Metalloproteinase Inhibition Reduces Thrombolytic (Tissue Plasminogen Activator)–Induced Hemorrhage After Thromboembolic Stroke

Abstract

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 (PϾ0.05 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; PϽ0.05). Both tPA and BB-94/tPA were similarly effective at lysing clots, at 49% and 35% (PϽ0.05), 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. (Stroke. 2000;31:3034-3040.)Key Words: cytokines Ⅲ intracerebral hemorrhage Ⅲ ischemia Ⅲ matrix metalloproteinases Ⅲ membranes Ⅲ neuroprotection Ⅲ tumor necrosis factor T hrombolysis is now gaining increasing acceptance for acute stroke management; however, only a small subset of potentially eligible patients are being treated with tissue plasminogen activator (tPA). 1-3 Overall, tPA is quite beneficial, even though there is a small window of opportunity for treatment and a potentially dangerous side effect of hemorrhages. 2,4 -6 A series of trials have shown that thrombolytics alone have limited efficacy, 7 suggesting that additional treatment strategies are needed. Nevertheless, the finding that at least one acute therapy is effective in reducing neurological damage was an important proof of concept. Even though tPA is efficacious, there is one major shortcoming to the drug. tPA significantly increases the intracerebral hemorrhage (ICH) rate in patients approximately 10 times greater than that observed in...

Matrix metalloproteinases in neuroinflammation

“…Studies in nonhuman primates have shown that the levels of MMP-9 were associated with hemorrhagic transformation, while MMP-2 correlated with neuronal injury (Heo et al, 1999). A recent study showed that hemorrhagic infarctions, induced in rabbits by the injection of autologous blood clots into the carotid, were reduced by treatment with the MMP inhibitor, Batimistat (BB-94) (Lapchak et al, 2000).…”

“…Treatments in several animal models of neurological diseases have produced encouraging results. These include intracerebral hemorrhage, experimental allergic neuritis, delayed hypersensitivity, and bacterial meningitis (Rosenberg and Navratil, 1997;Hughes et al, 1998;Lapchak et al, 2000;Leib et al, 2001).…”

A Highly Specific Inhibitor of Matrix Metalloproteinase-9 Rescues Laminin from Proteolysis and Neurons from Apoptosis in Transient Focal Cerebral Ischemia

“…In the past, efforts to ameliorate MMP-mediated brain damage with broad-spectrum MMP inhibitors (like sulfonamide or hydroxamate derivatives) have produced promising results in animal models of stroke (Asahi et al, 2000;Lapchak et al, 2000). However, the low specificity, and thus systemic toxicity, of hydroxamates and sulfonamides have precluded the use of these broad-spectrum inhibitors in clinical studies (Coussens et al, 2002;Overall and Lopez-Otin, 2002).…”

MMP-9 Deficiency Enhances Collagenase-Induced Intracerebral Hemorrhage and Brain Injury in Mutant Mice

“…MMPs are also involved in the hemorrhagic transformation after cerebral ischemia, especially after thrombolysis (Hosomi et al, 2001;Montaner et al, 2003;Sumii and Lo 2002). Hemorrhagic transformation is closely related to levels of plasma MMP-9 (Castellanos et al, 2003), and MMP inhibitors can reduce hemorrhage after thromboembolic stroke (Lapchak et al, 2000). MMPs are further associated with derangement of blood-brain barrier (Rosenberg et al, 1998), and MMP inhibition reduces brain edema after ICH (Rosenberg and Navratil, 1997).…”