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

Autor: Anders Hallberg, Kristin Lucht, Thomas Unger, Veronica Valero-Esquitino, Christa Thöne-Reineke, Masaru Iwai, Katja Schwengel, Kate M. Denton, Pawel Namsolleck, Masatsugu Horiuchi, Robert E Widdop, Bettina Hjelm Clausen, Francesco Boato, Susanne Müller, Björn Dahlöf, U. Muscha Steckelings, Kate Lykke Lambertsen
Přispěvatelé: Pathologie, Bedrijfsbureau CD, RS: CARIM School for Cardiovascular Diseases
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Male
medicine.medical_specialty
Cell Survival
Drug Evaluation
Preclinical
Apoptosis
Stimulation
Thiophenes
Tropomyosin receptor kinase B
030204 cardiovascular system & hematology
Receptor
Angiotensin
Type 2
Neuroprotection
03 medical and health sciences
0302 clinical medicine
Neurotrophic factors
Internal medicine
AT2-receptor
Drug Discovery
Animals
Medicine
cardiovascular diseases
Receptor
Stroke
Genetics (clinical)
Cerebral Cortex
Mice
Knockout
Neurons
Brain-derived neurotrophic factor
Sulfonamides
business.industry
Brain-Derived Neurotrophic Factor
Infarction
Middle Cerebral Artery
medicine.disease
Mice
Inbred C57BL
Neuroprotective Agents
Endocrinology
medicine.anatomical_structure
Cerebral cortex
Anesthesia
cardiovascular system
Molecular Medicine
MCAO
Renin-angiotensin system
business
030217 neurology & neurosurgery
Zdroj: 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, vol. 94, no. 8, pp. 957-966 . https://doi.org/10.1007/s00109-016-1406-3
Journal of Molecular Medicine, 94(8), 957-966. Springer
ISSN: 0946-2716
Popis: 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.
Databáze: OpenAIRE
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