PET AND THE BLOOD BRAIN BARRIER IN HUMAN EPILEPSY

宠物与人类癫痫病中的血脑屏障

• 批准号: 6330535
• 负责人: EAIN M CORNFORD
• 金额: $ 17.75万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-10 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6330535
• 关键词: Primates; bioimaging /biomedical imaging; blood brain barrier; brain circulation; brain imaging /visualization /scanning; brain metabolism; capillary; clinical research; disease /disorder model; epilepsy; glucose metabolism; glucose transporter; human subject; immunoelectron microscopy; in situ hybridization; northern blottings; partial seizure; phospholipase C; positron emission tomography; protein kinase C; western blottings

Brain glucose metabolism reaches metabolic extremes between human seizures. This study will determine if blood-brain barrier (BBB) capillary glucose transporter activity undergoes up-and down-regulation in response to seizures, and coincidentally seek a possible role of this Glut 1 transporter contributing to the interictal hypometabolism seen in PET studies. Recent work from our laboratory indicates that in pathological conditions, two distinctly different configurations of transporter protein density are seen. Large endothelia, with abundant Glut 1 transporter protein in the membranes; or smaller endothelia, with markedly less membrane Glut 1 transporter. This pattern suggests the possibility that discrete brain regions (on the order of a few cubic microns) may have markedly different glucose concentrations. It is postulated this paradigm may be an anticonvulsant adaptation, whereby epileptogenic neurons are inhibited by controlled access to substrate. We propose that in interictal epilepsy, BBB Glut 1 levels are down- regulated. Dynamic FDG-PET analyses of focal epilepsy patients with a previously identified hypometabolic zone should show reduced influx. In resected brain, quantitative immunogold studies of human capillary Glut 1 should show altered glucose transporter densities. In animal models of epilepsy, down-regulation of the BBB Glut 1 glucose transporter can presumably be more fully confirmed with "(interictal) quantitative Western blot studies of microvessels, together with in vivo analyses of transporter maximal velocity, and electron microscopic quantification of Glut 1 transporters. In acute seizures, the opposite situation is anticipated. Presumably, ictal upregulation of the BBB Glut 1 transporter can be demonstrated with seizure onset (in animal models, using similar methods), and subcellular mechanisms which control capillary Glut 1 levels can be analyzed.

在人类癫痫发作之间，大脑的葡萄糖代谢达到代谢的极值。这项研究将确定血脑屏障(BBB)毛细血管葡萄糖转运体的活性是否在癫痫发作时经历上下调节，并巧合地寻找这种过剩的1转运体在PET研究中出现的发作间期低代谢的可能作用。我们实验室最近的工作表明，在病理条件下，可以看到两种截然不同的转运蛋白密度配置。大的内皮细胞，膜上有丰富的Glut1转运蛋白；或较小的内皮细胞，膜Glut1转运蛋白明显减少。这种模式表明，大脑的离散区域(大约几个立方微米)可能具有明显不同的葡萄糖浓度。据推测，这一范例可能是一种抗惊厥适应，通过控制对底物的接触来抑制致痫神经元。我们认为，在发作间期癫痫中，BBB Glut 1水平下调。先前发现低代谢区的局灶性癫痫患者的动态FDG-PET分析应显示内流减少。在切除的大脑中，对人类毛细血管GLUT 1的定量免疫金研究应该显示葡萄糖转运体密度的改变。在癫痫的动物模型中，BBB-GLUT-1葡萄糖转运体的下调可能可以通过对微血管的(发作间期)定量Western印迹研究、体内转运体最大速度的分析以及GLUT-1转运体的电子显微镜定量来更充分地证实。在急性癫痫发作中，预计会出现相反的情况。推测，BBB-GLUT-1转运体的发作期上调可以在癫痫发作时得到证明(在动物模型中，使用类似的方法)，并且可以分析控制毛细血管GLUT-1水平的亚细胞机制。