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: 6477217
• 负责人: EAIN M CORNFORD
• 金额: $ 18.26万
• 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 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6477217
• 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.

大脑葡萄糖代谢在人类癫痫发作之间达到代谢极限。这项研究将确定血脑屏障 (BBB) 毛细血管葡萄糖转运蛋白活性是否会因癫痫发作而上调和下调，并同时寻找这种 Glut 1 转运蛋白在 PET 研究中发现的发作间期代谢低下中可能发挥的作用。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。内皮细胞大，膜上含有丰富的 Glut 1 转运蛋白；或更小的内皮细胞，膜 Glut 1 转运蛋白明显较少。这种模式表明离散的大脑区域（大约几立方微米）可能具有明显不同的葡萄糖浓度。据推测，这种范例可能是一种抗惊厥适应，通过控制对底物的访问来抑制致癫痫神经元。我们认为，在癫痫发作间期，BBB Glut 1 水平下调。对先前确定的代谢低下区的局灶性癫痫患者进行动态 FDG-PET 分析应显示流入量减少。在切除的大脑中，对人毛细血管 Glut 1 的定量免疫金研究应该显示葡萄糖转运蛋白密度的改变。在癫痫动物模型中，BBB Glut 1 葡萄糖转运蛋白的下调可能可以通过微血管的（发作间期）定量蛋白质印迹研究、转运蛋白最大速度的体内分析以及 Glut 1 转运蛋白的电子显微镜定量得到更充分的证实。在急性癫痫发作中，预计会出现相反的情况。据推测，发作期上调 BBB Glut 1 转运蛋白的作用可以通过癫痫发作来证明（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。

项目成果

New systems for delivery of drugs to the brain in neurological disease.

在神经系统疾病中将药物输送到大脑的新系统。

• DOI: 10.1016/s1474-4422(02)00136-9
• 发表时间: 2002
• 期刊: The Lancet. Neurology
• 作者: Cornford,EainM;Cornford,MarciaE
• 通讯作者: Cornford,MarciaE

Localization of brain endothelial luminal and abluminal transporters with immunogold electron microscopy.

• DOI: 10.1602/neurorx.2.1.27
• 发表时间: 2005-01-01
• 期刊: NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics
• 作者: Cornford, Eain M;Hyman, Shigeyo
• 通讯作者: Hyman, Shigeyo

Immunogold detection of microvascular proteins in the compromised blood-brain barrier.

受损血脑屏障中微血管蛋白的免疫金检测。

• DOI: 10.1385/1-59259-419-0:161
• 发表时间: 2003
• 期刊: Methods in molecular medicine.
• 作者: Cornford,EainM;Hyman,Shigeyo;Cornford,MarciaE
• 通讯作者: Cornford,MarciaE