FOCAL STROKE--METABOLISM AND PH USING NEUTRAL RED

这个项目的长期目标是确定组织的作用 梗死进展中的酸碱和代谢紊乱 在永久性局灶性缺血发作后。 实验性病灶 局部缺血与大多数人类中风的相关性比全局模型更高。 局灶性脑缺血模型的最新进展减少了脑缺血再灌注损伤。 缺血性病变的大小和位置的变异性 在以前的模型。 我们以前已经表明，恶化的焦周围区域， 如果在3小时后开始复流，则无法避免半暗带（P） 局部缺血 此应用程序的关键是确定这些事件 参与P.领域不可逆损害的演变。 减少缺血灶周围的血流量， 大脑动脉（MCA）闭塞显然可以生存的初始或 急性损伤，但最终屈服于一些继发性或慢性事件。 在缺血的前2h，P中的ATP水平接近正常 尽管乳酸盐的积累和能量的损失具有时间依赖性 储备 能量储备的减少表明 随着缺血时间的延长而增加能量债务， 纠正，能源故障将是不可避免的。 焦周区 在24小时内发生梗死，细胞死亡的机制， 由于能源故障或二次事件，只是一个问题， 投机 很明显，P的死亡有助于 长期残疾，局灶性卒中的有效治疗仍然存在 难以捉摸。 病灶代谢研究中的几个问题 中风已经部分得到解决。 脑内P区和局灶区 现在可以在空间上识别原位冷冻的代谢物， 可以使用微量定量的方法容易地测量组织片 组织化学 将这些方法与MRI和体内 微透析提供了一种独特的方法来研究代谢 P. 本申请的直接目标是确定代谢是否 条件的P触发一组继发性潜在致病性 事件，或者，如果P由于外部因素而恶化， 其施加超过P代谢能力的工作负荷。 的 要考虑的外在因素是：1）暂时性扩散性抑郁 和2）神经递质、乳酸和钾从 缺血核心 对焦周区域的额外能量需求， 它的血液流动受损，能量不平衡加剧， 导致能量衰竭、细胞体积失控和梗死。 这 可能性将通过以下目标进行测试：1）确定在 P物质与缺血核心区能量状态、酸碱平衡、水分的变化 脑缺血后不同时间脑组织中神经递质含量和神经递质稳态 闭塞，2）评估外力是否有助于最终 通过增加该区域的工作量来减少P的梗死，以及3） 确定是否改变了大脑温度，血糖水平或 高碳酸血症，其已知在治疗期间改变pHi和乳酸水平。 缺血和外在因素的特征， 改变梗塞形成的速率和大小以及大分子的变化。 从这些实验中获得的信息将有助于提供一个基础 制定一项干预措施， 内在和外在因素对P，从而改善结果 永久性局部缺血后。

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 the onset of permanent focal ischemia. Experimental focal ischemia is more relevant to most human strokes than are global models. Recent advances in the models of focal ischemia have decreased the variability in the size and location of the ischemic lesions encountered in previous models. We have previously shown that the deterioration of the perifocal region or penumbra (P) cannot be avoided if reflow is initiated after 3 hours of ischemia. The crux of this application is to determine those events involved in the evolution of irreversible damage in the P. Areas of reduced blood flow surrounding the ischemic focus following middle cerebral artery (MCA) occlusion apparently can survive the initial or acute insult, but eventually succumb to some secondary or chronic event. In the first 2 h of ischemia, the ATP levels in the P are near normal despite a time-dependent accumulation of lactate and loss of energy reserves. The loss of the energy reserves suggests that there is an ever increasing energy debt with longer periods of ischemia and if not corrected, energy failure will be inevitable. The perifocal region becomes infarcted within 24 h and the mechanisms of cell death, whether due to energy failure or secondary events, 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 remains elusive. The problems encountered in the investigation of metabolism in focal stroke have been, in part, resolved. The P and focal regions in brains frozen in situ now can be spatially identified and metabolites in micro-g pieces of tissue can be measured readily using microquantitative histochemistry. Combining these methodologies with MRI and in vivo microdialysis provides an unique approach to the study of metabolic derangements in the P. The immediate goals of this application are to determine if the metabolic conditions of the P trigger a set of secondary potentially pathogenic events, or alternatively, if the P deteriorates due to extrinsic factors which impose a workload which exceeds the capacity of P metabolism. The extrinsic factors to be considered are 1) transient spreading depression and 2) diffusion of neurotransmitters, lactic acid and potassium from the ischemic core. The additional energy demands on the perifocal region, 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 state, acid-base balance, water content and neurotransmitter homeostasis at various times after MCA occlusion, 2) to evaluate if extrinsic forces contribute to eventual infarction of the P by increasing the workload in that area and 3) to determine if altered brain temperature, blood glucose levels or hypercapnea, which are known to alter pHi and lactate levels during ischemia and also the characteristics of the extrinsic factors, will alter the rate and size of infarct formation and macromolecular changes. The information gained from these experiments will help provide a basis for developing an intervention which will neutralize the influence of intrinsic and extrinsic factors on the P and thereby improve the outcome following permanent focal ischemia.