大脑中动脉栓塞后慢性不可预见性应激大鼠下丘脑肿瘤坏死因子α及其信号通路的激活  

Activation of TNF-α and signaling pathway in the hypothalamus of the rats subjected to chronic unpredictable mild stressors after middle cerebral artery occlusion

作　　者：王姗姗[1] 陈海英[1] 孙虹[1] 王婷[1] 管锦群[1] 

机构地区：[1]解放军总医院南楼神经内科,北京100853

出　　处：《生理学报》2014年第4期463-468,共6页Acta Physiologica Sinica

基　　金：supported by the National Natural Science Foundation of China(No.81101011);Beijing Nova Program of Beijing Municipal Science and Technology Commission of China(No.Z141107001814103)

摘　　要：本研究旨在探讨大脑中动脉栓塞(middle cerebral artery occlusion,MCAO)后慢性不可预见性应激(chronic unpredictable mild stress,CUMS)状态下,下丘脑细胞因子及其调控通路蛋白表达的变化。成年Sprague Dawley(SD)大鼠经左侧MCAO后,再经过慢性不可预见的温和应激,建立脑卒中后抑郁模型。通过实时定量PCR(qRT-PCR)检测下丘脑细胞因子肿瘤坏死因子α(tumor necrosis factors-α,TNF-α)、促肾上腺皮质激素释放激素(corticotropin releasing factor,CRF)及细胞因子信号转导抑制因子3(suppressor of cytokines signaling 3,SOCS3)mRNA表达水平,用ELISA检测下丘脑TNF-α和CRF蛋白水平,用Western blot检测下丘脑SOCS3和磷酸化的信号转导和转录活化因子3(signal transducers and activators of transcription 3,STAT3)的蛋白水平。结果显示,与对照组相比,MCAO+CUMS组大鼠下丘脑CRF、TNF-α和SOCS3 mRNA水平明显升高,CRF、TNF-α、SOCS3和pSTAT3的蛋白水平显著上调。Spearman相关性分析结果显示,CRF与TNF-α、TNF-α与SOCS3及SOCS3与pSTAT3之间有相关性。以上结果提示,缺血性脑卒中合并慢性应激所导致的抑郁状态下,下丘脑-垂体-肾上腺轴活性上调,可能受到下丘脑细胞因子转导通路的调控,其中包括JAK/STAT3信号通路。This study was aimed to investigate the changes of the hypothalamic-pituitary-adrenal axis （HPAA） activity and the cyto- kines system in the hypothalamus of the depressive rats which were exposed to chronic unpredictable mild stressors （CUMS） after middle cerebral artery occlusion （MCAO）. By means of qRT-PCR, ELISA and Western blot, mRNA and/or protein expressions of corticotropin releasing factor （CRF）, tumor necrosis factors-u （TNF-α）, suppressor of cytokines signaling 3 （SOCS3）, phosphorylation of signal transducers and activators of transcription 3 （pSTAT3） were measured in the hypothalamus of rats. The results showed that, compared with control group, CUMS＋MCAO group exhibited increased mRNA levels of CRF, TNF-α, SOCS3, as well as up-regulated CRF, TNF-α, SOCS3 and pSTAT3 protein expressions. Furthermore, there were correlations between CRF and TNF-α, TNF-α and SOCS3, SOCS3 and pSTAT3, respectively. These observations indicated the CRF system was activated in the post stroke depression （PSD） status. The TNF-α and its signaling pathway, STAT3/SOCS3, were up-regulated in mRNA and protein levels. In conclusion, this study presents the evidence which supports the hypothesis of signaling cross-talk between the CRF system and TNF-α signaling pathway after ischemic stroke and CUMS.

关 键 词：大脑中动脉栓塞 慢性不可预见性温和应激 脑卒中后抑郁 肿瘤坏死因子α 促肾上腺皮质激素释放激素 细胞因子信号转导抑制因子3 信号转导和转录活化因子3 

分 类 号：R743.3[医药卫生—神经病学与精神病学]