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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及其信号通路的激活

王姗姗^*, 陈海英, 孙虹, 王婷, 管锦群

解放军总医院南楼神经内科，北京100853

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。

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

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

WANG Shan-Shan^*, CHEN Hai-Ying, SUN Hong, WANG Ting, GUAN Jin-Qun

Department of Neurology in Nanlou Clinical Division, PLA General Hospital, Beijng 100853, China

Abstract

This study was aimed to investigate the changes of the hypothalamic-pituitary-adrenal axis (HPAA) activity and the cytokines 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-α (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.

Key words: middle cerebral artery occlusion; chronic unpredictable mild stressors; post stroke depression; tumor necrosis factors-alpha; corticotropin releasing factor; suppressor of cytokines signaling 3; signal transducers and activators of transcription 3

收稿日期：2013-11-27　　录用日期：2014-04-29

通讯作者：王姗姗　　E-mail: jessicass33@gmail.com

引用本文：

王姗姗, 陈海英, 孙虹, 王婷, 管锦群. 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及其信号通路的激活[J]. 生理学报 2014; 66 (4): 463-468.

WANG Shan-Shan, CHEN Hai-Ying, SUN Hong, WANG Ting, GUAN Jin-Qun. [Activation of TNF-α and signaling pathway in the hypothalamus of the rats subjected to chronic unpredictable mild stressors after middle cerebral artery occlusion.] [Article in Chinese]. Acta Physiol Sin 2014; 66 (4): 463-468 (in Chinese with English abstract).