title: Oxygen glucose deprivation-induced astrocyte dysfunction provokes neuronal death through oxidative stress.
abstract: 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.
authors.affiliation: 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.
authors.forename: Elsa
authors.initials: E
authors.lastname: Gouix
authors.affiliation: Université Joseph Fourier - Inserm U 836-UJF-CEA-CHU, 38706 La Tronche Cedex, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Buisson
authors.affiliation: Aix Marseille Université, CNRS, IBDM UMR 7288, 13288, Marseille cedex 9, France.
authors.forename: André
authors.initials: A
authors.lastname: Nieoullon
authors.affiliation: Aix Marseille Université, CNRS, IBDM UMR 7288, 13288, Marseille cedex 9, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Kerkerian-Le Goff
authors.affiliation: National Research Council of Canada, Ottawa, ON, Canada K1A 0R6.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Tauskela
authors.affiliation: University of Nice Sophia Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), CNRS UMR7275, 06560 Valbonne, France. Electronic address: blondeau@ipmc.cnrs.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Blondeau
authors.affiliation: Aix Marseille Université, CNRS, IBDM UMR 7288, 13288, Marseille cedex 9, France. Electronic address: laurence.aissouni@univ-amu.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Had-Aissouni
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D016227:Benzoquinones / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D018920:Coculture Techniques; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D016227:Benzoquinones; D002264:Carboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D016859:Lipoxygenase Inhibitors; D011725:Pyridines; C521977:poly-2,6-pyridinedicarboxylic acid; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D053148:Caspase 3; D005947:Glucose; D010100:Oxygen; D000111:Acetylcysteine
keywords: Astrocyte differentiation; Glutamate transporters, Ischemia; Inflammation; Neuroprotection; ROS