CEREBRAL ISCHEMIA, VIABILITY AND OXIDATIVE METABOLISM

在脑缺血期间，代谢和那些需要三磷酸腺苷的活动是 其中变化最严重的是。这些变化引发了一系列 导致缺血性细胞死亡的事件。鲜为人知的是 缺血后再灌流期间的事件。这些信息是必不可少的 自再灌流以来，复氧和线粒体恢复 恢复离子传输和电活动的先决条件； 缺血(或再灌流！)造成的残留紊乱可以进一步推广 脑部受伤。该实验室和其他实验室之前的研究已经 提示缺血和/或再灌流引起的紊乱限制 向电子传输链提供电子。我们相信 这种局限性表现为线粒体离子的急性功能障碍。 运输和电活动，并调节随后的 电生理学和组织病理学的恢复。这一建议是 我们最近的研究发现，增加脑氧合后 缺血加重了线粒体的过氧化，但减少了诱发 潜伏期(EP)波幅降低，脑氧合作用增强 EP恢复。因为后遗症的许多错乱特征- 缺血性病理生理学和组织病理学可能与 线粒体功能障碍，拟议的研究将增加理解 通过检验四个假设来验证这种功能障碍：1)改变 脑缺血后线粒体、离子转运和E活性的预测 慢性病理生理学和组织病理学；2) 线粒体、离子运输和电紊乱，以及 缺血后组织病理学反映高能减少 3)脑缺血后氧合作用影响ATP水平， 线粒体活性、E恢复和组织病理学；以及4)增强 减少对线粒体电子载体的等量供应 缺血降低PIMHO和组织病理学，改善功能 恢复。为了验证这些假说，线粒体、离子转运和 电力活动将同时由光学和 电极技术，同时代谢物水平和组织病理学将 由化验取样和光学显微镜定义。合并的优势 这些方法包括：a)线粒体、离子之间的偶联 可以检查运输和电力活动；b)它们提供了 将剧烈变化与残差联系起来的事件的自然历史 病理生理学和组织病理学；以及c)操纵的后果 将对缺血后事件进行定义。通过这种方式，理解 缺血诱导的病理生理学和组织病理学将增加到 为治疗策略提供合理的基础 干预可以是有针对性的。

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.