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Evaluating therapeutic targets for reperfusion-related brain hemorrhage.
Ann Neurol. 2006 Jun; 59(6):929-38.AN

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+Show Affiliations

Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305-5487, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16673393

Citation

Maier, Carolina M., et al. "Evaluating Therapeutic Targets for Reperfusion-related Brain Hemorrhage." Annals of Neurology, vol. 59, no. 6, 2006, pp. 929-38.
Maier CM, Hsieh L, Crandall T, et al. Evaluating therapeutic targets for reperfusion-related brain hemorrhage. Ann Neurol. 2006;59(6):929-38.
Maier, C. M., Hsieh, L., Crandall, T., Narasimhan, P., & Chan, P. H. (2006). Evaluating therapeutic targets for reperfusion-related brain hemorrhage. Annals of Neurology, 59(6), 929-38.
Maier CM, et al. Evaluating Therapeutic Targets for Reperfusion-related Brain Hemorrhage. Ann Neurol. 2006;59(6):929-38. PubMed PMID: 16673393.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluating therapeutic targets for reperfusion-related brain hemorrhage. AU - Maier,Carolina M, AU - Hsieh,Lily, AU - Crandall,Trisha, AU - Narasimhan,Purnima, AU - Chan,Pak H, PY - 2006/5/5/pubmed PY - 2006/7/15/medline PY - 2006/5/5/entrez SP - 929 EP - 38 JF - Annals of neurology JO - Ann Neurol VL - 59 IS - 6 N2 - 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. SN - 0364-5134 UR - https://www.unboundmedicine.com/medline/citation/16673393/Evaluating_therapeutic_targets_for_reperfusion_related_brain_hemorrhage_ L2 - https://doi.org/10.1002/ana.20850 DB - PRIME DP - Unbound Medicine ER -