期刊
CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS
卷 7, 期 3, 页码 235-242出版社
BENTHAM SCIENCE PUBL
DOI: 10.2174/187152708784936635
关键词
tPA; extracellular protease; matrix metalloproteinases; extracellular proteolysis; blood-brain barrier; intracerebral hemorrhage; combination therapy
资金
- American Heart Association [0435087N]
- National Institute of Health [R01-NS049476, R01-NS37074, R01NS48422, R01-NS53560, P50-NS10828]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS048422, P50NS010828, R01NS049476, R01NS053560, R01NS037074] Funding Source: NIH RePORTER
To date, tPA-based thrombolytic therapy is the only FDA-approved treatment for achieving vascular reperfusion and clinical benefit, but this agent is given to only about 2-5% of stroke patients in the United States of America. This may be related, in part, to the elevated risks of symptomatic intracranial hemorrhage, and the consequently reduced therapeutic time window. Recent efforts have aimed at identifying new combination strategies that might increase thrombolytic efficacy of tPA to benefit reperfusion, while reducing its associated neurotoxicity and hemorrhagic complications. Emerging experimental studies demonstrate that the breakdown of neurovascular matrix initiates blood-brain barrier disruption with edema and/or hemorrhage. Perturbation of extracellular homeostasis triggered by dysregulated extracellular proteases may underlie processes responsible for the hemorrhagic complications of thrombolytic stroke therapy. This short review summarizes experimental investigations of this field in pre-clinical stroke models. The data strongly suggest that targeting the extracellular matrix proteolytic imbalance within the neurovascular unit may provide new approaches for improving the safety and efficacy of thrombolytic reperfusion therapy of stroke.
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