Mitochondrial Zn2+ in ischemic neurodegeneration: In vivo tests of principle studies in a rat cardiac arrest model

线粒体 Zn2 在缺血性神经变性中的作用：大鼠心脏骤停模型原理研究的体内测试

• 批准号: 9270096
• 负责人: JOHN H WEISS
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270096
• 关键词: Acute; Animal Model; Bioenergetics; Blood flow; Brain; Brain Injuries; Brain region; Cell Death; Cerebral Ischemia; Chelating Agents; Divalent Cations; Edetic Acid; Electron Microscopy; Environment; Event; Functional disorder; Glucose; Glutamates; Goals; Heart Arrest; Hippocampus (Brain); Homeostasis; In Vitro; Individual; Injury; Intervention; Investigation; Ischemia; Ischemic Brain Injury; Ischemic Neuronal Injury; Lead; Light; MK801; Measurement; Mitochondria; Modeling; Morbidity - disease rate; Motion; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Neuronal Injury; Neurons; Oxygen; Pathogenicity; Pathologic; Pathway interactions; Pharmaceutical Preparations; Phase; Physiological; Population; Rattus; Recovery; Reperfusion Therapy; Role; Ru 360; Ruthenium Red; Seizures; Slice; Stroke; Study models; Synapses; Testing; Therapeutic; Therapeutic Intervention; Time; Translations; aging population; brain tissue; chelation; deprivation; effective therapy; excitotoxicity; extracellular; hippocampal pyramidal neuron; improved outcome; in vivo; in vivo Model; insight; loss of function; mortality; neuron loss; neuronal patterning; postsynaptic neurons; restoration; therapeutic evaluation; uptake

Project Summary/Abstract Therapy for ischemic brain injury is poor in part because of our limited understanding of mechanisms leading to neuronal loss. While contributions of excessive glutamate release and neuronal Ca2+ accumulation have been much studied, recent evidence implicates critical contributions of another divalent cation, Zn2+. After ischemia or prolonged seizures, free Zn2+ accumulates in neurons, and observations that Zn2+ chelation is protective implicates a role in neuronal death. Culture studies have revealed that exogenously applied Zn2+ can enter neurons and accumulate in mitochondria, powerfully disrupting their function. However, little is known about mechanisms of injury caused by the accumulation of endogenous Zn2+ in native brain tissues. Using acute hippocampal slices subjected to oxygen glucose deprivation (OGD) to model ischemia, we recently made the first simultaneous measurements of cytosolic Zn2+ and Ca2+ changes, and found that Zn2+ accumulation is an early event in hippocampal pyramidal neurons, that precedes and contributes to subsequent cell death. These acute deleterious effects of Zn2+ appear to result specifically from Zn2+ uptake into mitochondria via the mitochondrial Ca2+ uniporter (MCU). The proposed studies are organized around a Hypothesis: Zn2+ contributes to the early stages of ischemic neuronal injury, in part via entering and inducing acute disruption of mitochondrial function. The primary goal of this study is to make an early assessment of this hypothesis in vivo, using of an established model of global cerebral ischemia resulting from asphyxial cardiac arrest. Aim I will use the cardiac arrest model to characterize Zn2+ and mitochondrial dependent changes and neuronal injury in different brain regions, as a function of both the duration of ischemia and the duration of recovery prior to assessment. Aim II will test a number of interventions targeting acute and subacute effects of Ca2+ and Zn2+, administered either alone or in combinations as suggested by our hippocampal slice studies, that we predict will abrogate certain shortcomings of the individual interventions. They will be delivered either before ischemia, or only upon reperfusion to assess potential for benefit with delayed administration. These studies will provide a bridge between compelling mechanistic clues derived from in vitro studies and efforts to forge better therapies for degeneration after in vivo ischemia, and we hope that they will lead to the elucidation of new types of interventions, to be delivered either during the acute phase of ischemia or upon reperfusion, that will disrupt the pathological cascade, enabling improved outcomes.

项目摘要/摘要 缺血性脑损伤的治疗部分是因为我们的理解有限 导致神经元丧失的机制。而过多的谷氨酸的贡献 释放和神经元Ca2+积累已经进行了大量研究，最近的证据 暗示了另一个二价阳离子Zn2+的关键贡献。缺血或 长时间的癫痫发作，游离Zn2+积聚在神经元中，并观察到Zn2+ 螯合是保护性的，这意味着在神经元死亡中起作用。文化研究表明 外源应用Zn2+可以进入神经元并积聚在线粒体中， 有力破坏他们的功能。但是，关于伤害机制知之甚少 由天然脑组织中内源性Zn2+的积累引起。 使用经受氧气葡萄糖剥夺（OGD）的急性海马切片 缺血模型，我们最近进行了第一个同时测量胞质的测量 Zn2+和Ca2+更改，发现Zn2+积累是早期事件 海马锥体神经元，之前并有助于随后的细胞 死亡。 Zn2+的这些急性有害作用似乎是由Zn2+专门产生的 通过线粒体Ca2+ Uniporter（MCU）摄取线粒体。提议 研究是围绕一个假设进行的：Zn2+有助于早期阶段 缺血性神经元损伤，部分是通过进入并引起急性中断 线粒体功能。这项研究的主要目标是对 该假设在体内使用了既定的全球脑缺血模型 由沥青心脏骤停导致。目的，我将使用心脏骤停模型 表征Zn2+和线粒体依赖性变化和神经元损伤 大脑区域，是缺血持续时间和恢复持续时间的函数 在评估之前。 AIM II将测试针对急性的许多干预措施 Ca2+和Zn2+的亚急性效应，单独或组合为 由我们的海马切片研究提出，我们预测将废除某些 个人干预的缺点。他们将在之前交付 缺血，或仅在再灌注后以评估延迟的利益潜力 行政。这些研究将在引人注目的机械之间提供桥梁 源于体外研究和努力为更好的疗法而得出的线索 体内缺血之后，我们希望它们能导致阐明新型的新型 干预措施，要么在缺血的急性阶段或在 再灌注，这将破坏病理级联，从而改善结果。