Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats.
Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats.
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DOI：
10.1371/journal.pone.0180738
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Sumners C
中科院分区：
文献类型：
--
作者：
Bennion DM;Isenberg JD;Harmel AT;DeMars K;Dang AN;Jones CH;Pignataro ME;Graham JT;Steckelings UM;Alexander JC;Febo M;Krause EG;de Kloet AD;Candelario-Jalil E;Sumners C
通过施用化合物21（C21）（一种选择性AT 2 R激动剂）激活血管紧张素II 2型受体（AT 2 R）在年轻成年动物的缺血性中风模型中诱导神经保护。这种神经保护作用的机制是多种多样的，可能包括AT 2 R激活的直接和间接作用。我们的目的是评估中风后C21治疗的长期保护作用，在临床相关的模型中风老年大鼠和表征的细胞定位的AT 2受体在小鼠脑中的转基因报告小鼠中风后。在由短暂的单丝大脑中动脉闭塞诱导的缺血性中风后，腹膜内注射C21（0.03mg/kg）产生保护作用，该保护作用持续至中风后至少3周。这些包括在多次评估中改善神经功能和通过磁共振成像评估的梗死体积显著减少。我们还发现，在正常雌性和雄性小鼠大脑中，AT 2 R表达在神经元上，而不是星形胶质细胞或小胶质细胞上。卒中后7天和14天评估时，卒中未诱导AT 2 R细胞定位改变。这些发现表明，先前仅在早期时间点使用年轻动物中风模型表征的神经保护在老年大鼠中长期持续，这意味着AT 2 R激动剂用于急性治疗人类疾病缺血性中风的研究具有更大的临床相关性。此外，似乎这种持续的神经保护可能是由于直接和间接作用的混合，所述直接和间接作用源于AT 2 R对神经元或除星形胶质细胞和小胶质细胞之外的其他细胞的选择性激活。
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.