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.

脑缺血期间细胞内酸中毒的发展和 再灌注过程中自由基的产生是两种机制 最近受到越来越注意的脑损伤 年。 该提议的总体目标是调查 细胞内pH和氧衍生的自由基在 恢复大脑高能磷酸盐，血流和 缺血后的电功能。 我们将在体内31p中使用 核磁共振光谱以跟踪 脑ATP，磷酸磷酸盐（PCR）和细胞内pH（PHI）。 我们将同时测量脑血流（CBF），02 吸收，体感诱发的电势（SEP）和 脑电图（EEG）。 我们将学习完整和 由颅内前的不完整的全球脑缺血 确定狗的高程。 滴定电气回收 功能（从正常恢复到不良），三个缺血性 将产生持续时间，以便可以进行干预措施的影响 以损伤剂量依赖的方式进行了研究。 我们将首先 确定ATP和PCR回收率的初始率是否为 线粒体功能的标记，与电气更好地相关 恢复比ATP和PCR的稳态回收水平遵循 完整和不完全缺血的各种持续时间。 我们将 然后检查缺血期间所获得的PHI的影响 再灌注期间的归一化率 ATP，PCR，SEP和EEG的作用，以操纵PHI，血糖水平 将会变化，从而改变乳酸的产生。 完全的 缺血将与不完整的缺血进行比较，范围 由于持续的葡萄糖，PHI改变应该更大 缺血期间分娩。 过度换气的影响 临床干预经常用于恢复PHI，ATP。 还将研究PCR，EEG和SEP。 我们将调查 通过测量时间，首先是氧气衍生的自由基的作用 超氧化阴离子的皮质外观和消失的过程 再灌注期间，其次是证明自由基 清除剂和抑制剂抑制超氧化物的外观 再灌注。 然后，我们将评估清道夫的功效 CBF，SEP，EEG，ATP和PCR的恢复。 最后，我们将确定酸中毒是否增强自由基 外观，如果清道夫可以有效地扭转这一点 酸中毒的有害作用。 这些研究应该增强我们的 了解大脑中缺血性再灌注损伤机制。