title: 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.affiliation: Center for Cardiovascular Research, Medical Faculty, Charité, Berlin, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Schwengel
authors.affiliation: CARIM, Maastricht University, Maastricht, The Netherlands.
authors.forename: Pawel
authors.initials: P
authors.lastname: Namsolleck
authors.affiliation: Center for Cardiovascular Research, Medical Faculty, Charité, Berlin, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Lucht
authors.affiliation: Department of Neurobiology, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Bettina H
authors.initials: BH
authors.lastname: Clausen
authors.affiliation: Department of Neurobiology, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Lambertsen
authors.affiliation: Center for Cardiovascular Research, Medical Faculty, Charité, Berlin, Germany.
authors.forename: Veronica
authors.initials: V
authors.lastname: Valero-Esquitino
authors.affiliation: Department of Veterinary Medicine, Free University, Berlin, Germany.
authors.forename: Christa
authors.initials: C
authors.lastname: Thöne-Reineke
authors.affiliation: Experimental Neurology, Medical Faculty, Charité, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Australia.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Widdop
authors.affiliation: Department of Physiology, Monash University, Clayton, Australia.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Denton
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Ehime, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Ehime, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.affiliation: Burke Medical Research Institute, Weill Cornell Medical College, Cornell University, White Plains, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Boato
authors.affiliation: Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Dahlöf
authors.affiliation: Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.affiliation: CARIM, Maastricht University, Maastricht, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.affiliation: Department of Cardiovascular and Renal Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark. usteckelings@health.sdu.dk.
authors.forename: U Muscha
authors.initials: UM
authors.lastname: Steckelings
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002470:Cell Survival; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D018696:Neuroprotective Agents; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013876:Thiophenes
keywords: AT2-receptor; MCAO; Neuroprotection; Renin-angiotensin system; Stroke