期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 30, 期 6, 页码 1137-1146出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2009.279
关键词
annexin A2; cerebral ischemia; combination therapy; thrombolysis; tPA
资金
- American Heart Association [0435087N]
- National Institute of Health [R01-NS049476, R01-HL042493, P01-046403, R01-NS37074, R01-NS48422, R01-NS53560, P50-NS10828]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL090895, R01HL042493] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS065998, R01NS053560, R01NS049476, P50NS010828, R01NS037074, R01NS048422] Funding Source: NIH RePORTER
Recent studies showed that soluble annexin A2 dramatically increases tissue plasminogen activator (tPA)-mediated plasmin generation in vitro, and reduces thrombus formation in vivo. Here, we hypothesize that combining annexin A2 with tPA can significantly enhance thrombolysis efficacy, so that lower doses of tPA can be applied in ischemic stroke to avoid neurotoxic and hemorrhagic complications. In vitro activity assays confirmed tPA-specific amplification of plasmin generation by recombinant annexin A2. In a rat focal embolic stroke model, combination therapy with tPA and recombinant annexin A2 protein at 2 h post-ischemia decreased the effective dose required for tPA by four-fold and reduced brain infarction. Combining annexin A2 with tPA also lengthened the time window for thrombolysis. Compared with tPA (10 mg/kg) alone, the combination of annexin A2 (5 mg/kg) plus low-dose tPA (2.5 mg/kg) significantly enhanced fibrinolysis, attenuated mortality, brain infarction, and hemorrhagic transformation, even when administered at 4 h post-ischemia. Combination with recombinant annexin A2, the effective thrombolytic dose of tPA can be decreased. As a result, brain hemorrhage and infarction are reduced, and the time window for stroke reperfusion prolonged. Our present findings provide a promising new approach for enhancing tPA-based thrombolytic stroke therapy. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1137-1146; doi: 10.1038/jcbfm.2009.279; published online 13 January 2010
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