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

  • J Mol Med (Berl). 2016 Aug;94(8):957-66. doi: 10.1007/s00109-016-1406-3.
Katja Schwengel  1 ,  Pawel Namsolleck  2 ,  Kristin Lucht  1 ,  Bettina H Clausen  3 ,  Kate L Lambertsen  3 ,  Veronica Valero-Esquitino  1 ,  Christa Thöne-Reineke  4 ,  Susanne Müller  5 ,  Robert E Widdop  6 ,  Kate M Denton  7 ,  Masatsugu Horiuchi  8 ,  Masaru Iwai  8 ,  Francesco Boato  9 ,  Björn Dahlöf  10 ,  Anders Hallberg  11 ,  Thomas Unger  2 ,  U Muscha Steckelings  12
Affiliations
  • 1. Center for Cardiovascular Research, Medical Faculty, Charité, Berlin, Germany.
  • 2. CARIM, Maastricht University, Maastricht, The Netherlands.
  • 3. Department of Neurobiology, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • 4. Department of Veterinary Medicine, Free University, Berlin, Germany.
  • 5. Experimental Neurology, Medical Faculty, Charité, Berlin, Germany.
  • 6. Department of Pharmacology, Monash University, Clayton, Australia.
  • 7. Department of Physiology, Monash University, Clayton, Australia.
  • 8. Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Ehime, Japan.
  • 9. Burke Medical Research Institute, Weill Cornell Medical College, Cornell University, White Plains, USA.
  • 10. Sahlgrenska University Hospital, Gothenburg, Sweden.
  • 11. Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
  • 12. Department of Cardiovascular and Renal Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark. [email protected].
PMID: 26983606 DOI: 10.1007/s00109-016-1406-3
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.

Keywords
AT2-receptor; MCAO; Neuroprotection; Renin-angiotensin system; Stroke.
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