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The Journal of Neuroscience, September 19, 2007, 27(38):10094-10105; doi:10.1523/JNEUROSCI.2459-07.2007

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Neurobiology of Disease
System x_c^– Activity and Astrocytes Are Necessary for Interleukin-1ß-Mediated Hypoxic Neuronal Injury

Birgit Fogal,¹ Jun Li,² Doug Lobner,³ Louise D. McCullough,² and Sandra J. Hewett¹

Departments of ¹Neuroscience and ²Neurology, University of Connecticut Health Center, Farmington, Connecticut 06030, and ³Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin 53233

Correspondence should be addressed to Dr. Sandra J. Hewett, University of Connecticut Health Center, Department of Neuroscience, 263 Farmington Avenue, Farmington, CT 06030-3401. Email: shewett{at}neuron.uchc.edu

The purpose of this study was to elucidate the cellular/biochemical pathway(s) by which interleukin-1ß (IL-1ß) contributes to the pathogenesis of hypoxic–ischemic brain damage. In vivo, IL-1 receptor type I (IL-1RI)-deficient mice showed smaller infarcts and less neurological deficits than wild-type animals after a 90 min reversible middle cerebral artery occlusion. In vitro, IL-1ß mediated an enhancement of hypoxic neuronal injury in murine cortical cultures that was lacking in cultures derived from IL-1RI null mutant animals and was blocked by the IL-1 receptor antagonist or an IL-1RI blocking antibody. This IL-1ß-mediated potentiation of hypoxic neuronal injury was associated with an increase in both cellular cystine uptake ([cystine]_i) and extracellular glutamate levels ([glutamate]_e) and was prevented by either ionotropic glutamate receptor antagonism or removal of L-cystine, suggesting a role for the cystine/glutamate antiporter (System x_c^–). Indeed, dual System x_c^–/metabotropic glutamate receptor subunit 1 (mGluR1) antagonism but not selective mGluR1 antagonism prevented neuronal injury. Additionally, cultures derived from mGluR1-deficient mice exhibited the same potentiation in injury after treatment with IL-1ß as wild-type cultures, an effect prevented by System x_c^–/mGluR1 antagonism. Finally, assessment of System x_c^– function and kinetics in IL-1ß-treated cultures revealed an increase in velocity of cystine transport (V_max), in the absence of a change in affinity (K_m). Neither the enhancement in [cystine]_i, [glutamate]_e, or neuronal injury were observed in chimeric cultures consisting of IL-1RI^+/+ neurons plated on top of IL-1RI^–/– astrocytes, highlighting the importance of astrocyte-mediated alterations in System x_c^– as a novel contributor to the development and progression of hypoxic neuronal injury.

Key words: interleukin-1ß; IL-1 receptor type I; hypoxia; excitotoxicity; astrocytes; System x_c^–

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Received Feb. 16, 2007; revised July 27, 2007; accepted July 28, 2007.

Correspondence should be addressed to Dr. Sandra J. Hewett, University of Connecticut Health Center, Department of Neuroscience, 263 Farmington Avenue, Farmington, CT 06030-3401. Email: shewett{at}neuron.uchc.edu

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