Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats.

Abstract

BACKGROUND AND PURPOSE:

Thrombolytic therapy with tissue plasminogen activator (tPA) for acute ischemic stroke remains complicated by risks of hemorrhagic transformation. In this study we used a previously established quantitative rat model of tPA-associated hemorrhage to test the hypothesis that matrix metalloproteinases (MMPs) are involved.

METHODS:

Spontaneously hypertensive rats were subjected to embolic focal ischemia by placing homologous blood clots into the middle cerebral artery. Three groups of rats were studied: (1) untreated controls that received saline at 6 hours after ischemia; (2) rats that received tPA alone (10 mg/kg at 6 hours after ischemia); and (3) rats that received tPA plus the broad-spectrum MMP inhibitor BB-94 (50 mg/kg of BB-94 before ischemia and at 3 and 6 hours after ischemia plus tPA at 6 hours). Gelatin zymography was used to quantify MMP levels. A hemoglobin spectrophotometry method was used to quantify cerebral hemorrhage. Ischemic lesions were measured at 24 hours with tetrazolium staining.

RESULTS:

At 6, 12, and 24 hours, pro-MMP-9 and cleaved MMP-9 were upregulated in ischemic brain. At 12 hours, tPA-treated rats showed significantly higher levels of pro-MMP-9 and cleaved MMP-9 than untreated controls. By 24 hours, all rats showed evidence of hemorrhagic transformation in the ischemic territory. Rats treated with BB-94 and tPA showed significantly reduced hemorrhage volumes compared with those that received tPA alone. There was no effect on infarct size.

CONCLUSIONS:

These results indicate that (1) tPA treatment increases levels of MMP-9 after embolic focal cerebral ischemia, (2) MMPs are involved in the mechanism of tPA-associated hemorrhage, and (3) combination therapies with MMP inhibitors may be useful for decreasing the risk and severity of this dreaded complication of thrombolytic therapy.

• Authors: Toshihisa Sumii, Eng H Lo
• Journal: Stroke (Stroke) Vol. 33 Issue 3 Pg. 831-6 (Mar 2002) ISSN: 1524-4628 [Electronic] United States
• PMID: 11872911 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Matrix Metalloproteinase Inhibitors
• Sodium, Dietary
• Thiophenes
• Phenylalanine
• batimastat
• Tissue Plasminogen Activator
• Matrix Metalloproteinases
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Animals
• Blood Flow Velocity (drug effects)
• Brain (drug effects, enzymology, pathology)
• Brain Ischemia (etiology, physiopathology)
• Cerebral Hemorrhage (etiology, physiopathology)
• Cerebrovascular Circulation (drug effects)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Intracranial Embolism (complications, drug therapy, physiopathology)
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinases (metabolism)
• Phenylalanine (analogs & derivatives, pharmacology)
• Rats
• Rats, Inbred SHR
• Sodium, Dietary
• Survival Rate
• Thiophenes (pharmacology)
• Thrombolytic Therapy (adverse effects)
• Tissue Plasminogen Activator (adverse effects)