FOCAL STROKE: METABOLISM AND PH USING NEUTRAL RED

该项目的长期目标是确定组织酸的作用 梗塞发生过程中的基础和代谢紊乱 局灶性中风。 实验性局灶性缺血与大多数人类更相关 笔画比全球模型。 从焦点模型获得的信息 然而，由于缺血的变异性，缺血的发生一直令人沮丧。 现有模型中病变的大小和位置。 中层缺血灶周围血流减少的区域 大脑动脉（MCA）闭塞显然可以在最初的损伤中幸存下来， 但最终屈服于一些次要事件。 当能量储存时 缺血灶立即耗尽，灶周的那些 尽管积累显着，但区域或半影 (P) 接近正常 乳酸。这种情况类似于抑郁症的蔓延 众所周知，代谢成本很高，而且 P 肯定已经处于危险之中 由于血流量低。 焦点周围区域在 24 天内发生梗塞 H和细胞死亡机制只是推测。 什么 很明显的是，P 的死亡会导致长期残疾，并且 局灶性中风的有效治疗仍然难以实现。 局灶性脑卒中代谢研究中遇到的问题 已解决。 冷冻在大脑中的焦点周围和焦点区域 现在可以根据定量血液进行原位识别和解剖 流量值。 可以轻松测量杯状组织中的代谢物 使用微定量组织化学。 结合这两种方法 提供了一种独特的方法来研究代谢紊乱 半影。 该应用程序的直接目标是确定不同的 两个相邻区域的代谢反应是 P 死亡。神经递质、乳酸和钾被释放 在缺血期间，每种物质都可以扩散到相邻的 P 区，从而产生 额外的工作负担。 P 的额外能量需求，其 血液流动受损，能量失衡加剧会导致 能量衰竭、细胞体积控制丧失和梗塞。 这个 可能性将通过以下目标进行测试：1）确定P 和缺血核心能量代谢、酸碱平衡的变化， MCA后不同时间的水含量和神经递质代谢 闭塞，2) 测量水肿形成的程度，或者直接在 解剖皮质组织或通过质子 MRI，并将这些变化关联起来 离散解剖组织的电解质水平发生变化 3) 确定高血糖是否会降低 pHi 和 增加缺血区域的乳酸水平，在 半影 a) 加速发生或增大 梗塞和 b) 影响水肿形成。 其他治疗针对 还将测试假定的致病事件。 从这些实验中获得的信息将有助于提供基础 开发一种干预措施来抵消缺血的影响 组织作用于邻近组织，从而改善以下结果 通过最大限度地减少梗塞范围来实现局灶性缺血。

The long-term goal of this project is to determine the role of tissue acid- base and metabolic derangements in the evolution of infarction following focal stroke. Experimental focal ischemia is more relevant to most human strokes than are global models. The information gained from focal models of ischemia, however, has been discouraging owing to the variability in the size and location of the lesion in existing models. Areas of reduced blood flow surrounding the ischemic focus following middle cerebral artery (MCA) occlusion apparently can survive the initial insult, but eventually succumb to some secondary event. While the energy stores are immediately depleted in the ischemic focus, those in the perifocal region or penumbra (P) are near normal despite a significant accumulation of lactate. This condition resembles that of spreading depression which is known to be metabolically costly, and certainly the P is already at risk owing to low blood flow. The perifocal region becomes infarcted within 24 H and the mechanisms of cell death are only a matter of speculation. What is clear is that the death of the P contributes to long-term disability and that effective treatment of focal stroke remain elusive. The problems encountered in the investigation of metabolism in focal stroke have been resolved. The perifocal and focal regions in brains frozen in situ now can be identified and dissected on the basis of quantitative blood flow values. Metabolites in mug pieces of tissue can be measured readily using microquantitative histochemistry. Combining these two methodologies provides an unique approach to study of the metabolic derangements in the penumbra. The immediate goal of this application is to determine if the disparate metabolic response of the two contiguous regions is the reason for the death of the P. Neurotransmitters, lactic acid and potassium are released during ischemia and each could diffuse to the adjacent P area, creating an additional work load. The additional energy demands on the P, its compromised blood flow, and an increasing energy imbalance would lead to energy failure, loss of cell volume control and infarction. This possibility will be tested by the following aims: 1) to determine in the P and ischemic core the changes in energy metabolism, acid-base balance, water content and neurotransmitter metabolism at various times after MCA occlusion, 2) to measure the extent of edema formation, either directly in dissected cortical tissues or by proton MRI, and to correlate these changes with alterations in electrolyte levels from discretely dissected tissues and 3) to determine if hyperglycemia, which is known to decrease pHi and increase lactate levels in ischemic areas, will act similarly in the penumbra to a) either hasten the onset of or increase the size of the infarct and b) affect edema formation. Other treatments targetted to putative pathogenic events will also be tested. The information gained from these experiments will help provide a basis for developing an intervention which will neutralize the influence of ischemic tissue on neighboring tissue and thereby improve the outcome following focal ischemia by minimizing the extent of the infarct.