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Angiotensin AT2-receptor stimulation improves survival and neurological outcome after experimental stroke in mice

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Abstract

This study investigated the effect of post-stroke, direct AT2-receptor (AT2R) stimulation with the non-peptide AT2R-agonist compound 21 (C21) on infarct size, survival and neurological outcome after middle cerebral artery occlusion (MCAO) in mice and looked for potential underlying mechanisms. C57/BL6J or AT2R-knockout mice (AT2-KO) underwent MCAO for 30 min followed by reperfusion. Starting 45 min after MCAO, mice were treated once daily for 4 days with either vehicle or C21 (0.03 mg/kg ip). Neurological deficits were scored daily. Infarct volumes were measured 96 h post-stroke by MRI. C21 significantly improved survival after MCAO when compared to vehicle-treated mice. C21 treatment had no impact on infarct size, but significantly attenuated neurological deficits. Expression of brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB) (receptor for BDNF) and growth-associated protein 43 (GAP-43) were significantly increased in the peri-infarct cortex of C21-treated mice when compared to vehicle-treated mice. Furthermore, the number of apoptotic neurons was significantly decreased in the peri-infarct cortex in mice treated with C21 compared to controls. There were no effects of C21 on neurological outcome, infarct size and expression of BDNF or GAP-43 in AT2-KO mice. From these data, it can be concluded that AT2R stimulation attenuates early mortality and neurological deficits after experimental stroke through neuroprotective mechanisms in an AT2R-specific way.

Key message

• AT2R stimulation after MCAO in mice reduces mortality and neurological deficits.

• AT2R stimulation increases BDNF synthesis and protects neurons from apoptosis.

• The AT2R-agonist C21 acts protectively when applied post-stroke and peripherally.

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Funding

This work was funded by EUREKA’s Eurostars programme of the European Union and the German Ministry for Research and Technology, by a fellowship from the Berlin-Padua-Gdansk Ph.D. programme to VVE and by internal sources from Charité, Universitätsmedizin Berlin.

Author information

Authors and Affiliations

  1. Center for Cardiovascular Research, Medical Faculty, Charité, Berlin, Germany

    Katja Schwengel, Kristin Lucht & Veronica Valero-Esquitino

  2. CARIM, Maastricht University, Maastricht, The Netherlands

    Pawel Namsolleck & Thomas Unger

  3. Department of Neurobiology, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Bettina H. Clausen & Kate L. Lambertsen

  4. Department of Veterinary Medicine, Free University, Berlin, Germany

    Christa Thöne-Reineke

  5. Experimental Neurology, Medical Faculty, Charité, Berlin, Germany

    Susanne Müller

  6. Department of Pharmacology, Monash University, Clayton, Australia

    Robert E. Widdop

  7. Department of Physiology, Monash University, Clayton, Australia

    Kate M. Denton

  8. Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Ehime, Japan

    Masatsugu Horiuchi & Masaru Iwai

  9. Burke Medical Research Institute, Weill Cornell Medical College, Cornell University, White Plains, USA

    Francesco Boato

  10. Sahlgrenska University Hospital, Gothenburg, Sweden

    Björn Dahlöf

  11. Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden

    Anders Hallberg

  12. Department of Cardiovascular and Renal Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark

    U. Muscha Steckelings

Authors
  1. Katja Schwengel
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  2. Pawel Namsolleck
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  3. Kristin Lucht
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  4. Bettina H. Clausen
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  5. Kate L. Lambertsen
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  6. Veronica Valero-Esquitino
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  7. Christa Thöne-Reineke
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  8. Susanne Müller
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  9. Robert E. Widdop
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  10. Kate M. Denton
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  11. Masatsugu Horiuchi
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  12. Masaru Iwai
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  13. Francesco Boato
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  14. Björn Dahlöf
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  15. Anders Hallberg
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  16. Thomas Unger
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  17. U. Muscha Steckelings
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Corresponding author

Correspondence to U. Muscha Steckelings.

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Conflict of interests

UMS has received modest research support from Vicore Pharma. BD has substantial ownership in Vicore Pharma Holding (publ.), the owner of Vicore Pharma. The other authors report no conflict of interest.

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Schwengel, K., Namsolleck, P., Lucht, K. et al. Angiotensin AT2-receptor stimulation improves survival and neurological outcome after experimental stroke in mice. J Mol Med 94, 957–966 (2016). https://doi.org/10.1007/s00109-016-1406-3

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  • DOI: https://doi.org/10.1007/s00109-016-1406-3

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