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Acid sphingomyelinase deactivation post-ischemia/ reperfusion promotes cerebral angiogenesis and brain remodeling via small extracellular vesicles
A Mohamud Yusuf, N Hagemann, X Zhang, M Zafar, T Hussner, C Bromkamp, C Martiny, T Tertel, V Börger, F Schumacher, FA Solari, M Hasenberg, View ORCID ProfileC Kleinschnitz, TR Doeppner, B Kleuser, A Sickmann, M Gunzer, B Giebel, R Kolesnick, E Gulbins, DM Hermann
doi: https://doi.org/10.1101/2021.03.01.433387
A Mohamud Yusuf
1Department of Neurology, University Hospital Essen, Essen, Germany
2Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
N Hagemann
1Department of Neurology, University Hospital Essen, Essen, Germany
2Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
X Zhang
1Department of Neurology, University Hospital Essen, Essen, Germany
2Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
M Zafar
1Department of Neurology, University Hospital Essen, Essen, Germany
2Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
T Hussner
1Department of Neurology, University Hospital Essen, Essen, Germany
2Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
C Bromkamp
1Department of Neurology, University Hospital Essen, Essen, Germany
2Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
C Martiny
1Department of Neurology, University Hospital Essen, Essen, Germany
2Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
T Tertel
3Institute of Transfusion Medicine, University Hospital Essen, Essen, Germany
V Börger
3Institute of Transfusion Medicine, University Hospital Essen, Essen, Germany
F Schumacher
4Institute of Molecular Biology, University Hospital Essen, Essen, Germany
5Department of Toxicology, University of Potsdam, Nuthetal, Germany
6Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany
FA Solari
7Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany
M Hasenberg
8Institute of Immunology and Experimental Imaging, University Hospital Essen, Essen, Germany
C Kleinschnitz
1Department of Neurology, University Hospital Essen, Essen, Germany
2Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
TR Doeppner
1Department of Neurology, University Hospital Essen, Essen, Germany
2Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
9Department of Neurology, University Medicine Göttingen, Göttingen, Germany
B Kleuser
5Department of Toxicology, University of Potsdam, Nuthetal, Germany
A Sickmann
7Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany
10Medizinisches Proteom-Center (MPC), Ruhr University, Bochum, Germany
11Department of Chemistry, College of Physical Sciences, University of Aberdeen, Aberdeen, Scotland, U.K.
M Gunzer
7Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany
8Institute of Immunology and Experimental Imaging, University Hospital Essen, Essen, Germany
B Giebel
3Institute of Transfusion Medicine, University Hospital Essen, Essen, Germany
R Kolesnick
12Memorial Sloan Kettering Cancer Center, New York, New York, U.S.A.
E Gulbins
4Institute of Molecular Biology, University Hospital Essen, Essen, Germany
DM Hermann
1Department of Neurology, University Hospital Essen, Essen, Germany
2Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
Abstract
Functional inhibitors of acid sphingomyelinase are clinically used as anti-depressants since ∼60 years. Here, we show that acid sphingomyelinase inhibition by the antidepressants amitriptyline, fluoxetine and desipramine protects from ischemia/reperfusion and elicits a profound brain remodeling response with increased angiogenesis, improved blood-brain barrier integrity, reduced brain leukocyte infiltration and increased neuronal survival. Angiogenesis is promoted by small extracellular vesicles with bona fide characteristics of exosomes, which are released from endothelial cells and which constitute an elegant target for the amplification of stroke recovery.
Competing Interest Statement
The authors have declared no competing interest.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Posted March 02, 2021.
Acid sphingomyelinase deactivation post-ischemia/ reperfusion promotes cerebral angiogenesis and brain remodeling via small extracellular vesicles
A Mohamud Yusuf, N Hagemann, X Zhang, M Zafar, T Hussner, C Bromkamp, C Martiny, T Tertel, V Börger, F Schumacher, FA Solari, M Hasenberg, C Kleinschnitz, TR Doeppner, B Kleuser, A Sickmann, M Gunzer, B Giebel, R Kolesnick, E Gulbins, DM Hermann
bioRxiv 2021.03.01.433387; doi: https://doi.org/10.1101/2021.03.01.433387
Acid sphingomyelinase deactivation post-ischemia/ reperfusion promotes cerebral angiogenesis and brain remodeling via small extracellular vesicles
A Mohamud Yusuf, N Hagemann, X Zhang, M Zafar, T Hussner, C Bromkamp, C Martiny, T Tertel, V Börger, F Schumacher, FA Solari, M Hasenberg, C Kleinschnitz, TR Doeppner, B Kleuser, A Sickmann, M Gunzer, B Giebel, R Kolesnick, E Gulbins, DM Hermann
bioRxiv 2021.03.01.433387; doi: https://doi.org/10.1101/2021.03.01.433387
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