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...

Background and Purpose-Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) may function as neurotrophic or neuroprotective factors to protect central nervous system (CNS) neurons against a variety of insults, including excitotoxicity. The present study evaluated the pharmacological effects of DHEAS in a reversible spinal cord ischemia model. Methods-DHEAS was administered (50 mg/kg IV) 5 or 30 minutes after the start of occlusion to groups of rabbits exposed to ischemia induced by temporary (15 to 60 minutes) occlusion of the infrarenal aorta. The group P 50 represents the duration of ischemia (in minutes) associated with 50% probability of resultant permanent paraplegia. Results-The P 50 of the vehicle-treated control group, when behavioral analysis was assessed 18 hours after aortal occlusion, was 28.8Ϯ2.0 minutes. Neuroprotection was demonstrated if a drug significantly prolonged the P 50 compared with the vehicle-treated control group. Treatment with DHEAS at 5 minutes significantly (PϽ0.05) prolonged the P 50 of the group to 36.8Ϯ3.9 minutes. In addition, the DHEAS effect appeared durable, because a significant difference between the control and DHEAS-treated groups was still measurable at the 4-day time point. At 4 days, the P 50 of the control group was 26.1Ϯ2.2 minutes, whereas the P 50 for the DHEAS-treated group was 38.6Ϯ5.9 minutes. DHEAS was not neuroprotective if administered 30 minutes after occlusion. In addition, the GABA A antagonist bicuculline abolished the neuroprotective effect of DHEAS. Conclusions-The present study suggests that neurosteroids may have substantial therapeutic benefit for the treatment of ischemic stroke.

Background and Purpose-It has been proposed that spin trap agents such as N-t-butyl-phenylnitrone (PBN) may be useful as neuroprotective agents in the treatment of ischemia and stroke. However, to date, there is little information concerning the effectiveness of spin trap agents when administered in combination with the only Food and Drug Administration-approved pharmacological agent for the treatment of stroke, the thrombolytic tissue plasminogen activator (tPA). Thus, we determined the effects of PBN when administered before tPA on hemorrhage and infarct rate and volume. We also compared the effects of PBN with those of 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), another spin trap agent that has a different chemical structure and trapping profile, on the incidence of infarcts and hemorrhage. Methods-One hundred sixty-five male New Zealand White rabbits were embolized by injecting a blood clot into the middle cerebral artery via a catheter. Five minutes after embolization, PBN or TEMPO (100 mg/kg) was infused intravenously. Control rabbits received saline, the vehicle required to solubilize the spin traps. In tPA studies, rabbits were given intravenous tPA starting 60 minutes after embolization. Postmortem analysis included assessment of hemorrhage, infarct size and location, and clot lysis. Results-In the control group, the hemorrhage rate after a thromboembolic stroke was 24%. The amount of hemorrhage was significantly increased to 77% if the thrombolytic tPA was administered. The rabbits treated with PBN in the absence of tPA had a 91% incidence of hemorrhage compared with 33% for the TEMPO-treated group. In the combination drug-treated groups, the PBN/tPA group had a 44% incidence of hemorrhage, and the TEMPO/tPA group had a 42% incidence of hemorrhage. tPA, PBN/tPA, and TEMPO/tPA were similarly effective at lysing clots (49%, 44%, and 33%, respectively) compared with the 5% rate of lysis in the control group. There was no significant effect of drug combinations on the rate or volume of infarcts. Conclusions-This study suggests that certain spin trap agents may have deleterious effects when administered after an embolic stroke. However, spin trap agents such as PBN or TEMPO, when administered in combination with tPA, may improve the safety of tPA by reducing the incidence of tPA-induced hemorrhage. Overall, the therapeutic benefit of spin trap agents for the treatment of ischemic stroke requires additional scrutiny before they can be considered "safe" therapeutics. Key Words: ischemia Ⅲ neuroprotection Ⅲ nitrogen radicals Ⅲ oxygen radicals Ⅲ reactive oxygen species Ⅲ reperfusion Ⅲ tissue plasminogen activator Ⅲ rabbits W ith the use of tissue plasminogen activator (tPA) for the treatment of thromboembolic stroke, 1-3 there is reason to be concerned that thrombolysis may expose patients to secondary intracerebral hemorrhage (ICH). 4,5 There is an approximately 6% incidence of subsequent symptomatic ICH, and half of these patients die. 4,6,7 Currently, there are no acceptable pharmacological treatments for ...

Hemorrhagic transformation (HT) is a frequent consequence of ischemic stroke that becomes more prevalent after thrombolytic therapy. Despite concerns about safety parameters, thrombolytic drugs remain the first course of action available to clinicians for stroke management. However, recent efforts in preclinical studies have attempted to discover other drugs that can lessen the risk of hemorrhage associated with thrombolytic administration. This review focuses on three classes of pharmacologic agents that have shown some promise in animal models of stroke, and can thus be considered as possible candidates for coadministration with thrombolytics in the treatment of stroke. These include the following: 1) spin trap agents, such as alpha-phenyl-N-t-butylnitrone (PBN) that scavenge free radicals; 2) matrix metalloproteinase (MMP) inhibitors, such as BB-94, that prevent membrane and vessel remodeling following ischemia; and 3) the novel glycoprotein (GP) IIb/IIIa platelet receptor antagonist SM-20302. Although these drugs affect different mechanisms, the common denominator seemed to be their effectiveness in reducing the incidence of hemorrhage in response to thrombolytic infusion following an embolic stroke.

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