CEREBRAL ISCHEMIA, VIABILITY AND OXIDATIVE METABOLISM

在脑缺血期间，代谢和那些需要ATP的活动， 其中最严重的改变。 这些变化引发了一系列的 导致缺血性细胞死亡的事件。 不太清楚的是 缺血后再灌注期间的事件。 这一信息至关重要 由于再灌注、再氧合和线粒体恢复 离子转运和电活动恢复的先决条件;然而 局部缺血（或再灌注！）可进一步促进 脑损伤 该实验室和其他实验室的先前研究 表明缺血和/或再灌注限制了 向电子传输链提供电子。 我们认为 这种局限性表现为线粒体、离子通道和细胞膜的急性功能障碍。 运输和电活动，并调节随后的 电生理学和组织病理学恢复。 这一建议 我们最近的发现支持了这一点， 缺血加重线粒体过氧化，但降低诱发的 电位（EP）振幅;而降低脑氧合增强 EP恢复。 由于许多混乱的特点后- 缺血性病理生理学和组织病理学可能与 线粒体功能障碍，拟议的研究将增加了解 通过测试四个假设来研究这种功能障碍：1） 缺血后线粒体、离子转运和E活性预测 慢性病理生理学和组织病理学; 2） 线粒体、离子转运和电紊乱，以及 缺血后组织病理学反映高能量降低 中间体; 3）缺血后脑氧合影响ATP水平， 线粒体活性、E恢复和组织病理学;以及4）增强 减少线粒体电子载体的等效供应， 缺血降低PIMHo和组织病理学，并改善功能 复苏 为了验证这些假设，线粒体，离子转运和 电活动将通过光学和 电极技术，而代谢物水平和组织病理学将 通过测定取样和光学显微镜检查确定。 合并的优势 这些方法包括：a）线粒体、离子、 可以检查运输和电活动; B）它们提供 事件的自然史，将急性变化与残留 病理生理学和组织病理学;以及c）操作的后果 将定义缺血后事件。 通过这种方式， 缺血诱导的病理生理学和组织病理学将增加， 提供了一个合理的基础， 干预是有针对性的。

During brain ischemia, metabolism and those activities requiring ATP, are among the most severely altered. These changes initiate a cascade of events that underlay ischemic cell death. Less well understood are events during reperfusion after ischemia. This information is essential since reperfusion, reoxygenation and mitochondrial recovery are prerequisite to recovery of ion transport and electrical activities; yet residual derangements form ischemia (or reperfusion!) may promote further brain injury. Previous research from this laboratory and others has suggested that derangements produced by ischemia and/or reperfusion limit the supply of electrons to the electron transport chain. We believe that this limitation is manifested by acute dysfunction of mitochondrial, ion transport and electrical activities and that it modulates subsequent recovery of electrophysiology and histopathology. This suggestion was supported by our recent finding that increasing brain oxygenation after ischemia exaggerated mitochondrial hyperoxidation but decreased evoked potential (EP) amplitudes; while decreasing brain oxygenation enhanced EP recovery. Since many of the derangements which characterize post- ischemic pathophysiology and histopathology may be linked to mitochondrial dysfunction, proposed research will increase understanding of such dysfunction by testing four hypotheses: 1) changes in mitochondrial, ion transport and E activities after ischemia predict chronic pathophysiology and histopathology; 2) the intensity of mitochondrial, ion transport and electrical derangements, and histopathology after ischemia reflect decreases in high energy intermediates; 3) Post-ischemic brain oxygenation influences ATP levels, mitochondrial activity, E recovery, and histopathology; and 4) enhancing reducing equivalent supply to the mitochondrial electron carriers after ischemia decreases PIMHo and histopathology and improves functional recovery. To test these hypotheses, mitochondrial, ion transport and electrical activities will be monitored simultaneously by optical and electrode techniques while metabolite levels and histopathology will be defined by assay sampling and light microscopy. Advantages of combining these approaches include that: a) the coupling among mitochondrial, ion transport and electrical activities can be examined; b) they provide a natural history of events to link acute changes with residual pathophysiology and histopathology; and c) consequences of manipulating post-ischemic events will be defined. In this manner, understanding of ischemia-induced pathophysiology and histopathology will be increased to provide a rational basis from which strategies for therapeutic intervention can be targeted.