Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury.
Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury.
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DOI：
10.1016/j.ejphar.2017.02.016
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发表时间：
2017-03-15
影响因子：
5
通讯作者：
Fagan SC
中科院分区：
文献类型：
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作者：
Fouda AY;Pillai B;Dhandapani KM;Ergul A;Fagan SC
我们和其他人已经证明，血管紧张素2型(AT2)受体激动剂，化合物21(C21)，在啮齿动物中风模型中提供神经保护和促进恢复，但涉及的机制尚不清楚。此外，C21治疗与抗炎反应有关。在这里，我们测试了C21通过上调神经保护和抗炎细胞因子IL-10来介导神经保护的假设。Wistar大鼠大脑中动脉闭塞3h后，再灌胃给予C21(0.03 mg/kg)+IL-10中和抗体(0.1 mg/kg)。在损伤后24小时进行脑梗塞范围、行为结果和分子分析。用原代培养的大鼠神经元检测C21的直接神经保护作用。与生理盐水相比，C21治疗缩小了缺血半球的梗塞范围，改善了功能结果，并降低了促炎细胞因子肿瘤坏死因子-α(Tumor-α)。抗IL-10联合治疗阻断了C21诱导的心肌梗死面积缩小和炎症反应，以及行为结局的改善。在体外，C21治疗增加了缺氧缺糖(OGD)和OGD/复氧后神经元的存活率，减少了细胞的凋亡。这些作用是通过刺激AT2R介导的。C21通过IL-10提供直接神经保护和间接保护。
We and others have shown that the angiotensin type 2 (AT2) receptor agonist, compound 21 (C21), provides neuroprotection and enhances recovery in rodent stroke models yet the mechanism involved is not known. Moreover, C21 treatment is associated with an anti-inflammatory response. Here we tested the hypothesis that C21 mediates neuroprotection by upregulating the neuroprotective and anti-inflammatory cytokine interleukin (IL)-10. Wistar rats were subjected to 3 h MCA suture occlusion and treated at reperfusion with C21 (0.03 mg/kg) ± IL-10 neutralizing antibody (0.1 mg/kg) both given i.p. Infarct size, behavioral outcomes, and molecular analysis were performed at 24 h post-injury. Primary rat neurons were used to test the direct neuroprotective effect of C21 in vitro. C21 treatment reduced infarct size, improved functional outcome and decreased the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) in the ischemic hemisphere compared to saline. Anti-IL-10 co-treatment blocked the C21 induced reduction in infarct size and inflammation, and the improvement in behavioral outcome. In vitro, C21 treatment increased neuron survival and reduced cell apoptosis after oxygen glucose deprivation (OGD) and OGD/reoxygenation. These effects were mediated through AT2R stimulation. C21 provides direct neuroprotection as well as indirect protection through IL-10.