Hyslop P A, Zhang Z, Pearson D V, Phebus L A
Department of Central Nervous System Research, Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
Brain Res. 1995 Feb 13;671(2):181-6. doi: 10.1016/0006-8993(94)01291-o.
Toxic reactive oxygen species have been implicated as important mediators of tissue injury after reperfusion of ischemic organs. When rats are subject to 30 min global forebrain ischemia, 24 h following this insult, there is substantial loss of medium-sized neurones as revealed by histological sectioning of the striatal region of the forebrain. The goal of this study was to utilize microdialysis to directly measure one of the more stable intermediates of reduced molecular oxygen, H2O2 in the rat striatum following 4-vessel occlusion and reperfusion, and to correlate these levels with H2O2 toxicity to neurones grown in culture. A significant rise in striatal H2O2 levels was observed for about 1 h during reperfusion, amounting to an increase of approximately 100 microM at the peak. In control experiments where the dialysis probe was embedded in cortical regions surrounding the striatum (where there is no neuronal loss due to the ischemic episode), there was no measurable increase in tissue H2O2 levels. H2O2 has been previously shown to be neurotoxic to PC12 cells as well as rat primary hippocampal neurones at comparable concentrations striatal neurones experience during reperfusion. We demonstrate that H2O2 is also neurotoxic to the human cortical neuronal cell line, HCN-1A. These experiments establish an important link between oxidant generation and neuronal loss in this tissue following global forebrain ischemia.
毒性活性氧已被认为是缺血器官再灌注后组织损伤的重要介质。当大鼠经历30分钟的全脑缺血时，在这种损伤24小时后，通过对前脑纹状体区域进行组织学切片检查发现，中等大小的神经元大量丢失。本研究的目的是利用微透析技术直接测量四血管闭塞和再灌注后大鼠纹状体中还原态分子氧的一种更稳定的中间体——过氧化氢（H2O2），并将这些水平与培养的神经元中H2O2的毒性进行关联。在再灌注期间约1小时内，观察到纹状体中H2O2水平显著升高，峰值时增加约100微摩尔。在对照实验中，将透析探针埋入纹状体周围的皮质区域（由于缺血事件该区域无神经元丢失），组织中H2O2水平没有可测量的增加。先前已表明，在再灌注期间纹状体神经元所经历的相当浓度下，H2O2对PC12细胞以及大鼠原代海马神经元具有神经毒性。我们证明H2O2对人皮质神经元细胞系HCN - 1A也具有神经毒性。这些实验建立了全脑缺血后该组织中氧化剂生成与神经元丢失之间的重要联系。
