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

Katja Schwengel, Pawel Namsolleck, Kristin Lucht, Bettina H. Clausen, Kate L. Lambertsen, Veronica Valero-Esquitino, Christa Thone-Reineke, Susanne Müller, Robert E. Widdop, Kate M. Denton, Masatsugu Horiuchi, Masaru Iwai, Francesco Boato, Bjorn Dahlof, Anders Hallberg, Thomas Unger, U. Muscha Steckelings

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22 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)957-966
Number of pages10
JournalJournal of Molecular Medicine
Volume94
Issue number8
DOIs
Publication statusPublished - Aug 2016

Keywords

  • MCAO
  • AT2-receptor
  • stroke
  • renin-angiotensin system
  • neuroprotection

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