BLOOD-BRAIN BARRIER TRANSPORT AND ISCHEMIC BRAIN INJURY

血脑屏障运输和缺血性脑损伤

• 批准号: 6539848
• 负责人: Richard F Keep
• 金额: $ 18.81万
• 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/6539848
• 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：（改编自申请人摘要）由于其并列 血液，脑内皮（形成血脑屏障，BBB） 被认为对大脑的影响有相对的抵抗力 缺血然而，检查牛磺酸，谷氨酰胺和肌醇流入， 进入大脑（所有Na+依赖性过程）表明明显早期（<1小时） 局灶性脑缺血期间转运减少，表明 内皮细胞损伤可能在原发性，而不是继发性， 缺血性脑损伤这可能是特别的情况下，如果流出，以及 因为这些流出系统参与了 控制大脑中潜在有毒因子的浓度 细胞外空间因此，这项建议有两个主要目标： 是否能量依赖性流出从大脑到血液被抑制， 脑缺血（具体目的1和2），并检查是否改变 血脑屏障的流入和流出转运机制有助于 缺血性脑损伤（具体目标3）。 [3 H]长春碱（a）达到的脑分布容积 P-糖蛋白底物）和p-[3 H]氨基马尿酸（PAH，一种有机酸 转运蛋白底物）将在大脑中动脉 在大鼠和小鼠中的闭塞（具体目标1）。是否增加了 局部缺血的分布反映了流入的变化或 然后确定血脑屏障处的流出，后者通过 检查在没有BBB P-糖蛋白的情况下脑缺血的作用 (the MDRLA敲除小鼠）或在丙磺舒诱导的有机 酸运输具体目标2将研究缺血的机制， 通过检测PAH、L-谷氨酸和甲基氨基丁酸， 脉络膜外排（A系统氨基酸转运蛋白底物）摄取 使用脑室池灌注的神经丛。具体目标3将决定 血脑屏障特异性转运体改变对缺血性脑损伤的影响 并将检查是否有已知的药物可以改善再灌注的影响 血脑屏障破坏实际上通过改变 在缺血期间运输。 确定早期BBB功能障碍是否应作为替代治疗 在脑缺血的早期， 缺血时血脑屏障的能量依赖性流出具有重要意义 将药物输送到受伤的大脑P-糖蛋白与有机酸 转运蛋白都发挥了重要作用，限制了一些药物的访问， 个脑袋