EXCITOTOXICITY IN CIRCULATORY ARREST BRAIN INJURY

循环骤停脑损伤中的兴奋性毒性

• 批准号: 7420427
• 负责人: WILLIAM Anthony BAUMGARTNER
• 金额: $ 1.27万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7420427
• 关键词: apoptosis; brain injury; death; diffusion; dogs; injury; measurement; mitochondrial membrane; model; necrosis; perfusion; potassium channel

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of the project is to define the mechanisms of excitotoxic neuronal injury caused by hypothermic circulatory arrest (HCA), and to develop the means to prevent it. In Dr Baumgartner's canine survival model of HCA, replicating clinical experience during cardiac operations, dogs subjected to 2 hours of circulatory arrest at 18xC sustain a consistent neurological deficit and histological pattern of selective neuronal death. Dr Baumgartner originally showed that administration of selective glutamate receptor antagonists before and after HCA reduced the neuronal necrosis. More recently, Dr Baumgartner's group have shown that neuronal death can occur by apoptopic or necrotic mechanisms. Glutamate release after HCA results in accumulation of nitric oxide (NO), which mediates neuronal death, and that inhibition of neuronal nitric oxide synthase (NOS) reduces production of NO in the brain and prevents apoptosis The main hypothesis to be tested in the latest renewal of this project is that mitochondrial dysfunction determines the mechanism of delayed excitotoxic neuronal injury after HCA by apoptosis or necrosis, and that neuronal apoptosis can be prevented by ischemic preconditioning (IPC), achieved pharmacologically by opening ATP-dependent potassium channels on the inner mitochondrial membrane. It is further hypothesized that NO may act as a mediator both of neuronal injury and neuronal protection by IPC. In preliminary experiments, Dr Baumgartner's group have shown that diazoxide, an ATP-dependent potassium channel opener, can produce pharmacologic IPC, and that this agent can prevent apoptosis in cardiomyocytes acting on the inner mitochondrial membrane. In their canine model, diazoxide has shown near total elimination of neurological deficit following HCA, with reduction in apoptosis in select neuronal populations. They have also showed that hypoxia can activate HIF-1 with induction of i NOS and production of NO, a putative molecular pathway of the late form of IPC. The purpose of this proposal is now to extend these observations using measurements of cerebral metabolism by 1H and 31P MRSI (as well as diffusion and perfusion-weighted imaging for the detection of ischemic changes) as surrogate markers of mitochondrial dysfunction in vivo, and to correlate these measures with neuronal survival, apoptosis and necrosis. These measurements will be made both in untreated HCA, and in animals with pharmacologic IPC with diazoxide. The proposed resource will interact with this project in a service capacity, since the required techniques (perfusion (and diffusion) imaging - TRD 1, proton and phosphorus MRSI - TRD 2) are already developed and available. Customized data acquisition protocols for perfusion and diffusion MRI, and for 1H and 31P MRSI in canine will be implemented for this project. The wide bore, short length and open design of the KKI magnet is particularly well suited for this particular large animal preparation which requires careful physiological monitoring during anesthesia.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。该项目的长期目标是确定由低温停循环（HCA）引起的兴奋毒性神经元损伤的机制，并开发预防方法。在Baumgartner博士的HCA犬存活模型中，复制心脏手术期间的临床经验，在18 ℃下停循环2小时的犬保持一致的神经功能缺损和选择性神经元死亡的组织学模式。Baumgartner博士最初表明，在HCA前后给予选择性谷氨酸受体拮抗剂可减少神经元坏死。最近，Baumgartner博士的研究小组发现，神经元死亡可以通过异位或坏死机制发生。HCA后谷氨酸的释放导致一氧化氮（NO）的积累，其介导神经元死亡，并且神经元型一氧化氮合酶（NOS）的抑制减少脑中NO的产生并防止细胞凋亡。在该项目的最新更新中要测试的主要假设是，线粒体功能障碍通过细胞凋亡或坏死决定HCA后迟发性兴奋毒性神经元损伤的机制，缺血预处理（IPC）可通过开放线粒体内膜ATP依赖性钾通道来预防神经元凋亡。进一步推测，NO可能是IPC引起神经元损伤和神经元保护的介质。在初步实验中，Baumgartner博士的研究小组已经表明，二氮嗪，一种ATP依赖性钾通道开放剂，可以产生药理学IPC，并且这种药物可以防止心肌细胞作用于线粒体内膜的凋亡。在他们的犬模型中，二氮嗪显示出HCA后神经功能缺损几乎完全消除，并在选定的神经元群体中减少细胞凋亡。他们还表明，缺氧可激活HIF-1，诱导iNOS和NO的产生，这是IPC晚期形式的推定分子途径。本建议的目的是扩展这些观察使用测量脑代谢的1H和31 P MRSI（以及扩散和灌注加权成像检测缺血性变化）作为替代标记物的线粒体功能障碍在体内，并将这些措施与神经元的存活，凋亡和坏死。这些测量将在未处理的HCA和使用二氮嗪进行药理学IPC的动物中进行。由于所需的技术（灌注（和扩散）成像- TRD 1、质子和磷MRSI - TRD 2）已经开发和可用，因此拟议资源将与本项目的服务能力相互作用。本项目将实施灌注和弥散MRI以及犬1H和31 P MRSI的定制数据采集方案。KKI磁体的宽孔、短长度和开放式设计特别适合于这种需要在麻醉期间进行仔细生理监测的特殊大型动物准备。