CARDIAC ARREST AND RESUSCITATION--MECHANISMS OF BRAIN INJURY

严重缺氧和完全窒息是心脏疾病最常见的原因。 新生儿和婴幼儿会停滞，并可能导致脑性瘫痪， 精神发育迟缓和严重癫痫发作。我们已经开发了一种模型 类似于临床的未成熟猪的窒息心脏骤停 选择性损伤基底节、皮质的新生儿窒息病程 和丘脑，一天后出现临床癫痫发作 复苏。我们的初步数据表明，对神经元和 星形胶质细胞，伴随着它们各自谷氨酸转运体的丢失 异构体，在24小时内在壳核中致密，而神经变性是 初级感觉运动皮质大部分延迟到48小时，直到96小时 丘脑感觉核团的时数。我们的目标是了解这一机制 在康复的每一步都有损伤，所以特定的治疗方式 可以设计成防止每个部位的损伤成熟。我们 将确定谷氨酸再摄取能力是否下降 转运蛋白发生在复氧的早期，当 可以看到电活动。亚低温与谷氨酸释放 将使用抑制剂拉莫三嗪来减少谷氨酸的溢出 进入细胞外空间，通过微透析法监测 康复的第一天。我们将确定抑制谷氨酸溢出是否 复苏后减少壳核早期神经元和星形胶质细胞的损失， 大脑皮质和丘脑迟发性丢失，以及神经行为缺陷。一个 感觉运动皮质和丘脑迟发性神经元丢失的成分 可能是由于a)继发性靶向剥夺导致的本质上的细胞凋亡 与感觉运动轴上其他神经元的丧失有关，以及b)癫痫。我们 将使用各种形态和生化的细胞凋亡标记物 确定细胞程序性死亡发生的时间和地点。苯巴比妥 负荷，临床上用来抑制新生儿窒息发作 将被用来确定癫痫发作活动在 损伤过程的进展。系统的整体性方法 神经病理学、免疫细胞化学定位、微透析和脑电 光谱分析将在一个模型中产生独特的机械见解 新生儿脑损伤。在成熟的大脑中，转基因小鼠一直是有用的 用于研究局灶性缺血性损伤，但这种方法尚未被 适用于心脏骤停。在心脏骤停和复苏的模型中 在小鼠身上，我们将测试这一假设，即神经元的组合 一氧化氮合酶基因缺失与铜锌过表达 超氧化物歧化酶提供更好的神经保护和改善记忆 而学习要比单独改变任何一个基因都要好。这项研究提供了一个 理解NO和氧自由基在脑损伤中作用的新方法 心脏骤停/心肺复苏后迟发性神经元损伤。

Severe hypoxia and complete asphyxia are the most common causes of cardiac arrest in newborn and infant children and can result in cerebral palsy, mental retardation and severe seizures. We have developed a model of asphyxic cardiac arrest in the immature pig that resembles the clinical course of birth asphyxia with selective injury to basal ganglia, cortex and thalamus and with emergence of clinical seizures one day after resuscitation. Our preliminary data indicate that injury to neurons and astrocytes, accompanied by loss of their respective glutamate transporter isoforms, is dense in putamen by 24 hours, whereas neurodegeneration is largely delayed until 48 hours in primary sensorimotor cortex and until 96 hours in thalamic sensory nuclei. Our goal is to understand the mechanism of injury at each step of recovery so that specific therapeutic modalities can be designed to prevent the maturation of injury at each location. We will determine if decreased capacity of the glutamate reuptake transporters occurs during the early hours of reoxygenation when bursts of electrical activity are seen. Mild hypothermia and the glutamate release inhibitor lamotrigine will be used to reduce the overflow of glutamate into the extracellular space as monitored by microdialysis during the first day of recovery. We will determine if suppressing glutamate overflow after resuscitation reduces early neuronal and astrocyte loss in putamen, delayed loss in cortex and thalamus, and neurobehavioral deficits. A component of the delayed neuronal loss in sensorimotor cortex and thalamus may be apoptotic in nature resulting from a) target deprivation secondary to loss of other neurons in the sensorimotor axis, and b) seizures. We will use various morphological and biochemical markers of apoptosis to determine when and where programmed cell death occurs. Phenobarbital loading, as used clinically to suppress birth asphyxia seizures in newborns, will be used to determine the role of seizure activity in the progression of the injury process. The integrative approach of systems neuropathology, immunocytochemical localization, microdialysis and EEG spectral analysis will generate unique mechanistic insights in a model of neonatal brain injury. In mature brain, transgenic mice have been useful for investigating focal ischemic injury, but this approach has not been applied to cardiac arrest. In a model of cardiac arrest and resuscitation in mice, we will test the hypothesis that the combination of neuronal nitric oxide (NO) synthase gene deletion with overexpression of Cu, Zn- superoxide dismutase provides better neuroprotection and improve memory and learning than either gene alteration alone. This study provides a novel approach for understanding the role of NO and oxygen radicals in delayed neuronal injury after cardiac arrest/CPR.