Abstract | BACKGROUND AND PURPOSE: 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.
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Authors | P A Lapchak, D F Chapman, J A Zivin |
Journal | Stroke
(Stroke)
Vol. 31
Issue 12
Pg. 3034-40
(Dec 2000)
ISSN: 1524-4628 [Electronic] United States |
PMID | 11108768
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Fibrinolytic Agents
- Protease Inhibitors
- Thiophenes
- Phenylalanine
- batimastat
- Tissue Plasminogen Activator
- Metalloendopeptidases
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Topics |
- Animals
- Cerebral Hemorrhage
(chemically induced, prevention & control)
- Disease Models, Animal
- Fibrinolytic Agents
(adverse effects, therapeutic use)
- Humans
- Intracranial Embolism
(drug therapy)
- Metalloendopeptidases
(antagonists & inhibitors)
- Phenylalanine
(analogs & derivatives, therapeutic use)
- Protease Inhibitors
(therapeutic use)
- Rabbits
- Stroke
(chemically induced, drug therapy)
- Thiophenes
(therapeutic use)
- Thromboembolism
(drug therapy)
- Tissue Plasminogen Activator
(adverse effects, therapeutic use)
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