EXCITOTOXICITY AND BRAIN INJURY IN CIRCULATORY ARREST

该项目的目标是通过以下方式确定兴奋性毒性的作用 神经递质谷氨酸在低温循环性脑损伤中的作用 逮捕(HCA)。高密度脂蛋白对谷氨酸受体的过度刺激 谷氨酸本身的浓度最近被认为与神经元有关 在代谢应激条件下死亡，如缺氧和缺血。 选择性神经元的特征性神经后遗症和类型 与HCA相关的坏死提示谷氨酸兴奋毒性的作用。 现在可以首次准确地定义这一角色 一种临床相关的HCA模型，因为最近开发的 选择性谷氨酸受体拮抗剂。 一种贴近临床实践的犬肝细胞癌存活模型 已经建立了。术后出现持续的神经损伤 在18摄氏度的脑温下停循环2小时。这个 神经功能缺失与选择性神经元的组织病理类型 临床上HCA术后出现的脑损伤与坏死平行 布景。实验证据表明， 在抑制谷氨酸释放和亚低温之间。 大脑温度从33摄氏度到33摄氏度变化的初步研究 37摄氏度的HCA术后脑部明显改善 对维持在较低温度下的动物的保护，提供 谷氨酸在HCA诱导的兴奋性毒性中的间接证据 脑部受伤。在进一步的前期工作中，谷氨酸的亚型 受体(NMDA和非NMDA)在狗的所有区域都有定义 脑部受体放射自显影。使用选择性NMDA谷氨酸 受体拮抗剂MK801选择性保护小鼠心肌细胞CA3区 已经证实了海马区和小脑浦肯野细胞， 第一个直接证据表明谷氨酸对HCA的兴奋性毒性- 相关损伤。 为了全面研究这一机制，选择性谷氨酸受体 拮抗剂将作为单用药和联合用药用于 犬HCA模型的建立。由此产生的选择性神经元模式 保护将通过组织病理学进行研究，并与 放射自显影标记谷氨酸的分布模式改变 受体亚型。这些研究的扩展将涉及到使用 单唾液酸神经节苷脂，已知抑制谷氨酸的化合物 离开谷氨酸生理作用的兴奋性毒性 不受影响。 这项拟议的研究不仅将定义兴奋性毒性在 但可能提供一种新的治疗方法来改善 相关的神经损伤。提供和扩展保险箱的能力 停循环一段时间可能会使患者病情好转 护理和拓宽许多心胸等非心源性疾病的范围 使用HCA的程序。

The goal of this project is to define the role of excitotoxicity by the neurotransmitter glutamate in brain injury due to hypothermic circulatory arrest (HCA). Excessive stimulation of glutamate receptors by high concentrations of glutamate itself has recently been linked to neuronal death in conditions of metabolic stress, such as hypoxia and ischemia. The characteristic neurologic sequelae and patterns of selective neuronal necrosis associated with HCA suggest a role for glutamate excitotoxicity. It is now possible to precisely define this role for the first time in a clinically relevant model of HCA because of the recently developed selective glutamate receptor antagonists. A canine survival model of HCA closely simulating clinical practice has been established. A consistent neurologic injury was obtained following 2 hrs of circulatory arrest at a brain temperature of 18degreeC. The neurologic deficit and the histopathologic pattern of selective neuronal necrosis parallel the brain injury seen after HCA in the clinical setting. Experimental evidence has demonstrated a close correlation between inhibition of glutamate release and mild hypothermia. Preliminary studies in which brain temperature varied from 33degreeC to 37degreeC following HCA demonstrated significantly improved cerebral protection in animals maintained at the lower temperature, providing indirect evidence for glutamate-induced excitotoxicity in HCA-induced brain injury. In further preliminary work subtypes of glutamate receptors (NMDA and non-NMDA) have been defined in all areas of the dog brain by receptor autoradiography. Using the selective NMDA glutamate receptor antagonist MK801, selective protection of the CA3 region of the Hippocampus and Cerebellar Purkinje cells has been demonstrated, yielding the first direct evidence implicating glutamate excitotoxicity in HCA- associated injury. To comprehensively examine this mechanism, selective glutamate receptor antagonists will be used as single agents and in combination in the canine model of HCA. The resulting patterns of selective neuronal protection will be studied by histopathology and correlated with the altered distribution patterns of autoradiographically labelled glutamate receptor subtypes. An extension of these studies will involve the use of monosialogangliosides, compounds known to inhibit glutamate excitotoxicity while leaving the physiologic actions of glutamate unaffected. The proposed research will not only define the role of excitotoxicity in HCA but may provide a novel therapeutic approach to ameliorating the associated neurologic injury. The ability to provide and extend a safe period of circulatory arrest could potentially result in better patient care and broaden the scope of many cardiothoracic and other non-cardiac procedures using HCA.