FOCAL STROKE--METABOLISM AND PH USING NEUTRAL RED

局灶性中风——使用中性红的代谢和 PH

• 批准号: 3405129
• 负责人: Wesley David LUST
• 金额: $ 17.12万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1995-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3405129
• 关键词: acid base balance; autoradiography; bioenergetics; brain edema; brain metabolism; cell death; cell morphology; cerebral ischemia /hypoxia; creatine; gamma aminobutyrate; glucose; glutamates; histology; laboratory rat; lactates; magnetic resonance imaging; neurotransmitter metabolism; pathology; potassium; spreading cortical depression; stroke

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.

该项目的长期目标是确定组织酸的作用- 基础和代谢紊乱在梗死的发展， 局灶性中风 实验性局灶性脑缺血与大多数人类 比全球模型的中风。 从震源模型获得的信息 然而，由于缺血的变异性， 现有模型中病变的大小和位置。 在中剂量给药后，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存活， 但最终会屈服于一些次要事件。 当能量储存 在缺血灶中立即耗尽， 区域或半暗带（P）接近正常，尽管有显著蓄积 乳酸盐这种情况类似于扩散性抑郁症， 众所周知，这是代谢成本高，当然，P已经处于危险之中， 因为血流量低。 病灶周围区域在24小时内梗死 H和细胞死亡的机制只是一个猜测的问题。 什么 很明显，P的死亡会导致长期残疾， 局灶性中风有效治疗仍然是难以捉摸的。 局灶性脑卒中代谢研究中存在的问题 已经解决了。 大脑中的焦周围和焦点区域被冻结在 现在可以根据定量血液来识别和解剖原位 流量值。 在马克杯的组织块中， 使用微量定量组织化学。 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 此应用程序的直接目标是确定不同的 这两个相邻区域的代谢反应是 神经递质，乳酸和钾被释放 在缺血期间，每一个都可以扩散到相邻的P区， 额外的工作负荷。 对P的额外能量需求， 血液流动受损，能量不平衡加剧会导致 能量衰竭、细胞体积控制丧失和梗塞。 这 可能性将通过以下目标进行测试：1）确定在P 和缺血核心的能量代谢、酸碱平衡的变化， MCA后不同时间脑含水量和神经递质代谢 闭塞，2）测量水肿形成的程度，或者直接在 解剖皮质组织或质子MRI，并将这些变化 分离的组织中电解质水平的改变 和3）确定高血糖症是否会降低pHi， 增加缺血区域的乳酸水平，将在 “要么是加速，要么是加速，要么是加速。 梗塞和B）影响水肿形成。 其他治疗目标是 还将测试推定的致病事件。 从这些实验中获得的信息将有助于为 开发一种干预措施， 从而改善以下结果： 通过最小化梗死范围来治疗局灶性缺血。