(Stroke. 2000;31:3034.)
© 2000 American Heart Association, Inc.
Original Contributions |
Metalloproteinase Inhibition Reduces Thrombolytic (Tissue Plasminogen Activator)–Induced Hemorrhage After Thromboembolic Stroke
From the Department of Neuroscience, University of California at San Diego, La Jolla.
Correspondence to Dr Paul A. Lapchak, Department of Neuroscience, University of California at San Diego, MTF 316, 9500 Gilman Dr, La Jolla, CA 92093-0624. E-mail plapchak{at}ucsd.edu
Background
and Purpose—A potentially dangerous
side effect associated with tissue plasminogen
activator (tPA) use is cerebral hemorrhage. We have
focused on developing drugs that could be administered with tPA to
reduce the rate of hemorrhage. Since recent studies suggest
that various matrix metalloproteinases (MMPs) are important in
tumor necrosis factor-
production and membrane and vessel
remodeling after ischemia, we investigated whether MMP
inhibition affected the rate of hemorrhage and infarct
production in the absence or presence of tPA
treatment.
Methods—We occluded the middle cerebral artery of New Zealand White rabbits with radiolabeled blood clots. Five minutes after embolization, we administered either the MMP inhibitor BB-94 (30 mg/kg SC) or its vehicle. Additional groups received BB-94 or vehicle in combination with tPA, administered 60 minutes after embolization (3.3 mg/kg tPA). After 48 hours, the rabbits were killed and brains were removed, immersion fixed for 1 week in 4% paraformaldehyde, and then cut into 5-mm coronal sections that were examined for the presence of hemorrhage, infarcts, and recanalization.
Results—Hemorrhage after embolic stroke was detected in 24% of the control group. tPA induced macroscopically visible hemorrhage in 77% of the tPA-treated group. The rabbits treated with BB-94 had an 18% incidence of hemorrhage (P>0.05 compared with control). However, when the combination of BB-94 and tPA was administered to rabbits, there was only a 41% incidence of hemorrhage (compared with 77% in the tPA group; P<0.05). Both tPA and BB-94/tPA were similarly effective at lysing clots, at 49% and 35% (P<0.05), respectively, compared with the 5% rate of lysis in the control group. There was a trend for a reduction in the number of infarcts, but it did not reach statistical significance.
Conclusions—Our data suggest that MMP inhibition attenuates mechanisms involved in tPA-induced hemorrhage. This novel form of combination therapy may show promise as a treatment strategy for acute stroke.
Editorial Comment
Department of Neurology Washington University School of Medicine St Louis, Missouri
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