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），因为它并置 为了血液，大脑内皮（形成血脑屏障，BBB） 被认为对脑的影响相对抵抗力 缺血。但是，检查牛磺酸，谷氨酰胺和肌醇涌入 进入大脑（所有依赖Na+的过程）表示早期明显的（<1小时） 局灶性脑缺血期间的运输减少表明 内皮细胞损伤可能在初级而不是次要中发挥作用 缺血性脑损伤。如果从中排出也是如此 由于这些外排系统涉及到大脑的涌入。 控制大脑潜在有毒因素的浓度 extracelluar空间。因此，该建议有两个主要目标：确定 能量依赖于大脑到血液的流出是否受到抑制 脑缺血（特定目的1和2），并检查是否改变 血脑屏障的涌入和外排运输机制有助于 缺血性脑损伤（特定目标3）。 [3H] vinblastine达到的大脑分布量（a P-糖蛋白底物）和p- [3H]氨基酸酸（PAH，有机酸 转运蛋白底物将在大脑中动脉后确定 大鼠和小鼠的阻塞（特定目标1）。是否增加了数量 缺血的分布反映了涌入的变化或变化 然后，将确定血脑屏障处的外排，后者通过 在没有BBB P-糖蛋白的情况下检查脑缺血的作用 （MDR la敲出小鼠）或在探针诱导的有机抑制期间 酸转运。具体目标2将检查缺血的机制 通过检查PAH，L-谷氨酸和甲基氨基丁酸来抑制外排 外排（A系统氨基酸转运蛋白底物）吸收脉络膜 使用脑室灌注的丛。特定目标3将确定 在BBB上改变特定转运蛋白对缺血性脑损伤的影响 并将检查已知的药物是否可以改善再灌注对 血脑屏障的破坏实际上通过改变会产生其影响 缺血期间的运输。 确定早期BBB功能障碍是否应为替代治疗 脑缺血期间早期的靶标，发现存在抑制作用 缺血期间BBB的能量依赖性外排具有重大影响 为受伤的大脑输送药物。 P-糖蛋白和有机酸 转运蛋白都在限制某些药物进入的情况下起着重要作用 脑。