CARDIAC ARREST AND RESUSCITATION--MECHANISMS OF BRAIN INJURY

严重缺氧和完全窒息是心脏病最常见的原因 在新生儿和婴儿中停止并可导致脑瘫， 智力迟钝和严重癫痫我们开发了一个模型， 窒息性心脏骤停在未成熟的猪，类似于临床 新生儿窒息伴选择性基底节、皮质损伤 和丘脑，并在一天后出现临床癫痫发作 复苏术我们的初步数据表明， 星形胶质细胞，伴随着其各自的谷氨酸转运蛋白的丢失 同种型，在24小时时在壳核中是致密的，而神经变性是 在初级感觉运动皮层中，大部分延迟至48小时， 在丘脑感觉核中的时间。我们的目标是了解 每一步的恢复，使特定的治疗方式， 可以设计成防止在每个位置处损伤的成熟。我们 将决定谷氨酸再摄取能力的降低 转运蛋白发生在复氧的早期， 可见电活动。轻度低温与谷氨酸释放 抑制剂拉莫三嗪将用于减少谷氨酸的溢出 进入细胞外空间，如在微透析期间通过微透析监测的。 康复的第一天我们将确定抑制谷氨酸溢出 复苏后减少了壳核中早期神经元和星形胶质细胞的损失， 皮质和丘脑的延迟损失以及神经行为缺陷。一 感觉运动皮层和丘脑迟发性神经元丢失的组成部分 在性质上可能是凋亡性的，这是由于a）靶剥夺继发性的 感觉运动轴中其他神经元的丧失，和B）癫痫发作。我们 将使用细胞凋亡的各种形态学和生化标记， 确定程序性细胞死亡发生的时间和地点。苯巴比妥 负荷，临床上用于抑制出生窒息癫痫发作， 新生儿，将被用来确定癫痫活动的作用， 损伤过程的进展。系统的综合方法 神经病理学、免疫细胞化学定位、微透析和EEG 光谱分析将产生独特的机械见解的模型， 新生儿脑损伤在成熟的大脑中，转基因小鼠是有用的， 用于研究局灶性缺血性损伤，但这种方法还没有 适用于心脏骤停在心脏骤停和复苏的模型中 在小鼠中，我们将测试神经元和神经元的组合的假设， 一氧化氮（NO）合酶基因缺失伴Cu，Zn- 超氧化物歧化酶提供更好神经保护和改善记忆 和学习能力都比单独改变基因强这项研究提供了一个 了解NO和氧自由基在 心脏骤停后迟发性神经元损伤/CPR。

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.