血管紧张素Ⅱ 2 型受体活化在缺血再灌损伤中的神经保护作用及机制研究

Neuro-protective effect of angiotensin II type 2 receptor activation in rat model of ischemia/ reperfusion injury

摘要:

目的 评估血管紧张素Ⅱ 2 型（AT2）受体激动剂CGP42112 在体内、外脑缺血/ 再灌损伤中的保护作用及机制探讨。方法 Wistar 大鼠行3 h 大脑中动脉阻塞（MCAO），再灌21 h。再灌期间大鼠腹腔注射CGP42112（1 mg/kg）和（或）IL-10 中和抗体（0.1 mg/kg）。大鼠手术24 h 后进行梗死体积、行为结果和ELISA 分析。并采用大鼠原代神经元氧糖剥夺/ 复氧（OGD/R）模型用来观察CGP42112 在体外的神经保护作用。结果 与对照大鼠比较，CGP42112 处理可减少缺血大脑半球梗死体积、改善神经功能预后，并减少肿瘤坏死因子α（TNF-α）表达。而IL-10 中和抗体可逆转CGP42112 处理引起的梗死体积、炎症缓解及神经功能改善。在体外，CGP42112 可使OGD/R 神经元活力增加，并减少细胞凋亡。结论 在体内CGP42112 可能通过IL-10 发挥神经保护作用；在体外则具有直接神经保护作用。

Abstract:

Objective To investigate neuro-protective effect of angiotensin type 2 (AT2) receptor agonist in rat model of brain ischemia / reperfusion injury. Methods Wistar rats in IR group were subjected to 3 hours of ischemia(middle cerebral artery suture occlusion) followed by reperfusion for 21 hours. Rats from control received sham operative procedures without ischemia nor reperfusion. Rats received CGP42112 (AT2 agonist, 1 mg/kg) and / or IL-10 antibody (0.1 mg/kg) through intraperitoneal injection. Infarction size and behavioral outcomes were recorded at 24 hours post-injury. TNF-α were measured by ELISA. Primary rat neurons were utilized to test neuroprotective effect of CGP42112 ex vivo. Cell model of oxygen / glucose deprivation and reperfusion (OGD/R) was established based on standard protocol. Results Treatment of CGP42112 reduced infarct size, enhanced functional recovery,and decreased the expression of pro-inflammatory cytokine (TNF-α) in IR group compared with control group. Anti- IL-10 antibody reversed the CGP42112-induced neuro-protective effect including infarction size, improvement in behavioral outcome, and inflammatory response. In ex vivo, CGP42112 preserved OGD/R induced neuron loss, while reduced cell apoptosis. Conclusion CGP42112 provides direct neuroprotection in ischemia and reperfusion model,potentially through modulating IL-10 pathway.