two major goals: to determine whether energy-dependent efflux from brain to blood is inhibited during cerebral ischemia (Specific Aims 1 and 2) and to examine whether changes in influx and efflux transport mechanisms at the blood-brain barrier contribute to ischemic brain damage (Specific Aim 3). The cerebral volume of distribution reached by [3H] vinblastine (a P-glycoprotein substrate) and p-[3H] aminohippuric acid (PAH, an organic acid transporter substrate) will be determined following middle cerebral artery occlusion in rat and mouse (Specific Aim 1). Whether an increased volume of distribution with ischemia reflects a change in influx or an alteration in efflux at the blood-brain barrier will then be determined, the latter by examining the effect of cerebral ischemia in the absence of BBB P-glycoprotein (the mdr la knock out mouse) or during probenecid-induced inhibition of organic acid transport. Specific Aim 2 will examine the mechanism by which ischemia inhibits efflux, by examining PAH, L-glutamate and methyl aminosobutyric acid efflux (an A-system amino acid transporter substrate) uptake into choroid plexus using ventriculo-cisternal perfusion. Specific Aim 3 will determine the effect of altering specific transporters at the BBB on ischemic brain injury and will examine whether drugs known to ameliorate the effect of reperfusion on blood-brain barrier disruption actually have their effects by altering transport during ischemia. Determining whether early BBB dysfunction should be an alternate therapeutic target early during cerebral ischemia, the finding that there is an inhibition of energy-dependent efflux at the BBB during ischemia has major implications for drug delivery to the injured brain. P-glycoprotein and the organic acid transporter both play a major role in limiting the access of some drugs to the brain.

描述：（改编自申请人的摘要）由于其并置 血液、脑内皮（形成血脑屏障，BBB） 被认为对大脑的影响相对有抵抗力 缺血。然而，牛磺酸、谷氨酰胺和肌醇流入的检查 进入大脑（所有 Na+ 依赖性过程）表明明显提前（<1 小时） 局灶性脑缺血期间运输减少表明 内皮细胞损伤可能在原发性损伤中发挥作用，而不是继发性损伤 缺血性脑损伤。如果也从以下位置流出，情况可能尤其如此： 由于流入大脑的流量受到影响，因为这些流出系统涉及 控制大脑中潜在有毒因素的浓度 细胞外空间。因此，该提案有两个主要目标： 从大脑到血液的能量依赖性流出是否受到抑制 脑缺血（具体目标 1 和 2）并检查脑缺血是否发生变化 血脑屏障的流入和流出运输机制有助于 缺血性脑损伤（具体目标 3）。 [3H]长春花碱达到的脑分布容积（a P-糖蛋白底物）和 p-[3H] 氨基马尿酸（PAH，一种有机酸） 转运底物）将根据大脑中动脉进行测定 大鼠和小鼠的闭塞（具体目标 1）。是否增加体积 缺血分布反映了流入的变化或 然后将确定血脑屏障的流出量，后者通过 检查 BBB P-糖蛋白缺失情况下脑缺血的影响 （mdr la 敲除小鼠）或在丙磺舒诱导的有机物抑制过程中 酸运输。具体目标 2 将检查缺血的机制 通过检查 PAH、L-谷氨酸和甲基氨基异丁酸抑制外流 外排（A 系统氨基酸转运底物）摄取至脉络膜 使用脑室池灌注的神经丛。具体目标 3 将决定 改变血脑屏障特定转运蛋白对缺血性脑损伤的影响 并将检查是否已知可以改善再灌注影响的药物 血脑屏障破坏实际上是通过改变 缺血期间的运输。 确定早期 BBB 功能障碍是否应作为替代治疗 脑缺血期间的早期目标，发现存在抑制 缺血期间血脑屏障的能量依赖性流出具有重大意义 用于将药物输送到受伤的大脑。 P-糖蛋白和有机酸 转运蛋白在限制某些药物进入体内方面发挥着重要作用 脑。