Sinomenine activates astrocytic dopamine D2 receptors and alleviates neuroinflammatory injury via the CRYAB/STAT3 pathway after ischemic stroke in mice.
Sinomenine activates astrocytic dopamine D2 receptors and alleviates neuroinflammatory injury via the CRYAB/STAT3 pathway after ischemic stroke in mice.
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青藤碱通过 CRYAB/STAT3 通路激活小鼠缺血性脑卒中星形细胞多巴胺 D2 受体并减轻神经炎症损伤
DOI：
10.1186/s12974-016-0739-8
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发表时间：
2016-10-10
影响因子：
9.3
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Qiu J;Yan Z;Tao K;Li Y;Li Y;Li J;Dong Y;Feng D;Chen H
研究背景星形胶质细胞介导的神经炎症反应在缺血性脑卒中继发性脑损伤中起重要作用。以往的研究表明，多巴胺D2受体（DRD 2）作为一个关键的目标，在调节神经炎症反应。然而，潜在的分子机制仍然未知，并且缺乏有效的DRD 2激动剂。在本研究中，我们研究了青藤碱（Sino）的抗炎和神经保护作用，单体化合物具有潜在的免疫调节特性在nervoussystem.MethodsTTC染色，细胞凋亡测定，脑水肿的评价，和神经功能的评估进行大脑中动脉闭塞（MCAO）小鼠模型。在体外实验中使用暴露于氧葡萄糖剥夺（OGD）的原代星形胶质细胞。应用定量PCR检测炎性细胞因子水平。多标记免疫荧光，Western印迹，免疫共沉淀，电泳迁移率变动分析（EMSA）也被用来探讨潜在的中国介导的抗炎作用在体内和体外的分子机制。ResultsSino显着衰减脑梗死和神经细胞凋亡，降低炎症细胞因子的水平，减轻神经功能缺损MCAO小鼠。Sino显著抑制MCAO后星形胶质细胞活化和STAT 3磷酸化，并增加DRD 2和α B-晶体蛋白（α B-crystallin，α B-AB）表达。在体外，Sino阻断OGD诱导的STAT 3活化和原代星形胶质细胞中促炎细胞因子的产生，并且这些作用被DRD 2或DRIAB敲低显著消除。此外，Sino还可诱导星形胶质细胞中DRD 2的表达上调和核转位，并增强DRD 2与STAT 3的相互作用，进而抑制STAT 3的活化和DNA结合活性。结论Sino可通过DRD 2/STAT 3通路抑制神经炎症反应，为缺血性脑卒中的治疗提供了新的思路。
BackgroundAstrocyte-mediated neuroinflammation plays a critical role in ischemic stroke-induced secondary cerebral injury. Previous studies have suggested that the dopamine D2 receptor (DRD2) acts as a key target in regulating the neuroinflammatory response. However, the underlying molecular mechanisms are still unknown, and effective DRD2 agonists are lacking. In the present study, we examined the anti-inflammatory and neuroprotective effects of sinomenine (Sino), a monomeric compound with potential immunoregulatory properties in nervous system.MethodsTTC staining, apoptosis assay, evaluation of brain edema, and neurological assessment were performed in the middle cerebral artery occlusion (MCAO) mouse model. Primary astrocytes exposed to oxygen glucose deprivation (OGD) were used in the in vitro experiments. Quantitative PCR was applied to assess the levels of inflammatory cytokines. Multi-labeling immunofluorescence, Western blot, co-immunoprecipitation, and electrophoretic mobility shift assay (EMSA) were also used to investigate the molecular mechanisms underlying the Sino-mediated anti-inflammatory effects in vivo and in vitro.ResultsSino remarkably attenuated the cerebral infarction and neuronal apoptosis, reduced the levels of inflammatory cytokines, and alleviated neurological deficiency in MCAO mice. Sino significantly inhibited astrocytic activation and STAT3 phosphorylation as well as increased DRD2 and αB-crystallin (CRYAB) expression after MCAO. In vitro, Sino blocked OGD-induced activation of STAT3 and generation of pro-inflammatory cytokines in primary astrocytes, and these effects were significantly abolished by either DRD2 or CRYAB knockdown. Additionally, Sino induced up-regulation and nuclear translocation of CRYAB in astrocytes and enhanced the interaction between CRYAB and STAT3, which further inhibited the activation and DNA-binding activity of STAT3.ConclusionsOur study demonstrates that Sino activates astrocytic DRD2 and thereby suppresses neuroinflammation via the CRYAB/STAT3 pathway, which sheds some light on a promising therapeutic strategy for ischemic stroke.
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