Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats.
Activation of the angiotensin II type 2 receptor (AT2R) by administration of Compound 21 (C21), a selective AT2R agonist, induces neuroprotection in models of ischemic stroke in young adult animals. The mechanisms of this neuroprotective action are varied, and may include direct and indirect effects...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5495490?pdf=render |
| _version_ | 1828897472143949824 |
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| author | Douglas M Bennion Jacob D Isenberg Allison T Harmel Kelly DeMars Alex N Dang Chad H Jones Megan E Pignataro Justin T Graham U Muscha Steckelings Jon C Alexander Marcelo Febo Eric G Krause Annette D de Kloet Eduardo Candelario-Jalil Colin Sumners |
| author_facet | Douglas M Bennion Jacob D Isenberg Allison T Harmel Kelly DeMars Alex N Dang Chad H Jones Megan E Pignataro Justin T Graham U Muscha Steckelings Jon C Alexander Marcelo Febo Eric G Krause Annette D de Kloet Eduardo Candelario-Jalil Colin Sumners |
| author_sort | Douglas M Bennion |
| collection | DOAJ |
| description | Activation of the angiotensin II type 2 receptor (AT2R) by administration of Compound 21 (C21), a selective AT2R agonist, induces neuroprotection in models of ischemic stroke in young adult animals. The mechanisms of this neuroprotective action are varied, and may include direct and indirect effects of AT2R activation. Our objectives were to assess the long-term protective effects of post-stroke C21 treatments in a clinically-relevant model of stroke in aged rats and to characterize the cellular localization of AT2Rs in the mouse brain of transgenic reporter mice following stroke. Intraperitoneal injections of C21 (0.03mg/kg) after ischemic stroke induced by transient monofilament middle cerebral artery occlusion resulted in protective effects that were sustained for up to at least 3-weeks post-stroke. These included improved neurological function across multiple assessments and a significant reduction in infarct volume as assessed by magnetic resonance imaging. We also found AT2R expression to be on neurons, not astrocytes or microglia, in normal female and male mouse brains. Stroke did not induce altered cellular localization of AT2R when assessed at 7 and 14 days post-stroke. These findings demonstrate that the neuroprotection previously characterized only during earlier time points using stroke models in young animals is sustained long-term in aged rats, implying even greater clinical relevance for the study of AT2R agonists for the acute treatment of ischemic stroke in human disease. Further, it appears that this sustained neuroprotection is likely due to a mix of both direct and indirect effects stemming from selective activation of AT2Rs on neurons or other cells besides astrocytes and microglia. |
| first_indexed | 2024-12-13T14:58:17Z |
| format | Article |
| id | doaj.art-2f126957e27142a5a4ea9abb14c8c32f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T14:58:17Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-2f126957e27142a5a4ea9abb14c8c32f2022-12-21T23:41:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01127e018073810.1371/journal.pone.0180738Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats.Douglas M BennionJacob D IsenbergAllison T HarmelKelly DeMarsAlex N DangChad H JonesMegan E PignataroJustin T GrahamU Muscha SteckelingsJon C AlexanderMarcelo FeboEric G KrauseAnnette D de KloetEduardo Candelario-JalilColin SumnersActivation of the angiotensin II type 2 receptor (AT2R) by administration of Compound 21 (C21), a selective AT2R agonist, induces neuroprotection in models of ischemic stroke in young adult animals. The mechanisms of this neuroprotective action are varied, and may include direct and indirect effects of AT2R activation. Our objectives were to assess the long-term protective effects of post-stroke C21 treatments in a clinically-relevant model of stroke in aged rats and to characterize the cellular localization of AT2Rs in the mouse brain of transgenic reporter mice following stroke. Intraperitoneal injections of C21 (0.03mg/kg) after ischemic stroke induced by transient monofilament middle cerebral artery occlusion resulted in protective effects that were sustained for up to at least 3-weeks post-stroke. These included improved neurological function across multiple assessments and a significant reduction in infarct volume as assessed by magnetic resonance imaging. We also found AT2R expression to be on neurons, not astrocytes or microglia, in normal female and male mouse brains. Stroke did not induce altered cellular localization of AT2R when assessed at 7 and 14 days post-stroke. These findings demonstrate that the neuroprotection previously characterized only during earlier time points using stroke models in young animals is sustained long-term in aged rats, implying even greater clinical relevance for the study of AT2R agonists for the acute treatment of ischemic stroke in human disease. Further, it appears that this sustained neuroprotection is likely due to a mix of both direct and indirect effects stemming from selective activation of AT2Rs on neurons or other cells besides astrocytes and microglia.http://europepmc.org/articles/PMC5495490?pdf=render |
| spellingShingle | Douglas M Bennion Jacob D Isenberg Allison T Harmel Kelly DeMars Alex N Dang Chad H Jones Megan E Pignataro Justin T Graham U Muscha Steckelings Jon C Alexander Marcelo Febo Eric G Krause Annette D de Kloet Eduardo Candelario-Jalil Colin Sumners Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats. PLoS ONE |
| title | Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats. |
| title_full | Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats. |
| title_fullStr | Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats. |
| title_full_unstemmed | Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats. |
| title_short | Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats. |
| title_sort | post stroke angiotensin ii type 2 receptor activation provides long term neuroprotection in aged rats |
| url | http://europepmc.org/articles/PMC5495490?pdf=render |
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