Urokinase, a promising candidate for fibrinolytic therapy for intracerebral hemorrhage

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OBJECTIVE

Intracerebral hemorrhage (ICH) is associated with a high rate of mortality and severe disability, while fibrinolysis for ICH evacuation is a possible treatment. However, reported adverse effects can counteract the benefits of fibrinolysis and limit the use of tissue-type plasminogen activator (tPA). Identifying appropriate fibrinolytics is still needed. Therefore, the authors here compared the use of urokinase-type plasminogen activator (uPA), an alternate thrombolytic, with that of tPA in a preclinical study.

METHODS

Intracerebral hemorrhage was induced in adult male Sprague-Dawley rats by injecting autologous blood into the caudate, followed by intraclot fibrinolysis without drainage. Rats were randomized to receive uPA, tPA, or saline within the clot. Hematoma and perihematomal edema, brain water content, Evans blue fluorescence and neurological scores, matrix metalloproteinases (MMPs), MMP mRNA, blood-brain barrier (BBB) tight junction proteins, and nuclear factor–κB (NF-κB) activation were measured to evaluate the effects of these 2 drugs in ICH.

RESULTS

In comparison with tPA, uPA better ameliorated brain edema and promoted an improved outcome after ICH. In addition, uPA therapy more effectively upregulated BBB tight junction protein expression, which was partly attributed to the different effects of uPA and tPA on the regulation of MMPs and its related mRNA expression following ICH.

CONCLUSIONS

This study provided evidence supporting the use of uPA for fibrinolytic therapy after ICH. Large animal experiments and clinical trials are required to further explore the efficacy and safety of uPA in ICH fibrinolysis.

ABBREVIATIONSBBB = blood-brain barrier; EB = Evans blue; GAPDH = glyceraldehyde 3-phosphate dehydrogenase; ICH = intracerebral hemorrhage; IVH = intraventricular hemorrhage; MISTIE = minimally invasive surgery plus rtPA for ICH evacuation; MMP = matrix metalloproteinase; NF-κB = nuclear factor–κB; PHE = perihematomal edema; RBC = red blood cell; RT-PCR = real-time polymerase chain reaction; tPA = tissue-type plasminogen activator; uPA = urokinase-type plasminogen activator; vWF = von Willebrand factor.
Article Information

Contributor Notes

Drs. Tan and Q. Chen contributed equally to this work

INCLUDE WHEN CITING Published online April 22, 2016; DOI: 10.3171/2016.1.JNS152287.Correspondence Zhi Chen, Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan St., Chongqing, 400038, The People's Republic of China. email: zhichen@tmmu.edu.cn.
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