Michael K Schuhmann1, Michael Bieber1, Maximilian Franke1, Alexander M Kollikowski2, David Stegner3,4, Katrin G Heinze3, Bernhard Nieswandt3,4, Mirko Pham2, Guido Stoll5. 1. Department of Neurology, University Hospital Würzburg, Würzburg, Germany. 2. Department of Neuroradiology, University Hospital Würzburg, Würzburg, Germany. 3. Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany. 4. Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany. 5. Department of Neurology, University Hospital Würzburg, Würzburg, Germany. stoll_g@ukw.de.
Abstract
BACKGROUND: In acute ischemic stroke, cessation of blood flow causes immediate tissue necrosis within the center of the ischemic brain region accompanied by functional failure in the surrounding brain tissue designated the penumbra. The penumbra can be salvaged by timely thrombolysis/thrombectomy, the only available acute stroke treatment to date, but is progressively destroyed by the expansion of infarction. The underlying mechanisms of progressive infarction are not fully understood. METHODS: To address mechanisms, mice underwent filament occlusion of the middle cerebral artery (MCAO) for up to 4 h. Infarct development was compared between mice treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab) or rat immunoglobulin G (IgG) Fab as control treatment. Moreover, Rag1-/- mice lacking T-cells underwent the same procedures. Infarct volumes as well as the local inflammatory response were determined during vessel occlusion. RESULTS: We show that blocking of the platelet adhesion receptor, glycoprotein (GP) Ibα in mice, delays cerebral infarct progression already during occlusion and thus before recanalization/reperfusion. This therapeutic effect was accompanied by decreased T-cell infiltration, particularly at the infarct border zone, which during occlusion is supplied by collateral blood flow. Accordingly, mice lacking T-cells were likewise protected from infarct progression under occlusion. CONCLUSIONS: Progressive brain infarction can be delayed by blocking detrimental lymphocyte/platelet responses already during occlusion paving the way for ultra-early treatment strategies in hyper-acute stroke before recanalization.
BACKGROUND: In acute ischemic stroke, cessation of blood flow causes immediate tissue necrosis within the center of the ischemic brain region accompanied by functional failure in the surrounding brain tissue designated the penumbra. The penumbra can be salvaged by timely thrombolysis/thrombectomy, the only available acute stroke treatment to date, but is progressively destroyed by the expansion of infarction. The underlying mechanisms of progressive infarction are not fully understood. METHODS: To address mechanisms, mice underwent filament occlusion of the middle cerebral artery (MCAO) for up to 4 h. Infarct development was compared between mice treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab) or rat immunoglobulin G (IgG) Fab as control treatment. Moreover, Rag1-/- mice lacking T-cells underwent the same procedures. Infarct volumes as well as the local inflammatory response were determined during vessel occlusion. RESULTS: We show that blocking of the platelet adhesion receptor, glycoprotein (GP) Ibα in mice, delays cerebral infarct progression already during occlusion and thus before recanalization/reperfusion. This therapeutic effect was accompanied by decreased T-cell infiltration, particularly at the infarct border zone, which during occlusion is supplied by collateral blood flow. Accordingly, mice lacking T-cells were likewise protected from infarct progression under occlusion. CONCLUSIONS: Progressive brain infarction can be delayed by blocking detrimental lymphocyte/platelet responses already during occlusion paving the way for ultra-early treatment strategies in hyper-acute stroke before recanalization.
Authors: J M Hallenbeck; A J Dutka; T Tanishima; P M Kochanek; K K Kumaroo; C B Thompson; T P Obrenovitch; T J Contreras Journal: Stroke Date: 1986 Mar-Apr Impact factor: 7.914
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Authors: Axel Haarmann; Lena Zimmermann; Michael Bieber; Christine Silwedel; Guido Stoll; Michael K Schuhmann Journal: Int J Mol Sci Date: 2022-06-25 Impact factor: 6.208
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Authors: Guido Stoll; Michael K Schuhmann; Bernhard Nieswandt; Alexander M Kollikowski; Mirko Pham Journal: J Cereb Blood Flow Metab Date: 2022-06-08 Impact factor: 6.960
Authors: Lena Zimmermann; Mirko Pham; Alexander G März; Alexander M Kollikowski; Guido Stoll; Michael K Schuhmann Journal: J Cereb Blood Flow Metab Date: 2022-02-02 Impact factor: 6.960