Evaluating therapeutic targets for reperfusion-related brain hemorrhage.

Abstract

OBJECTIVE:

Early reperfusion after an ischemic stroke can cause blood-brain barrier injury with subsequent cerebral edema and devastating brain hemorrhage. These complications of early reperfusion, which result from excess production of reactive oxygen species, significantly limit the benefits of stroke therapies. In this article, we use a novel animal model that facilitates identification of specific components of the reperfusion injury process, including vascular injury and secondary brain damage, and allows assessment of therapeutic interventions.

METHODS:

Knock-out (KO) mice containing 50% manganese-superoxide dismutase activity (SOD2-KO) and transgenic mice overexpressing SOD2 undergo transient focal ischemia and reperfusion followed by assessment of infarct, edema, hemorrhage rates, metalloproteinase activation, and microvascular injury.

RESULTS:

SOD2-KO mice demonstrate delayed (>24h) blood-brain barrier breakdown associated with activation of matrix metalloproteinases, inflammation, and high brain hemorrhage rates. These adverse consequences are absent in wild-type littermates and minocycline-treated SOD2-KO animals. Increased hemorrhage rates also are absent in SOD2 overexpressors, which have reduced vascular endothelial cell death. Finally, we show that the tight junction membrane protein, occludin, is an early and specific target in oxidative stress-induced microvascular injury.

INTERPRETATION:

This model is ideal for studying ischemia/reperfusion-induced vascular injury and secondary brain hemorrhage and offers a unique opportunity to evaluate antioxidant-based neurovascular protective strategies as potential adjunct treatments to currently approved stroke therapies such as thrombolysis and endovascular clot retrieval.

• Authors: Carolina M Maier, Lily Hsieh, Trisha Crandall, Purnima Narasimhan, Pak H Chan
• Journal: Annals of neurology (Ann Neurol) Vol. 59 Issue 6 Pg. 929-38 (Jun 2006) ISSN: 0364-5134 [Print] United States
• PMID: 16673393 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Ann Neurol 2006.

Chemical References

• Enzyme Inhibitors
• Superoxide Dismutase
• Matrix Metalloproteinase 9
• Minocycline

Topics

• Animals
• Blood-Brain Barrier (pathology)
• Blotting, Western
• Brain (blood supply, pathology, physiopathology)
• Brain Ischemia (complications, pathology, physiopathology)
• Cerebral Hemorrhage (etiology, pathology, physiopathology)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• In Situ Nick-End Labeling
• Matrix Metalloproteinase 9 (drug effects, metabolism)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Minocycline (pharmacology)
• Oxidative Stress (drug effects, physiology)
• Reperfusion Injury (complications, pathology, physiopathology)
• Superoxide Dismutase (genetics, metabolism)