Effects of SC99 on cerebral ischemia-perfusion injury in rats: Selective modulation of microglia polarization to M2 phenotype via inhibiting JAK2-STAT3 pathway
Effects of SC99 on cerebral ischemia-perfusion injury in rats: Selective modulation of microglia polarization to M2 phenotype via inhibiting JAK2-STAT3 pathway
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DOI：
10.1016/j.neures.2018.05.002
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发表时间：
2019-05-01
影响因子：
2.9
通讯作者：
Chen, Gang
中科院分区：
文献类型：
--
作者：
Ding, Yiping;Qian, Jinhong;Chen, Gang
抑制Janus激酶2-信号转导和转录激活因子3 （JAK2-STAT3）通路已被证明具有抗炎作用。SC99是一种靶向JAK2-STAT3通路的新型特异性抑制剂，已被证实可在体外负调控血小板活化和聚集。本研究建立了Sprague Dawley大鼠大脑中动脉闭塞再灌注（MCAO/R）模型，并对体外培养的原代小胶质细胞进行氧葡萄糖剥夺（OGD/R）处理。采用不同剂量的SC99检测其对脑缺血-灌注（I/R）损伤的影响，并探讨其机制。我们的研究结果表明，脑室内注射SC99 （10 mmol/L, 15 μ L）对JAK2和STAT3的磷酸化有有效的抑制作用。相应地，SC99改善了神经元凋亡和变性、神经行为缺陷、炎症反应和脑水肿。SC99促进小胶质细胞极化到抗炎的M2表型。我们得出结论，SC99可以减轻脑损伤，并通过促进小胶质细胞极化到抗炎表型而发挥抗炎作用，这为未来的研究提供了一个新兴的和有希望的替代方案，以保护大脑免受MCAO/R损伤。(C) 2018 Elsevier B.V.和日本神经科学学会。版权所有。
Inhibition of Janus kinases 2-Signal transducers and activators of transcription3 (JAK2-STAT3) pathway has been shown to exert anti-inflammatory actions. SC99, a novel specific inhibitor targeting JAK2-STAT3 pathway, has been verified to negatively modulate platelet activation and aggregation in vitro. In current study, a middle cerebral artery occlusion and reperfusion (MCAO/R) model was established in Sprague Dawley rats and primary cultured microglia was exposed to oxygen and glucose deprivation (OGD/R) in vitro. Different dosages were employed to detect the effects of SC99 on cerebral ischemia-perfusion (I/R) injury and evaluate the underlying mechanisms. Our results showed that intracerebroventricular injection of SC99 (10 mmol/L, 15 mu L) produced an effective inhibitory effect on the phosphorylation of JAK2 and STAT3. Correspondingly, SC99 ameliorated neuronal apoptosis and degeneration, neurobehavioral deficits, inflammatory response and brain edema. And SC99 promoted microglia polarization to an anti-inflammatory M2 phenotype. We concluded that SC99 could alleviate brain damage and play an anti-inflammatory action by promoting microglia polarization to an anti-inflammatory phenotype after I/R injury, which provides an emerging and promising alternative to protect the brain against MCAO/R injury in the future investigations. (C) 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.