BLOOD-BRAIN BARRIER TRANSPORT AND ISCHEMIC BRAIN INJURY

描述：(改编自申请人的摘要)，因为它是并列的 对于血液，大脑内皮细胞(形成血脑屏障，BBB) 一直被认为对大脑的影响具有相对抵抗力 缺血症。然而，牛磺酸、谷氨酰胺和肌醇内流的检测 进入大脑(所有钠离子依赖的过程)表明明显的提早(&lt；1小时) 局灶性脑缺血时转运减少提示 内皮细胞损伤可能在原发，而不是继发性， 缺血性脑损伤。如果外流也是如此，情况可能尤其如此 因为这些外流系统参与了 控制大脑中潜在有毒因素的浓度 细胞外空间。因此，这项提案有两个主要目标：确定 脑部对血液的能量依赖性外流是否受到抑制 脑缺血(特定目标1和2)，并检查 血脑屏障的内流和外流转运机制有助于 缺血性脑损伤(特定目标3)。 [~3H]长春花碱(A)达到的脑分布体积 P-糖蛋白底物)和p-[~3H]氨基马尿酸(PAH，一种有机酸 转运蛋白底物)将在大脑中动脉后确定 大鼠和小鼠的闭塞(特异靶1)。是不是增加了 脑缺血的分布反映了内流的变化或 然后，血脑屏障的外流将被确定，后者由 血脑屏障P-糖蛋白缺失对脑缺血的影响 (mdr1a基因敲除小鼠)或在丙磺舒诱导的有机抑制期间 酸运输。《特殊目标2》将研究缺血的机制 通过检测多环芳烃、L-谷氨酸和甲氨基丁酸来抑制外流 外流(A系统氨基酸转运体底物)摄取脉络膜 神经丛采用脑室-脑池灌注法。具体目标3将决定 改变血脑屏障特异性转运体对缺血性脑损伤的影响 并将研究已知的改善再灌流影响的药物是否 血脑屏障的破坏实际上通过改变 缺血时的运输。 确定早期血脑屏障功能障碍是否应作为替代治疗 靶点在脑缺血早期，发现有抑制作用 脑缺血时血脑屏障能量依赖性外流的研究具有重要意义 将药物输送到受伤的大脑。P-糖蛋白与有机酸 转运体和转运体都在限制某些药物进入 大脑。

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.