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22. European Stroke Conference 14 Experimental studies B 17:10 - 17:20 Urokinase versus rtPA for intraventricular hemorrhage fibrinolysis T. Gaberel1, A. Montagne2, F. Lesept3, M. Gauberti4, C. Orset5, E. Emery6, D. Vivien7 Department of Neurosurgery, Caen University Hospital,, Caen, FRANCE1,INSERM, U919, serine protease and pathophysiology of the neurovascular unit, SP2U, GIP Cyceron, Uni-versity Caen Lower Normandy, Caen, FRANCE2, INSERM, U919, serine protease and patho-physiology of the neurovascular unit, SP2U, GIP Cyceron, University Caen Lower Normandy, Caen, FRANCE3, INSERM, U919, serine protease and pathophysiology of the neurovascular unit, SP2U, GIP Cyceron, University Caen Lower Normandy, Caen, FRANCE4, INSERM, U919, serine protease and pathophysiology of the neurovascular unit, SP2U, GIP Cyceron, Uni-versity Caen Lower Normandy, Caen, FRANCE5, Department of Neurosurgery, Caen Univer-sity Hospital,, Caen, FRANCE6, INSERM, U919, serine protease and pathophysiology of the neurovascular unit, SP2U, GIP Cyceron, University Caen Lower Normandy, Caen, FRANCE7 Background Intraventricular hemorrhage (IVH) is the most severe form of stroke. Intraventricular fibri-nolysis (IVF) is an hopeful treatment of IVH. Either urokinase (uPA) or recombinant tissue plasminogen activator (rtPA) could be used for IVF in human. No study to date evaluated the differential impact of these two fibrinolytic agents when used for IVF. Our aim was to compare the impacts of uPA and rtPA, both in vitro and in an original rat model of IVH. Methods For the in vitro studies, neuronal cultured were subjected to a paradigm of excitotoxicty either alone or in combination with rtPA or uPA. For animal studies, IVH was induced by collagenase injection within the right striatum. A ventricular catheter was inserted into the lateral ventricle. Rats were then randomized to receive intraventricular injection of either uPA, rtPA or saline. Functional evaluation, hematoma volume, ventricular volume, brain edema and histological ex-amination were performed at day three post treatments. Results In vitro, although rtPA increased excitotoxicity in a dose dependant manner, uPA did not. In rats, injection of 0.5 IU of collagenase led to reproducible IVH. In this model, both uPA- and rtPA-mediated IVF failed to influence hematoma volumes, but led to reduced ventricular vol-umes. Compared to rtPA, uPA allows to decrease intraventricular and peri-hematomal inflam-mation. These observations were associated with a better functional outcome for the uPA-treat-ed animals when compared with saline or rtPA. Conclusions Urokinase, unlike rtPA, did not promote inflammation and excitotoxicity, leading to better func-tional outcomes in a rat model of IVH. A clinical trial to evaluate the respective efficiency of rtPA and urokinase in human IVH is warranted. 13 Experimental studies B 17:00 - 17:10 FTY720 ameliorates ischemic neurodegeneration by direct axon protection and reduction of microvascular dysfunction P. Kraft1, E. Göb2, K. Göbel3, S.G. Meuth4, W. Pfeilschifter5, C. Kleinschnitz6 University of Wuerzburg, Wuerzburg, GERMANY1,University of Wuerzburg, Wuerzburg, GERMANY2, University of Muenster, Muenster, GERMANY3, University of Muenster, Muen-ster, GERMANY4, University of Frankfurt, Frankfurt, GERMANY5, University of Wuerzburg, Wuerzburg, GERMANY6 Background: Lymphocytes are critically involved in stroke development. FTY720 blocks the egress of lymphocytes from lymphoid organs. It has been shown that FTY720 reduces stroke size and improves neurological outcome in models of stroke but the underlying mechanisms are incompletely understood. We investigated the modes of FTY720 action in a mouse model of ischemic stroke. Methods: 60 and 90 min transient middle cerebral artery occlusion (tMCAO) was induced in C57Bl/6 mice treated with FTY720 (1 μg/g) or vehicle i.p. immediately before reperfusion. 24h later infarct volumes were calculated from TTC-stained brain sections and functional scores were assessed. Immune cell counts in the blood and brain were determined by flow cytometry. The integrity of the blood-brain-barrier (BBB) was evaluated using the vascular tracer Evans Blue (EB) and the expression of tight junction proteins was assessed by Western Blot. Patency of cerebral microvessels and axonal damage were analyzed using immunohistochemistry. Results: FTY720 treatment caused a rapid reduction in peripheral lymphocyte counts (p<0.01). In addition, FTY720 significantly reduced stroke size (p<0.05) and improved neurological out-come (p<0.05) 24h after MCAO. SMI32 staining showed that FTY720 directly protects neu-rons from axonal damage (p<0.05). Moreover, FTY720 treatment reduced the accumulation of fibrin(ogen), i.e. thrombus formation, in the ischemic cortex (p<0.01) and enhanced the patency of the cerebral microvasculature (p<0.01). In contrast, the invasion of immune cells into the brain was unchanged following FTY720 application and there was no effect on BBB function. Conclusion: FTY720 attenuates acute ischemic stroke in mice by a direct axon-protective mechanism and by reducing microvascular dysfunction. This dual mode of action renders FTY720 an interesting compound in stroke prevention and therapy. Further mechanistic studies are ongoing. 80 © 2013 S. Karger AG, Basel Scientific Programme


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