Department of Medicine, Augusta University/University of Georgia Medical Partnership, Athens, GA 30602, USA.
Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA 30912, USA.
Int J Mol Sci. 2021 Jan 29;22(3):1356. doi: 10.3390/ijms22031356.
About 70% of stroke victims present with comorbid diseases such as diabetes and hypertension. The integration of comorbidities in pre-clinical experimental design is important in understanding the mechanisms involved in the development of stroke injury and recovery. We recently showed that administration of compound C21, an angiotensin II type 2 receptor agonist, at day 3 post-stroke improved sensorimotor outcomes by lowering neuroinflammation in diabetic male animals. In the current study, we hypothesized that a delayed administration of C21 would also lower chronic inflammation post-stroke in diabetic female animals. Young female diabetic rats were subjected to 1 h of middle cerebral artery occlusion (MCAO). Three days post-stroke, rats were administered C21 or vehicle in drinking water at a dose of 0.12 mg/kg/day for 4 weeks. The impact of C21 on microglial polarization was analyzed by flow cytometry in vivo and in vitro. Compound 21 treatment improved fine motor skills after MCAO through modulation of the microglia/macrophage inflammatory properties. In addition, C21 increased M2 polarization and reduced the M1:M2 ratio in vitro. In conclusion, delayed administration of C21 downregulates post-stroke inflammation in female diabetic animals. C21 may be a useful therapeutic option to lower neuro-inflammation and improve the post-stroke recovery in diabetes.
约 70%的中风患者伴有糖尿病和高血压等合并症。在理解中风损伤和恢复过程中涉及的机制时，将合并症纳入临床前实验设计非常重要。我们最近表明，在中风后第 3 天给予血管紧张素 II 型 2 型受体激动剂 C21 复合物可通过降低糖尿病雄性动物的神经炎症来改善感觉运动功能。在本研究中，我们假设 C21 的延迟给药也会降低糖尿病雌性动物中风后的慢性炎症。年轻的雌性糖尿病大鼠接受 1 小时的大脑中动脉闭塞（MCAO）。中风后 3 天，用 0.12 mg/kg/天的剂量通过饮用水给予大鼠 C21 或载体 4 周。通过体内和体外流式细胞术分析 C21 对小胶质细胞极化的影响。C21 通过调节小胶质细胞/巨噬细胞炎症特性，改善 MCAO 后的精细运动技能。此外，C21 增加了体外 M2 极化并降低了 M1:M2 比值。总之，延迟给予 C21 可下调雌性糖尿病动物中风后的炎症。C21 可能是一种有用的治疗选择，可降低神经炎症并改善糖尿病中风后的恢复。
