期刊
ANNALS OF NEUROLOGY
卷 64, 期 6, 页码 654-663出版社
WILEY
DOI: 10.1002/ana.21511
关键词
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资金
- Juvenile Diabetes Research Foundation [2-2006-113]
- NIH NINDS [NS051855, P50 NS14543, NS40516]
- Department ol Veterans Affairs Merit Review Program
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.
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