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 and increase risks of neurovascular cell death, blood-brain barrier leakage, edema, and hemorrhage. Understanding these pleiotropic actions of t-PA may reveal new therapeutic opportunities for increasing the safety and efficacy of reperfusion strategies for stroke therapy. © 2007 Springer-Verlag US.