Potential conflict of interest: Nothing to report.
Glucose and NADPH oxidase drive neuronal superoxide formation in stroke†
Article first published online: 23 DEC 2008
Copyright © 2008 American Neurological Association
Annals of Neurology
Volume 64, Issue 6, pages 654–663, December 2008
How to Cite
Suh, S. W., Shin, B. S., Ma, H., Van Hoecke, M., Brennan, A. M., Yenari, M. A. and Swanson, R. A. (2008), Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann Neurol., 64: 654–663. doi: 10.1002/ana.21511
- Issue published online: 23 DEC 2008
- Article first published online: 23 DEC 2008
- Manuscript Accepted: 7 AUG 2008
- Manuscript Revised: 23 JUL 2008
- Manuscript Received: 8 MAY 2008
- Juvenile Diabetes Research Foundation. Grant Number: 2-2006-113
- NIH NINDS. Grant Numbers: NS051855, P50 NS14543, NS405I6
- Department of Veterans Affairs Merit Review Program
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 p47phox 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 p47phox 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. Ann Neurol 2008;64:654–663