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 脑梗塞演变过程中的酸碱和代谢紊乱 在永久性局灶性脑缺血发作后。实验焦点 与全球模型相比，缺血与大多数人类中风更相关。 大鼠局灶性脑缺血模型的最新研究进展 遇到的缺血性损害的大小和位置的变异性 在以前的型号中。 我们之前已经表明，病灶周围区域的恶化 或半暗带(P)如果在3小时后开始回流，则无法避免 脑缺血的症状。这个应用程序的关键是确定这些事件 参与了P.地区不可逆转破坏的演变 中期后缺血灶周围血流量减少 大脑动脉(MCA)闭塞显然可以在最初或 急性侮辱，但最终会屈服于一些次要或慢性事件。 在缺血的前2小时，P区的ATP水平接近正常 尽管乳酸的积累和能量的损失依赖于时间 预备队。能源储备的损失表明有一种前所未有的 随着缺血时间的延长，能源债务增加，如果不是 更正，能源故障将是不可避免的。病灶周围区域 在24小时内发生梗塞以及细胞死亡的机制，无论是 由于能源故障或次要事件，只是 投机。很明显的是，P的死亡导致了 长期残疾和对局灶性中风的有效治疗仍然存在 难以捉摸。 疫源地新陈代谢研究中遇到的问题 中风在一定程度上已经得到解决。脑内的P区和局灶区 冷冻在原位现在可以在空间上识别和代谢产物在微克 利用微定量技术可以很容易地测量组织块 组织化学。将这些方法与核磁共振和活体实验相结合 微渗析为代谢研究提供了一种独特的方法 P。 该应用程序的直接目标是确定新陈代谢是否 P的状态触发了一系列继发性潜在致病因素 事件，或者如果P由于外部因素而恶化 这会造成超过磷代谢能力的工作负荷。这个 需要考虑的外在因素有：1)暂时性扩散抑制 2)神经递质、乳酸和钾的扩散。 缺血核心。对周围区域的额外能源需求， 它的血液流动受损，不断增加的能量失衡将导致 到能量衰竭、细胞体积失去控制和脑梗塞。这 可能性将通过以下目标进行测试：1)确定在 P与缺血核心能量状态、酸碱平衡、水分的变化 大脑中动脉术后不同时间含量和神经递质的动态平衡 咬合，2)评估外力是否对最终 通过增加该地区的工作量来增加P的梗塞和3)到 确定大脑温度、血糖水平或 高碳酸血症，已知会改变phi和乳酸水平 缺血也是外在因素的特点，会 改变梗塞形成的速度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为 开发了一种干预措施，将中和 内因和外因对P的影响，从而改善结局 在永久性局灶性缺血后。

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.