Abstract
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.
Highlights
Targeting of angiotensin type 2 receptors (AT2R) in ischemic stroke by pharmacological activation has reproducibly induced decreases in infarct size and improvements in neurological function in young adult rodents when measured at early ( 7 days post-stroke) time points [1,2,3,4,5,6,7,8,9]
In the present study, we have investigated the potential sustained neuroprotective effects of systemically administered Compound 21 (C21) at reducing infarct volume and improving neurological function in aged Sprague Dawley rats using a transient middle cerebral artery occlusion (MCAO) model of ischemic stroke
To assess the long-term efficacy of post-stroke injections of C21in aged rats, experiments were performed as described in Experiment 1 of the Experimental Protocols section of the Methods
Summary
Targeting of angiotensin type 2 receptors (AT2R) in ischemic stroke by pharmacological activation has reproducibly induced decreases in infarct size and improvements in neurological function in young adult rodents when measured at early ( 7 days post-stroke) time points [1,2,3,4,5,6,7,8,9]. Our group was the first to report that post-stroke activation of AT2Rs with a selective agonist, Compound 21 (C21), was effective at reducing stroke-induced brain damage when administered systemically to 8–10 week old rats [4]. The mechanisms for these neuroprotective actions of AT2R in stroke appear to be multiple, and potentially include neurotrophic, antiinflammatory, anti-chemotactic and anti-oxidant actions, as well as increasing neurogenesis, angiogenesis and cerebral blood flow [10, 11]. Progress in this area has been hampered by limitations of the available immunostaining and autoradiography techniques
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