COMPLETE AND INCOMPLETE CEREBRAL ISCHEMIA

完全性和不完全性脑缺血

• 批准号: 3882283
• 负责人: RAYMOND C KOEHLER
• 金额: --
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3882283
• 关键词: acidity /alkalinity; adenosine triphosphate; allopurinol; blood glucose; brain metabolism; cerebral ischemia /hypoxia; creatine phosphate; dogs; electroencephalography; evoked potentials; free radicals; high energy compound; nonsurgical revascularization; nuclear magnetic resonance spectroscopy; oxygen transport; particle; radiotracer; reperfusion; superoxide dismutase; superoxides

Development of intracellular acidosis during cerebral ischemia and generation of free radicals during reperfusion are two mechanisms of brain injury that have received increasing attention in recent years. The overall goal of this proposal is to investigate the role of intracellular pH and oxygen-derived free radicals on the recovery of cerebral high energy phosphates, blood flow and electrical function following ischemia. We will use in vivo 31P nuclear magnetic resonance spectroscopy to track the recovery of cerebral ATP, phosphocreatine (PCr) and intracellular pH (pHi). We will simultaneously measure cerebral blood flow (CBF), 02 uptake, somatosensory evoked potentials (SEP), and electroencephalogram (EEG). We will study both complete and incomplete global cerebral ischemia produced by intracranial pres- sure elevations in dogs. To titrate recovery of electrical function (from normal to poor restoration), three ischemic durations will be produced so that effects of interventions can be studied in an injury-dose dependent manner. We will first determine whether the initial rate of recovery of ATP and PCr, as marker of mitochondrial function, correlate better with electrical recovery than steady state recovery level of ATP and PCr following various durations of complete and incomplete ischemia. We will then examine the influence of pHi achieved during ischemia and its rate of normalization during reperfusion on the rate of recovery of ATP, PCr, SEP, and EEG, To manipulate pHi, blood glucose levels will be varied, thereby altering lactic acid production. Complete ischemia will be compared to incomplete ischemia, where the range of pHi alterations should be greater because of sustained glucose delivery during ischemia. The influence of hyperventilation, a clinical intervention frequently used, on recovery of pHi, ATP. PCr, EEG and SEP will also be studied. We will investigate the role of oxygen-derived free radicals first by measuring the time course of cortical appearance and disappearance of superoxide anion during reperfusion, and second by demonstrating that free radical scavengers and inhibitors suppress superoxide appearance during reperfusion. We will then evaluate the efficacy of scavenger administration on the restoration of CBF, SEP, EEG, ATP and PCr. Finally, we will determine if acidosis potentiates free radical appearance and if scavengers can effectively reverse this detrimental effect of acidosis. These studies should enhance our understanding of ischemic-reperfusion injury mechanisms in brain.

脑缺血期间细胞内酸中毒的发展 再灌注过程中自由基的产生有两种机制 近年来越来越受到人们关注的脑损伤 年。 该提案的总体目标是调查 细胞内pH值和氧自由基对细胞内pH值的影响 恢复脑部高能磷酸盐、血流量和 缺血后的电功能。 我们将使用vivo 31P 核磁共振波谱追踪回收 脑 ATP、磷酸肌酸 (PCr) 和细胞内 pH (pHi)。 我们将同时测量脑血流量（CBF），02 摄取、体感诱发电位 (SEP) 和 脑电图（EEG）。 我们将学习完整的和 颅内压引起的不完全性全脑缺血 狗的肯定海拔。 滴定回收电 功能（从正常到恢复不良），三级缺血 将产生持续时间，以便干预措施的效果可以 以损伤剂量依赖性方式进行研究。 我们首先会 确定 ATP 和 PCr 的初始恢复率是否为 线粒体功能标记，与电相关性更好 ATP 和 PCR 的恢复高于稳态恢复水平 不同持续时间的完全和不完全缺血。 我们将 然后检查缺血期间 pHi 的影响及其 再灌注期间的正常化率对恢复率的影响 ATP、PCr、SEP 和 EEG，控制 pHi、血糖水平 会发生变化，从而改变乳酸的产生。 完全的 将缺血与不完全缺血进行比较，其中范围 由于持续的葡萄糖，pHi 的变化应该更大 缺血期间分娩。 过度换气的影响 经常使用的临床干预措施，用于恢复 pHi、ATP。 还将研究 PCr、EEG 和 SEP。 我们将调查 首先通过测量氧自由基的作用时间 皮质出现和超氧阴离子消失的过程 再灌注期间，其次通过证明自由基 清除剂和抑制剂抑制超氧化物的出现 再灌注。 然后我们将评估清除剂的功效 给药对 CBF、SEP、EEG、ATP 和 PCR 恢复的影响。 最后，我们将确定酸中毒是否会增强自由基 外观以及拾荒者是否可以有效扭转这种情况 酸中毒的不利影响。 这些研究应该增强我们的 了解脑缺血再灌注损伤机制。