PET AND THE BLOOD BRAIN BARRIER IN HUMAN EPILEPSY

大脑葡萄糖代谢在人类癫痫发作之间达到代谢极限。本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在癫痫发作时经历上调和下调，并碰巧寻找Glut - 1转运蛋白在PET研究中发现的间期低代谢中的可能作用。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构型。内皮大，膜内有丰富的Glut - 1转运蛋白；或内皮细胞变小，膜供过于1转运蛋白明显减少。这种模式表明，大脑中离散的区域（以几立方微米为数量级）可能具有明显不同的葡萄糖浓度。据推测，这种模式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，在癫痫发作期间，血脑屏障供过于求1水平下调。动态FDG-PET分析局灶性癫痫患者先前确定的低代谢区应显示减少的内流。在切除的大脑中，定量免疫金研究人类毛细血管Glut 1应显示葡萄糖转运蛋白密度的改变。在癫痫动物模型中，可以通过微血管的定量Western blot研究，以及体内转运蛋白最大速度分析和Glut 1转运蛋白的电镜定量分析，更充分地证实血脑屏障Glut 1葡萄糖转运蛋白的下调。在急性癫痫发作中，预期情况正好相反。据推测，血脑屏障供过于瘾1转运蛋白的急剧上调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供过于瘾1水平的亚细胞机制。

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.