Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke.
OBJECTIVE
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-alpha 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.
Lapchak
P A
PA
Department of Neuroscience, University of California at San Diego, La Jolla 92093-0624, USA. plapchak@ucsd.edu
Chapman
D F
DF
Zivin
J A
JA
D000818:Animals; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000517:prevention & control*; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D020766:Intracranial Embolism / Q000188:drug therapy; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011817:Rabbits; D020521:Stroke / Q000139:chemically induced / Q000188:drug therapy*; D013876:Thiophenes / Q000627:therapeutic use*; D013923:Thromboembolism / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000627:therapeutic use
D005343:Fibrinolytic Agents; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D010959:Tissue Plasminogen Activator; D008666:Metalloendopeptidases