COMPLETE AND INCOMPLETE CEREBRAL ISCHEMIA

完全性和不完全性脑缺血

• 批准号: 3846749
• 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/3846749
• 关键词: acidity /alkalinity; adenosine triphosphate; allopurinol; blood glucose; brain metabolism; cerebral ischemia /hypoxia; creatine phosphate; dogs; electroencephalography; evoked potentials; free radical oxygen; 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.

脑缺血时细胞内酸中毒的发生和发展 再灌流过程中产生自由基是两种机制 脑损伤在最近受到越来越多的关注 好几年了。这项提案的总体目标是调查 细胞内pH和氧自由基在细胞内氧化损伤中的作用 脑高能磷酸盐的恢复、血流量和 缺血后的电功能。我们将在体内使用31p 核磁共振波谱技术用于跟踪药物的恢复 脑三磷酸腺苷、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(EEG)。我们将研究完整的和 颅内压致不完全性全脑缺血 当然，狗的海拔也很高。滴定回收电气量 功能(从正常到恢复较差)，三个缺血 将产生持续时间，以便干预措施的效果可以 以损伤剂量依赖的方式进行研究。我们将首先 确定ATP和PCR的初始回收率是否为AS 线粒体功能的标志物，与电学相关性更好 三磷酸腺苷和聚合酶链式反应恢复到稳态水平 不同时间的完全性和不完全性缺血。我们会 然后检测在缺血过程中PHI的影响以及其 再灌注期复常率对恢复率的影响 三磷酸腺苷，聚合酶链式反应，体感诱发电位和脑电，以控制phi，血糖水平 会有所不同，从而改变乳酸的生产。完成 缺血将被比作不完全性缺血，其中 的变化应该更大，因为持续的葡萄糖 在缺血期分娩。过度通风的影响，a 临床常用干预措施，对PHI、ATP的恢复。 还将对聚合酶链式反应、脑电和体感诱发电位进行研究。我们将调查 氧自由基的作用首先通过测量时间来实现 大脑皮层超氧阴离子的出现和消失过程 在再灌流期间，第二，通过证明自由基 清除剂和抑制剂抑制超氧化物歧化 再灌流。然后我们将评估清道夫的疗效 恢复脑血流量、体感诱发电位、脑电、三磷酸腺苷和聚合酶链式反应。 最后，我们将确定酸中毒是否会增强自由基。 如果食腐动物能有效地扭转这一局面 酸中毒的有害影响。这些研究应该会增强我们的 对脑缺血再灌注损伤机制的认识。