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 Thöne-Reineke, Susanne Müller, Robert E Widdop, Kate M Denton, Masatsugu Horiuchi, Masaru Iwai, Francesco Boato, Björn Dahlöf, Anders Hallberg, Thomas Unger, U Muscha Steckelings

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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.

Original languageEnglish
JournalJournal of Molecular Medicine
Volume94
Issue number8
Pages (from-to)957-966
ISSN0946-2716
DOIs
Publication statusPublished - 2016

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Schwengel, K., Namsolleck, P., Lucht, K., Clausen, B. H., Lambertsen, K. L., Valero-Esquitino, V., Thöne-Reineke, C., Müller, S., Widdop, R. E., Denton, K. M., Horiuchi, M., Iwai, M., Boato, F., Dahlöf, B., Hallberg, A., Unger, T., & Steckelings, U. M. (2016). Angiotensin AT2-receptor stimulation improves survival and neurological outcome after experimental stroke in mice. Journal of Molecular Medicine, 94(8), 957-966. https://doi.org/10.1007/s00109-016-1406-3