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Glucose and NADPH oxidase drive neuronal superoxide formation in stroke
Author(s) -
Suh Sang Won,
Shin Byung Seop,
Ma Hualong,
Van Hoecke Michaël,
Brennan Angela M.,
Yenari Midori A.,
Swanson Raymond A.
Publication year - 2008
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21511
Subject(s) - superoxide , apocynin , nadph oxidase , nicotinamide adenine dinucleotide phosphate , pentose phosphate pathway , pharmacology , ischemia , endocrinology , oxidase test , reactive oxygen species , medicine , chemistry , biochemistry , biology , metabolism , glycolysis , enzyme
Objective Hyperglycemia has been recognized for decades to be an exacerbating factor in ischemic stroke, but the mechanism of this effect remains unresolved. Here, we evaluated superoxide production by neuronal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase as a possible link between glucose metabolism and neuronal death in ischemia‐reperfusion. Methods Superoxide production was measured by the ethidium method in cultured neurons treated with oxygen‐glucose deprivation and in mice treated with forebrain ischemia‐reperfusion. The role of NADPH oxidase was examined using genetic disruption of its p47 phox subunit and with the pharmacological inhibitor apocynin. Results In neuron cultures, postischemic superoxide production and cell death were completely prevented by removing glucose from the medium, by inactivating NADPH oxidase, or by inhibiting the hexose monophosphate shunt that generates NADPH from glucose. In murine stroke, neuronal superoxide production and death were decreased by the glucose antimetabolite 2‐deoxyglucose and increased by high blood glucose concentrations. Inactivating NADPH oxidase with either apocynin or deletion of the p47 phox subunit blocked neuronal superoxide production and negated the deleterious effects of hyperglycemia. Interpretation These findings identify glucose as the requisite electron donor for reperfusion‐induced neuronal superoxide production and establish a previously unrecognized mechanism by which hyperglycemia can exacerbate ischemic brain injury. Ann Neurol 2008;64:654–663

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