DOPAMINE IN NEONATAL HYPOXIC-ISCHEMIC BRAIN INJURY

这项中央情报局提案的假设是，过量的多巴胺 新纹状体中的释放可能导致脑损伤 新生儿缺氧缺血性脑病这是根据最近 研究表明，中枢神经系统缺血伴随着30倍的增加 在这种情况下，细胞外的多巴胺可能是神经毒性的。 提出了两个阶段的研究。体内研究（1期）将使用 新生大鼠模型。神经化学和组织学方法（包括GFAP 免疫细胞化学，计算纹状体面积和体积， 多巴胺DI受体和外周苯二氮卓类放射自显影 结合位点）将被用来定量的程度和范围 脑损伤一个消耗者的潜在神经保护作用 内源性多巴胺（α-甲基-酪氨酸），多巴胺拮抗剂， 非选择性（氟奋乃静和氟噻草胺）和选择性（SCH 23390; 舒必利），和抗氧化剂将在该模型中进行评估。机制 多巴胺诱导的神经元损伤的百分比（%阶段2”）接下来将在 体外使用纹状体组织培养来确定多巴胺诱导的脑 损伤是通过刺激特异性受体或通过 氧自由基的产生。多巴胺拮抗剂 与自由基清除剂相比， 多巴胺将被确定。拟议研究的结果应 有助于理解中枢神经系统损伤的病理生理学， 新生儿缺氧缺血，并可能建议治疗干预， 人类新生儿 Filloux博士将在这项研究奋进中受到监督， 博士托马斯N.帕克斯是一位著名的受人尊敬的发育神经生物学家 在兴奋性毒性细胞效应和中枢神经系统组织中具有记录在案的专业知识 培养技术所有的实验室空间和设备以及 为顺利完成这项工作所需的辅助援助 项目将由帕克斯博士和通过 儿科、神经科和精神科的统一支持 在犹他州大学。

The hypothesis of this proposal for a CIA is that excessive dopamine release in the neostriatum may contribute to the cerebral damage incurred in neonatal hypoxic-ischemic encephalopathy. This is based on recent studies indicating that CNS ischemia is accompanied by a 30-fold increase in extracellular dopamine which, in these circumstances, May be neurotoxic. Two phases of study are proposed. In vivo studies (phase 1) will utilize a neonatal rat model. Neurochemical and histologic methods (including GFAP immunocytochemistry, calculation of striatal area and volume, autoradiography of dopamine DI receptors and of peripheral benzodiazepine binding sites) will be employed to quantitate the degree and extent of brain damage. The potential neuroprotective effects of a depleter of endogenous dopamine (alpha-methyl-ptyrosine), of dopamine antagonists, both non-selective (fluphenazine and flupenthioxl) and selective (SCH 23390; sulpiride), and of antioxidants will be assessed in this model. Mechanisms of dopamine-induced neuronal damage will next be examined (%phase 2") in vitro using striatal tissue culture to determine if dopamine-induced brain injury is mediated through stimulation of specific receptors, or through the generation of oxygen free radicals. The ability of dopamine antagonists versus free radical scavengers to protect neurons in culture from excess dopamine will be determined. The results of the proposed research should contribute to the understanding of the pathophysiology of CNS injury in neonatal hypoxic-ischemia, and may suggest therapeutic interventions in the human neonate. Dr. Filloux will be supervised in this research endeavor by Dr. Thomas N. Parks, a well-known, respected developmental neurobiologist with documented expertise in excitotoxic cellular effects and in CNS tissue culture techniques. All the laboratory space and equipment as well as ancillary assistance necessary for the successful completion of this project will be made available to Dr. Filloux by Dr. Parks and through the unified support of the Departments of Pediatrics, Neurology, and Psychiatry at the University of Utah.