Manganese superoxide dismutase protects mouse cortical neurons from chronic intermittent hypoxia-mediated oxidative damage
Manganese superoxide dismutase protects mouse cortical neurons from chronic intermittent hypoxia-mediated oxidative damage
复制标题
DOI：
10.1016/j.nbd.2007.07.013
复制
发表时间：
2007-11-01
影响因子：
6.1
通讯作者：
Liu, Rugao
中科院分区：
文献类型：
--
作者：
Shan, Xiaoyang;Chi, Liying;Liu, Rugao
阻塞性睡眠呼吸暂停（OSA）综合征已被认为是一个高度流行的公共卫生问题，并与主要的神经行为发病率。慢性间歇性缺氧（CIH）是OSA的主要病理组成部分，在类似于人类OSA的啮齿动物模型中增加了脑皮质的氧化损伤并降低了神经认知功能。我们采用体外和体内的方法来确定特定的阶段和亚细胞区室，其中增强活性氧（ROS）在CIH过程中产生。此外，我们利用细胞培养和动物模型来分析增加ROS的产生对皮质神经元细胞损伤和神经认知功能障碍的后果。在原代皮层神经元培养系统中，我们证明了CIH期间从缺氧到常氧（NOX）的过渡阶段比从NOX到缺氧或单独缺氧的过渡阶段产生更多的ROS，所有这些都比NOX产生更多的ROS。使用选择性抑制剂的主要途径的ROS产生的细胞膜，胞质溶胶，和线粒体，我们表明，线粒体是增强的ROS产生在CIH在小鼠皮层神经元细胞的主要来源。此外，在细胞培养和转基因小鼠中，我们证明了MnSOD的过度表达降低CIH介导的皮质神经元凋亡，并减少空间学习障碍与Morris水迷宫测定。总之，来自体外和体内实验的数据表明，CIH介导的线粒体氧化应激可能在OSA中的神经元细胞损失和神经认知功能障碍中起主要作用。因此，旨在减少线粒体产生ROS的治疗策略可能会改善OSA的神经行为发病率。(c)2007年爱思唯尔公司All rights reserved.
Obstructive sleep apnea (OSA) syndrome has been recognized as a highly prevalent public health problem and is associated with major neurobehavioral morbidity. Chronic intermittent hypoxia (CIH), a major pathological component of OSA, increases oxidative damage to the brain cortex and decreases neurocognitive function in rodent models resembling human OSA. We employed in vitro and in vivo approaches to identify the specific phases and subcellular compartments in which enhanced reactive oxygen species (ROS) are generated during CIH. In addition, we utilized the cell culture and animal models to analyze the consequences of enhanced production of ROS on cortical neuronal cell damage and neurocognitive dysfunction. In a primary cortical neuron culture system, we demonstrated that the transition phase from hypoxia to normoxia (NOX) during CIH generates more ROS than the transition phase from NOX to hypoxia or hypoxia alone, all of which generate more ROS than NOX. Using selective inhibitors of the major pathways underlying ROS generation in the cell membrane, cytosol, and mitochondria, we showed that the mitochondria are the predominant source of enhanced ROS generation during CIH in mouse cortical neuronal cells. Furthermore, in both cell culture and transgenic mice, we demonstrated that overexpression of MnSOD-decreased CIH-mediated cortical neuronal apoptosis, and reduced spatial learning deficits measured with the Morris water maze assay. Together, the data from the in vitro and in vivo experiments indicate that CIH-mediated mitochondrial oxidative stress may play a major role in the neuronal cell loss and neurocognitive dysfunction in OSA. Thus, therapeutic strategies aiming at reducing ROS generation from mitochondria may improve the neurobehavioral morbidity in OSA. (c) 2007 Elsevier Inc. All rights reserved.