Urokinase, a promising candidate for fibrinolytic therapy for intracerebral hemorrhage

Abstract

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.

Minimally Invasive Surgery for Intracerebral Hematoma Evacuation followed by Rosiglitazone Infusion Therapy Increased Perihematomal Occludin, Zonula Occludens-1 Expression and Decreased the Blood Brain Barrier Permeability in Rabbits

“…Liquid and semisolid hemorrhage was 30-50% of total hematoma volume [36]. In our study, although MIS can effectively reduce liquid and semisolid blood clot,only use of urokinase infusion therapy can dissolve solid blood clot and completely remove the whole blood clot.…”

“…Using RSG could down regulate MMP-9 expression by upregulating PPARγ expression [36]. It is reasonable to hypothesize that performing MIS for hematoma evacuation following ICH with infusion of RSG into the hematoma region could be more effective for treating ICH-induced secondary brain injury.…”

“…It was suggested as a safe and practical technique for the treatment of ICH [8]. Tan Q et al reported that in comparison with tissue-type plasminogen activator, urokinase-type plasminogen activator (uPA) better ameliorated brain edema and promoted an improved outcome after ICH, uPA therapy more effectively upregulated BBB tight junction protein expression [36].…”

In-Vitro Study of Urokinase Thrombolysis Following Stereotactic Aspiration of Intracerebral Hematoma

“…Spontaneous intracerebral hemorrhage (SICH) is one of the most devastating types of stroke. It represents a significant cause of mortality and morbidity 18) . Stereotactic aspiration and subsequent thrombolysis have been considered a less invasive and more effective treatment modality for spontaneous intracerebral hematoma, especially deep-seated hematoma 13,17) .…”

“…So far, t-PA has been the most widely used fibrinolytic agent for SICH thrombolysis 8,9,14,18,21) . The first use of t-PA to lyse remnant SICH after stereotactic aspiration was in 1994 by the Gilsbach group 15) .…”