Oxygen glucose deprivation-induced astrocyte dysfunction provokes neuronal death through oxidative stress
Oxygen glucose deprivation-induced astrocyte dysfunction provokes neuronal death through oxidative stress
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DOI：
10.1016/j.phrs.2014.06.002
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发表时间：
2014-09-01
影响因子：
9.3
通讯作者：
Had-Aissouni, Laurence
中科院分区：
文献类型：
--
作者：
Gouix, Elsa;Buisson, Alain;Had-Aissouni, Laurence
了解星形胶质细胞在中风中的作用越来越重要，不仅是因为它本身是神经血管单位中的重要组成部分，而且因为星形胶质细胞可以影响神经元的结果。缺血可能会诱导星形胶质细胞增生和其他表型变化，但这些仍然知之甚少，部分原因是在体外复制这些变化的限制。二丁酰环AMP分化的培养星形胶质细胞更能代表体内星形胶质细胞的表型，并且比未分化的星形胶质细胞更容易受到缺血样应激、氧-葡萄糖剥夺（OGD）的影响。在分化的星形胶质细胞中，OGD改变了胶质细胞谷氨酸转运体的表达/分布和活性，损害了细胞谷氨酸摄取，并优先降低了细胞内谷胱甘肽水平。通过用DEVD-CHO抑制半胱天冬酶-3和通过抗氧化剂N-乙酰半胱氨酸（NAC）抑制氧化应激来赋予对OGD的抗性。未分化的星形胶质细胞对OGD的抗性可能是由于短暂但选择性的形态转化为阿尔茨海默氏II型星形胶质细胞，这是转化为反应性星形胶质细胞之前的中间阶段。神经元与OGD暴露的星形胶质细胞的共培养导致神经毒性，但令人惊讶的是，与垂死的分化的星形胶质细胞的水平较低。抗氧化剂NAC或5-LOX抑制剂AA 861在共培养时加入延迟（第1天），但不能防止神经毒性（第3天）。缺血导致的星形胶质细胞凋亡可能是一种短暂的神经保护机制，通过缺血诱导的谷胱甘肽释放，但氧化应激是负责神经元死亡时，缺血损害星形胶质细胞的支持功能。(C)2014爱思唯尔有限公司版权所有。
Understanding the role of astrocytes in stroke is assuming increasing prominence, not only as an important component on its own within the neurovascular unit, but also because astrocytes can influence neuronal outcome. Ischemia may induce astrogliosis and other phenotypic changes, but these remain poorly understood, in part due to limitations in reproducing these changes in vitro. Dibutyryl cyclic AMP-differentiated cultured astrocytes are more representative of the in vivo astroglial cell phenotype, and were much more susceptible than undifferentiated astrocytes to an ischemic-like stress, oxygen-glucose deprivation (OGD). OGD altered the expression/distribution and activity of glial glutamate transporters, impaired cellular glutamate uptake and decreased intracellular levels of glutathione preferentially in differentiated astrocytes. Resistance to OGD was conferred by inhibiting caspase-3 with DEVD-CHO and oxidative stress by the antioxidant N-acetylcysteine (NAC). The resistance of undifferentiated astrocytes to OGD may result from a transient but selective morphological transformation into Alzheimer type II astrocytes, an intermediary stage prior to transforming into reactive astrocytes. Co-culture of neurons with OGD-exposed astrocytes resulted in neurotoxicity, but at surprisingly lower levels with dying differentiated astrocytes. The antioxidant NAC or the 5-LOX inhibitor AA861 added upon co-culture delayed (day 1) but did not prevent neurotoxicity (day 3). Astrocytes undergoing apoptosis as a result of ischemia may represent a transient neuroprotective mechanism via ischemia-induced release of glutathione, but oxidative stress was responsible for neuronal demise when ischemia compromised astrocyte supportive functions. (C) 2014 Elsevier Ltd. All rights reserved.