Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke

Background and Purpose-A potentially dangerous side effect associated with tissue plasminogen activator (tPA) use is cerebral hemorrhage. We have focu sed on developing drugs that could be administered with tPA to reduce the r ate of hemorrhage. Since recent studies suggest that various matrix metallo proteinases (MMPs) are important in tumor necrosis factor-alpha production and membrane and vessel remodeling after ischemia, we investigated whether MMP inhibition affected the rate of hemorrhage and infarct production in th e 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 adminis tered either the MMP inhibitor BE-94 (30 mg/kg SC) or its vehicle. Addition al groups received BE-94 or vehicle in combination with tPA, administered 6 0 minutes after embolization (3.3 mg/kg tPA). After 48 hours, the rabbits w ere killed and brains were removed, immersion fixed for 1 week in 4% parafo rmaldehyde, 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-tre ated group. The rabbits treated with BE-94 had an 18% incidence of hemorrha ge (P>0.05 compared with control). However, when the combination of BE-94 a nd tPA was administered to rabbits, there was only a 41% incidence of hemor rhage (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), respecti vely, 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 stat istical significance. Conclusions-Our data suggest that MMP inhibition attenuates mechanisms invo lved in tPA-induced hemorrhage. This novel form of combination therapy may show promise as a treatment strategy for acute stroke.