Version of Record online: 14 OCT 2011
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 70, Issue 4, pages 583–590, October 2011
How to Cite
Won, S. J., Tang, X. N., Suh, S. W., Yenari, M. A. and Swanson, R. A. (2011), Hyperglycemia promotes tissue plasminogen activator-induced hemorrhage by Increasing superoxide production. Ann Neurol., 70: 583–590. doi: 10.1002/ana.22538
S.J.W. and X.N.T. contributed equally to this work.
Potential Conflicts of Interest
Nothing to report.
- Issue online: 25 OCT 2011
- Version of Record online: 14 OCT 2011
- Accepted manuscript online: 11 JUL 2011 12:52PM EST
- Manuscript Accepted: 24 JUN 2011
- Manuscript Revised: 13 JUN 2011
- Manuscript Received: 24 OCT 2010
Risk of intracerebral hemorrhage is the primary factor limiting use of tissue plasminogen activator (tPA) for stroke. Clinical studies have established an association between admission hyperglycemia and the risk of hemorrhage with tPA use, independent of prior diabetes. Here we used an animal model of tPA-induced reperfusion hemorrhage to determine if this clinical association reflects a true causal relationship.
Rats underwent 90 minutes of focal ischemia, and tPA infusion was begun 10 minutes prior to vessel reperfusion. Glucose was administered during ischemia to generate blood levels ranging from 5.9 ± 1.8mM (normoglycemia) to 21 ± 2.3mM. In some studies, apocynin was administered to block superoxide production by nicotinamide adenine dinucleotide phosphate (NADPH). Brains were harvested 1 hour or 3 days after reperfusion to evaluate the effects of hyperglycemia and apocynin on oxidative stress, blood–brain barrier breakdown, infarct volume, and hemorrhage volume.
Rats that were hyperglycemic during tPA infusion had diffusely increased blood–brain barrier permeability in the postischemic territory, and a 3- to 5-fold increase in intracerebral hemorrhage volumes. The hyperglycemic rats also showed increased superoxide formation in the brain parenchyma and vasculature during reperfusion. The effects of hyperglycemia on superoxide production, blood–brain barrier disruption, infarct size, and hemorrhage were all attenuated by apocynin.
These findings demonstrate a causal relationship between hyperglycemia and hemorrhage in an animal model of tPA stroke treatment, and suggest that this effect of hyperglycemia is mediated through an increase in superoxide production by NADPH oxidase. ANN NEUROL 2011