Article

Glucose and NADPH oxidase drive neuronal superoxide formation in stroke.

Department of Neurology, University of California, San Francisco, CA, USA.
Annals of Neurology (impact factor: 11.09). 01/2009; 64(6):654-63. DOI:10.1002/ana.21511 pp.654-63
Source: PubMed

ABSTRACT 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.
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.
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.
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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Keywords

blood glucose concentrations
 
cell death
 
cultured neurons
 
deleterious effects
 
ethidium method
 
exacerbating factor
 
forebrain ischemia-reperfusion
 
glucose antimetabolite 2-deoxyglucose
 
hexose monophosphate
 
Inactivating NADPH oxidase
 
ischemic brain injury
 
ischemic stroke
 
neuronal death
 
neuronal nicotinamide adenine dinucleotide phosphate
 
neuronal superoxide production
 
oxygen-glucose deprivation
 
pharmacological inhibitor apocynin
 
postischemic superoxide production
 
reperfusion-induced neuronal superoxide production
 
requisite electron donor
 

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