Brain Oxygen and Metabolism in Cardiopulmonary Bypass

描述(由申请人提供)：心脏和循环系统的出生缺陷比任何其他类型的出生缺陷对婴儿的影响更大。在每年出生的所有婴儿中，大约每115人中就有1人患有心脏和/或循环缺陷，其中大多数需要进行体外循环手术。尽管外科手术取得了显著的进步，但这些患者中有相当一部分表现出神经和发育异常。与深低温停循环相关的新生脑神经损伤的细胞和分子机制尚不清楚。在拟议的研究中，我们实验室开发的一种非侵入性光学测量氧气的方法--氧依赖磷光猝灭将被用于测量新生仔猪脑微血管中的氧。该方法首次实现了对组织氧合、深低温停搏和停搏后恢复状态的连续评估。氧气直方图将与血流量、大脑新陈代谢状况和脑损伤程度的测量相结合。我们的研究将确定纹状体内神经元损伤的多巴胺依赖机制。我们还将评估一些有希望的方法来保护大脑免受深低温停循环所致的神经元损伤。 这项提议有两个主要目标： (A)确定多巴胺和多巴胺依赖的生化和分子改变在循环骤停后纹状体损伤中的作用。 (B)确定循环停止后保护神经的潜在策略，特别是在纹状体。 为实现这些目标，我们将测试以下具体目标： 1.低氧诱导的纹状体细胞外多巴胺水平升高是新生仔猪纹状体神经元损伤的主要原因之一。 2.新生仔猪停搏后，多巴胺通过增加自由基的产生，对纹状体产生神经毒性作用。 3.纹状体细胞外多巴胺的增加，通过D1和D2受体的作用，改变了一系列关键的调控过程，这些过程在很大程度上促进了深低温停循环诱导的神经元损伤。 4.深低温停循环期间，脑缺氧导致细胞外多巴胺大量增加，脑损伤可通过选择性脑灌流(SCP)来预防。 5.间歇性短时间LFCPB可减轻长时间深低温停搏对纹状体的多巴胺依赖性损伤。

DESCRIPTION (provided by applicant): Birth defects of the heart and circulatory system affect more infants than any other type of birth defect. Of all infants born each year, approximately 1 in 115 has heart and/or circulatory defects and most of them require cardiopulmonary bypass surgery. Despite remarkable advances in surgery, a substantial fraction of these patients manifest neurological and developmental abnormalities. The cellular and molecular mechanisms of neurologic injury in the newborn brain, associated with DHCA, are poorly understood. In proposed studies, oxygen dependent quenching of phosphorescence, a noninvasive optical method for measuring oxygen developed in our laboratory, will be used to measure the oxygen in the microvasculature of the brain of newborn piglets. This method allows for the first time continuous evaluation of the status of tissue oxygenation DHCA and post-arrest recovery. The oxygen histograms will be coupled with measurements of the blood flow, status of brain metabolism and the extent of brain injury. Our study will determine the dopamine dependent mechanisms of neuronal injury within the striatum. We will also evaluate some promising approaches in the protection of the brain from neuronal injury caused by DHCA. This proposal has two major goals: (a) To determine the role of dopamine and dopamine dependent biochemical and molecular alterations on striatal injury following circulatory arrest. (b) To identify potential strategies for neural protection, particularly in striatum, following circulatory arrest. To achieve these goals, we will test the following specific aims: 1. Hypoxia induced increase in extracellular levels of dopamine in the striatum during DHCA is a major contributor of neuronal injury in the striatum of newborn piglets. 2. Dopamine exerts a neurotoxic effect in striatum of newborn piglets by increasing production of free radicals during post-arrest period. 3. Increased extracellular dopamine in the striatum, acting through the D1 and D2 receptors, alters a cascade of key regulatory processes that contribute substantially to neuronal injury induced by DHCA. 4. During DHCA, brain oxygen deficiency results in a massive increase in extracellular dopamine and brain injury, and this can be prevented by selective cerebral perfusion (SCP). 5. Dopamine dependent striatal injury from prolonged periods of DHCA can be decreased with intermittent brief rescue periods of LFCPB.