Gouix Elsa, Buisson Alain, Nieoullon André, Kerkerian-Le Goff Lydia, Tauskela Joseph S, Blondeau Nicolas, Had-Aissouni Laurence
Aix Marseille Université, CNRS, IBDM UMR 7288, 13288, Marseille cedex 9, France; University of Nice Sophia Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), CNRS UMR7275, 06560 Valbonne, France.
Université Joseph Fourier - Inserm U 836-UJF-CEA-CHU, 38706 La Tronche Cedex, France.
Pharmacol Res. 2014 Sep;87:8-17. doi: 10.1016/j.phrs.2014.06.002. Epub 2014 Jun 11.
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.
了解星形胶质细胞在中风中的作用正变得越来越重要，这不仅是因为它自身是神经血管单元中的一个重要组成部分，还因为星形胶质细胞会影响神经元的转归。缺血可能会诱发星形胶质细胞增生及其他表型变化，但人们对这些变化仍知之甚少，部分原因是在体外再现这些变化存在局限性。二丁酰环磷腺苷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对缺血样应激——氧糖剥夺（OGD）更敏感。OGD改变了胶质谷氨酸转运体的表达/分布及活性，损害了细胞对谷氨酸的摄取，并优先降低了分化星形胶质细胞内的谷胱甘肽水平。用DEVD-CHO抑制半胱天冬酶-3可赋予对OGD的抗性，而抗氧化剂N-乙酰半胱氨酸（NAC）可对抗氧化应激。未分化星形胶质细胞对OGD的抗性可能源于其短暂但选择性地形态转变为阿尔茨海默II型星形胶质细胞，这是转变为反应性星形胶质细胞之前的一个中间阶段。将神经元与暴露于OGD的星形胶质细胞共培养会导致神经毒性，但令人惊讶的是，与濒死的分化星形胶质细胞共培养时神经毒性水平较低。共培养时添加抗氧化剂NAC或5-脂氧合酶抑制剂AA861可延迟（第1天）但不能预防神经毒性（第3天）。因缺血而发生凋亡的星形胶质细胞可能通过缺血诱导的谷胱甘肽释放代表一种短暂的神经保护机制，但当缺血损害星形胶质细胞的支持功能时，氧化应激是神经元死亡的原因。
