TY - JOUR
T1 - Angiotensin AT2-receptor stimulation improves survival and neurological outcome after experimental stroke in mice
AU - Schwengel, Katja
AU - Namsolleck, Pawel
AU - Lucht, Kristin
AU - Clausen, Bettina H.
AU - Lambertsen, Kate L.
AU - Valero-Esquitino, Veronica
AU - Thoene-Reineke, Christa
AU - Mueller, Susanne
AU - Widdop, Robert E.
AU - Denton, Kate M.
AU - Horiuchi, Masatsugu
AU - Iwai, Masaru
AU - Boato, Francesco
AU - Dahlof, Bjorn
AU - Hallberg, Anders
AU - Unger, Thomas
AU - Steckelings, U. Muscha
PY - 2016/8
Y1 - 2016/8
N2 - 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.
AB - 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.
KW - MCAO
KW - AT2-receptor
KW - Stroke
KW - Renin-angiotensin system
KW - Neuroprotection
U2 - 10.1007/s00109-016-1406-3
DO - 10.1007/s00109-016-1406-3
M3 - Article
C2 - 26983606
SN - 0946-2716
VL - 94
SP - 957
EP - 966
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
IS - 8
ER -