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Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation

Abramov, AY; Scorziello, A; Duchen, MR; (2007) Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J NEUROSCI , 27 (5) 1129 - 1138. 10.1523/JNEUROSCI.4468-06.2007.

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Abstract

Ischemia is a major cause of brain damage, and patient management is complicated by the paradoxical injury that results from reoxygenation. We have now explored the generation of reactive oxygen species (ROS) in hippocampal and cortical neurons in culture in response to oxygen and glucose deprivation or metabolic inhibition and reoxygenation. Fluorescence microscopy was used to measure the rate of ROS generation using hydroethidine, dicarboxyfluorescein diacetate, or MitoSOX. ROS generation was correlated with changing mitochondrial potential (rhodamine 123), [Ca2+](c) (fluo-4, fura-2, or Indo-1), or ATP consumption, indicated by increased [Mg2+](c). We found that three distinct mechanisms contribute to neuronal injury by generating ROS and oxidative stress, each operating at a different stage of ischemia and reperfusion. In response to hypoxia, mitochondria generate an initial burst of ROS, which is curtailed once mitochondria depolarize or prevented by previous depolarization with uncoupler. A second phase of ROS generation that followed after a delay was blocked by the xanthine oxidase (XO) inhibitor oxypurinol. This phase correlated with a rise in [Mg2+](c), suggesting XO activation by accumulating products of ATP consumption. A third phase of ROS generation appeared at reoxygenation. This was blocked by NADPH oxidase inhibitors and was absent in cells from gp91(phox-/-) knock-out mice. It was Ca2+ dependent, suggesting activation by increased [Ca2+](c) during anoxia, itself partly attributable to glutamate release. Inhibition of either the NADPH oxidase or XO was significantly neuroprotective. Thus, oxidative stress contributes to cell death over and above the injury attributable to energy deprivation.

Type: Article
Title: Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation
DOI: 10.1523/JNEUROSCI.4468-06.2007
Keywords: ischemia, neurons, reactive oxygen species, mitochondria, xanthine oxidase, NADPH oxidase, HYPOXIC PULMONARY VASOCONSTRICTION, RAT HIPPOCAMPAL-NEURONS, NADPH OXIDASE, OXIDATIVE STRESS, XANTHINE-OXIDASE, ALLOPURINOL, REPERFUSION, ASTROCYTES, ISCHEMIA, BRAIN
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: http://discovery.ucl.ac.uk/id/eprint/151830
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