title: A Cytotoxic, Co-operative Interaction Between Energy Deprivation and Glutamate Release From System xc- Mediates Aglycemic Neuronal Cell Death.
abstract: The astrocyte cystine/glutamate antiporter (system xc(-)) contributes substantially to the excitotoxic neuronal cell death facilitated by glucose deprivation. The purpose of this study was to determine the mechanism by which this occurred. Using pure astrocyte cultures, as well as, mixed cortical cell cultures containing both neurons and astrocytes, we found that neither an enhancement in system xc(-) expression nor activity underlies the excitotoxic effects of aglycemia. In addition, using three separate bioassays, we demonstrate no change in the ability of glucose-deprived astrocytes--either cultured alone or with neurons--to remove glutamate from the extracellular space. Instead, we demonstrate that glucose-deprived cultures are 2 to 3 times more sensitive to the killing effects of glutamate or N-methyl-D-aspartate when compared with their glucose-containing controls. Hence, our results are consistent with the weak excitotoxic hypothesis such that a bioenergetic deficiency, which is measureable in our mixed but not astrocyte cultures, allows normally innocuous concentrations of glutamate to become excitotoxic. Adding to the burgeoning literature detailing the contribution of astrocytes to neuronal injury, we conclude that under our experimental paradigm, a cytotoxic, co-operative interaction between energy deprivation and glutamate release from astrocyte system xc(-) mediates aglycemic neuronal cell death.
authors.affiliation: Department of Biology, Program in Neuroscience, Syracuse University, NY, USA Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: Trista L
authors.initials: TL
authors.lastname: Thorn
authors.affiliation: Department of Biology, Program in Neuroscience, Syracuse University, NY, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Jackman
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, WI, USA.
authors.forename: Doug
authors.initials: D
authors.lastname: Lobner
authors.affiliation: Department of Biology, Program in Neuroscience, Syracuse University, NY, USA Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Hewett
authors.affiliation: Department of Biology, Program in Neuroscience, Syracuse University, NY, USA Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA shewett@syr.edu.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Hewett
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D003553:Cystine / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D016202:N-Methylaspartate / Q000378:metabolism / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
chemical_list: D027182:Amino Acid Transport System y+; D016194:Receptors, N-Methyl-D-Aspartate; C492255:Slc7a11 protein, mouse; D001224:Aspartic Acid; D018698:Glutamic Acid; D003553:Cystine; D016202:N-Methylaspartate; D000255:Adenosine Triphosphate
keywords: aglycemia; cell culture; cystine; glucose deprivation; glutamate; neuronal injury