HYPOTHERMIC TREATMENT OF NEONATAL ASPHYXIC BRAIN INJURY

新生儿窒息性脑损伤的低温治疗

• 批准号: 6393106
• 负责人: DAWN M AGNEW
• 金额: $ 1.44万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-22 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6393106
• 关键词: autoradiography; brain metabolism; cerebral ischemia /hypoxia; corpus striatum; cytochrome oxidase; disease /disorder model; electroencephalography; enzyme activity; glucose metabolism; glutamate transporter; glutamates; heart arrest; hypoxia neonatorum; induced hypothermia; nervous system disorder therapy; newborn animals; nonhuman therapy evaluation; somesthetic sensory cortex; swine; western blottings

Perinatal hypoxia-ischemia (HI) has potential lifelong consequences for infants and children including movement disorders, epilepsy, and developmental delay. Therapeutic and pharmacologic interventions are either unsuccessful or controversial, limiting treatment to supportive care. Hypothermia is a potential intervention suggested to provide protection in some newborn animal models of HI, however through unclear mechanisms. Its long-term protection is unknown. HI injury leads to brain damage through a variety of pathways, including excitotoxicity mediated via glutamate pathways, and energy failure. Therefore, the purpose of this study is to investigate in a clinically relevant animal model of HI, the effects of hypothermia related to I) neuroprotection at 14-days 2) extra-cellular glutamate concentrations and glutamate transporters (GLT1, EAAC1), and 3) energy metabolism (glucose consumption and mitochondrial function). One-week old anesthetized piglets will be subjected to asphyxic cardiac arrest. After cardiopulmonary resuscitation animals will be randomly assigned to undergo mild hypothermia or normothermia for 24 hrs. Neuronal cell density will be counted at 14-days of survival. Microdialysate determination of extracellular glutamate concentrations, expression of glutamate reuptake transporters measured by western immunoblots and immunocytochemistry, autoradiographic determination of regional glucose consumption, and cytochrome oxidase histochemistry will be investigated during the transition from hypothermia to normothermia when cortical electrical activity emerges and when seizure activity often occurs. Neurological assessment will be performed daily. Through investigation of hypothermia in a clinically relevant animal model of HI, it is expected that the findings from this study will contribute to the understanding of potential mechanisms of protecting the human newborn from the sequelae of HI encephalopathy and for optimizing protocols for clinical implementation of hypothermia.

围产期缺氧 - 缺血（HI）对婴儿和儿童（包括运动障碍，癫痫和发育延迟）有潜在的终生后果。 治疗和药理学干预措施是不成功或有争议的，限制了治疗以提供支持。体温过低是一种潜在的干预措施，该干预措施可在一些HI的新生动物模型中提供保护，但是通过不清楚的机制。 它的长期保护尚不清楚。 HI损伤导致通过多种途径造成脑损伤，包括通过谷氨酸途径介导的兴奋性毒性和能量衰竭。 因此，这项研究的目的是在HI的临床相关动物模型中进行研究，与I）与I）14天的神经保护作用的作用2）14天2）细胞外谷氨酸浓度和谷氨酸转运蛋白转运蛋白（GLT1，EAAC1）和3）和3）能量代谢（葡萄糖消耗和葡萄糖消耗和线粒体型功能）。 一周的大麻醉小猪将遭受沥青心脏骤停。 心肺复苏后，动物将随机分配给轻度体温过低或正常温度24小时。 神经元细胞密度将在生存的14天计数。 微溶解细胞外谷氨酸浓度的测定，通过西方免疫印迹和免疫细胞化学测量的谷氨酸再摄取转运蛋白表达，自摄影酶消耗的放射自显影测定以及在孔疗中何时何时进行氧化氧化酶氧化酶活性的调查，并在孔疗中何时进行氧化氧化酶活性。 每天将进行神经系统评估。 通过在HI的临床相关动物模型中调查体温过低，预计这项研究的发现将有助于理解保护人类新生儿免受HI脑病后遗症的潜在机制，并优化用于临床实施体温过低的方案。