Matrix Metalloproteinases and Tissue Plasminogen Activator Reperfusion Therapy for Stroke
Reperfusion therapy with intravenous tissue plasminogen activator (t‐PA) is the only FDA‐approved Medical therapy for acute ischemic stroke. Properly titrated use of t‐PA improves clinical outcomes. However, the near tenfold‐associated risk of intracerebr
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Matrix Metalloproteinases and Tissue Plasminogen Activator Reperfusion Therapy for Stroke
M. M. Ning . J. Montaner . X. Wang . S.‐R. Lee . K. Tsuji . E. Tejima . A. M. Buchan . E. H. Lo
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
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t‐PA Trials in Acute Stroke: Clinical Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
3 Mechanisms of t‐PA‐Related Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 3.1 How Does t‐PA Work? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 3.2 Animal Studies of t‐PA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 4 4.1 4.2 4.3
The Neurovascular Unit and the t‐PA–MMP Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 The Concept of the Neurovascular Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 What are MMPs? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 MMP and t‐PA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
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Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
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Springer-Verlag Berlin Heidelberg 2007
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Matrix metalloproteinases and tissue plasminogen activator reperfusion therapy for stroke
Abstract: Reperfusion therapy with intravenous tissue plasminogen activator (t‐PA) is the only FDA‐ approved Medical therapy for acute ischemic stroke. Properly titrated use of t‐PA improves clinical outcomes. However, the near tenfold‐associated risk of intracerebral hemorrhage after t‐PA may keep this therapy from many acute stroke patients. Emerging data now suggest that some of the potentially neurotoxic side effects of t‐PA may be due to its signaling actions in the neurovascular unit. Besides its intended role in clot lysis, t‐PA is also an extracellular protease and signaling molecule in the brain. t‐PA mediates matrix remodeling during brain development and plasticity. By interacting with the NMDA‐type glutamate receptor, t‐PA may amplify potentially excitotoxic calcium currents. At selected concentrations, t‐PA may be vasoactive. Finally, by augmenting matrix metalloproteinase (MMP) dysregulation after stroke, t‐PA may degrade extracellular matrix integrity
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