贵州医科大学学报

2020, v.45;No.234(03) 292-297+303

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雷帕霉素改善血管性痴呆小鼠认知功能的机制
The Effect of Rapamycin on Cognitive Function of Mice with Vascular Dementia and its Mechanism

陈丽;杨帆;赵志红;秦洁;
CHEN Li;YANG Fan;ZHAO Zhihong;QIN Jie;Department of Neurology,Tianjin Huanhu Hospital;

摘要(Abstract):

目的:探讨雷帕霉素对Va D大鼠海马区M1/M2(前炎状态/抗炎状态)的影响表型标志性产物基因(CD16、i NOS及TNF-α)及M2表型标志性产物基因(IL-10、TGF-β及Arg1)的表达。方法:20只雄性C57BL/6J小鼠采用双侧颈总动脉缩窄(BCAS)制备Va D模型,造模2周后随机分为雷帕霉素治疗组(2. 24 mg/kg的雷帕霉素灌胃4周)及BCAS组(同体积的PBS灌胃4周);于灌胃4周后采用Morris水迷宫行为学实验观察小鼠学习记忆能力,证实造模成功;处死小鼠取海马组织,采用HE及Tunnel染色观察海马区组织结构及神经细胞凋亡,采用逆转录实时定量荧光PCR(RT-qPCR)法检测小胶质细胞M1表型标志性产物基因CD16、i NOS及TNF-α及M2表型标志性产物基因IL-10、TGF-β及Arg1表达,采用Western blot检测海马区m TOR通路的P-Akt及Pp70S6k蛋白表达。结果:雷帕霉素显著提高了小鼠学习和记忆能力。HE染色可见治疗组海马区细胞层数及数量减少、细胞排列紊乱、神经细胞呈缺血样改变,核固缩、深染,胞浆内容物减少、结构疏松等情况较BACS组有明显改善,Tunnel阳性细胞数明显减少(P <0. 05); CD16、i NOS及TNF-α相对表达量明显下调,IL-10、TGF-β及Arg1相对表达量明显上调(P <0. 05); m TOR通路P-Akt蛋白表达水平显著增加、P-p70s6k蛋白表达水平显著降低(P <0. 05)。结论:雷帕霉素可改善Va D模型鼠学习记忆功能,其机制可能与下调M1表型标志性产物基因CD16、i NOS及TNF-α和上调M2表型标志性产物基因IL-10、TGF-β及Arg1表达有关。
Objective: To examine the effect of rapamycin on the marker expression levels of M1/M2( pro-inflammatory/anti-inflammatory state) in hippocampus of VaD mice. In this study,analyzed M1 markers included CD16,i NOS and TNF-α),and analyzed M2 markers were IL-10,TGF-β and Arg1.Methods: Twenty male C57 BL/6 J mice were given bilateral common carotid artery stenosis( BCAS)to establish VaD model. After 2 weeks of modeling,they were randomly divided into rapamycin group given by gavage with 2. 24 mg/kg rapamycin and BCAS group given with the same volume of PBS for 4 weeks. Morris water maze was used to observe the learning and memory ability of mice after 4 weeks of gavage. HE and Tunnel staining were used to observe the hippocampal tissue structure and neuronal apoptosis. Reverse transcription real-time quantitative PCR( RT-qPCR) was used to detect m RNA levels of CD16,iNOS,TNF-α,IL-10,TGF-β and Arg1. P-Akt and P-p70 S6k were detected by western blot. Results: The rapamycin significantly improved learning and memory of VaD mice. HE staining showed that reduced neuronal changes in the hippocampus compared to the BCAS group.Rapamycin significantly reduced the number of Tunnel positive cells( P < 0. 05),and remarkably downregulated M1 markers, but upregulated M2 markers. The Western blot showed that the Rapamycin upregulated P-Akt,while downregulated P-p70 S6 k( P < 0. 05). Conclusion: Rapamycin can improve the learning and memory function of VaD mice. The mechanism may be related to downregulating the M1 markers and upregulating the M2 markers.

关键词(KeyWords): 缺血性脑血管病;认知功能障碍;mTOR通路;M1/M2平衡;雷帕霉素;小胶质细胞
ischemic cerebrovascular disease;cognitive dysfunction;mTOR pathway;M1/M2 balance;rapamycin;microglia

Abstract:

Keywords:

基金项目(Foundation): 天津市科技计划项目(16ZXMJSY00010)

作者(Author): 陈丽;杨帆;赵志红;秦洁;
CHEN Li;YANG Fan;ZHAO Zhihong;QIN Jie;Department of Neurology,Tianjin Huanhu Hospital;

Email:

DOI: 10.19367/j.cnki.1000-2707.2020.03.009

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