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

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.

• Authors: 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
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 94 Issue 8 Pg. 957-66 (08 2016) ISSN: 1432-1440 [Electronic] Germany
• PMID: 26983606 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Brain-Derived Neurotrophic Factor
• N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide
• Neuroprotective Agents
• Receptor, Angiotensin, Type 2
• Sulfonamides
• Thiophenes

Topics

• Animals
• Apoptosis (drug effects)
• Brain-Derived Neurotrophic Factor (metabolism)
• Cell Survival
• Cerebral Cortex (drug effects, pathology)
• Drug Evaluation, Preclinical
• Infarction, Middle Cerebral Artery (drug therapy, pathology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Neurons (drug effects, physiology)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Receptor, Angiotensin, Type 2 (agonists, genetics, metabolism)
• Sulfonamides (pharmacology, therapeutic use)
• Thiophenes (pharmacology, therapeutic use)