趋化因子CCL2对大鼠学习记忆的影响及其机制
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摘要
目的研究CC类趋化因子配体2(CCL2)对大鼠学习记忆的影响及机制。方法 40只♂SD大鼠随机分为5组:空白对照组、假手术组、CCL2(0. 5、5、50 ng)组。除空白对照组外,其余各组均进行双侧海马注射。注射后的d 3～8进行Morris水迷宫实验,d 10分离各组大鼠海马,q PCR检测凋亡蛋白caspase-8、caspase-3以及磷酸激活谷氨酰胺酶(PAG) mRNA的相对表达水平; ELISA检测肿瘤坏死因子ɑ(TNF-ɑ)、乙酰胆碱酯酶(ACh E)的含量,以及谷氨酰胺合成酶(GS)的活力。结果与假手术组相比,各CCL2处理组大鼠逃避潜伏期及游泳路程均明显增长,原平台穿越次数和原平台象限路程百分比均明显减少;各CCL2处理组大鼠海马组织中caspase-8、caspase-3、PAG mRNA相对表达量增加;各CCL2处理组大鼠海马组织内TNF-ɑ、ACh E的表达量增加,GS活力下降。结论 CCL2能损伤大鼠的学习记忆力,其机制与参与炎症反应、神经兴奋毒性、导致ACh含量下降以及介导细胞凋亡有关。
Aim To investigate the role of chemokine CC motif ligand 2( CCL2) in leaning memory of rats and its mechanisms. Methods Forty male SD rats were randomly divided into five groups,namely,control,sham,CCL2( 0. 5,5,50 ng) group. Except control group,stereotaxic technique was used in this study to perform bilateral hippocampal injection. Morris water maze( MWM) was employed to assess the learning and memory ability of rats from day 3 to day8. Hippocampus was removed on the 10 th day. q PCR was used to detect the relative mRNA expression of caspase-8,caspase-3 and phosphate-activated glutaminase( PAG). ELISA was used to calculate the content of tumor necrosis factor α( TNF-α),acetylcholine( AChE) and the activity of glutamine synthetase( GS). Results Compared to sham group,the latency and swimming distance in each CCL2-treated group were significantly extended,and the crossing times and the percentage of distance in target quadrant of each CCL2-treated group were shorter; the relative mRNA expression of caspase-8,caspase-3 and PAG in each CCL2-treated group were higher than those of shamgroup; each CCL2-treated group had elevated expression of TNF-ɑ and AChE while the activity of GS in each group decreased. Conclusions CCL2 can impair learning and memory in rats,which may involve inflammation,excitotoxicity,decreased ACh expression and mediated cell apoptosis.
Aim To investigate the role of chemokine CC motif ligand 2( CCL2) in leaning memory of rats and its mechanisms. Methods Forty male SD rats were randomly divided into five groups,namely,control,sham,CCL2( 0. 5,5,50 ng) group. Except control group,stereotaxic technique was used in this study to perform bilateral hippocampal injection. Morris water maze( MWM) was employed to assess the learning and memory ability of rats from day 3 to day8. Hippocampus was removed on the 10 th day. q PCR was used to detect the relative mRNA expression of caspase-8,caspase-3 and phosphate-activated glutaminase( PAG). ELISA was used to calculate the content of tumor necrosis factor α( TNF-α),acetylcholine( AChE) and the activity of glutamine synthetase( GS). Results Compared to sham group,the latency and swimming distance in each CCL2-treated group were significantly extended,and the crossing times and the percentage of distance in target quadrant of each CCL2-treated group were shorter; the relative mRNA expression of caspase-8,caspase-3 and PAG in each CCL2-treated group were higher than those of shamgroup; each CCL2-treated group had elevated expression of TNF-ɑ and AChE while the activity of GS in each group decreased. Conclusions CCL2 can impair learning and memory in rats,which may involve inflammation,excitotoxicity,decreased ACh expression and mediated cell apoptosis.
引文
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[2] Tian D S,Peng J,Murugan M,et al. Chemokine CCL2–CCR2signaling induces neuronal cell death via STAT3 activation and IL-1βproduction after status epilepticus[J]. J Neurosci,2017,37(33):7878.
[3] Landreneau,Mullen M T,MesséS R,et al. CCL2 and CXCL10are associated with poor outcome after intracerebral hemorrhage[J]. Ann Clin Transl Neurol,2018,5(8):962–70.
[4] Semple B D,Kossmann T,Morgantikossmann M C. Role of chemokines in CNS health and pathology:a focus on the CCL2/CCR2and CXCL8/CXCR2 networks[J]. J Cereb Blood Flow Metab,2010,30(3):459.
[5] Thames A D,Briones M S,Magpantay L I,et al. The role of chemokine C-C motif ligand 2 genotype and cerebrospinal fluid chemokine C-C motif ligand 2 in neurocognition among HIV-infected patients[J]. AIDS,2015,29(12):1483-91.
[6] Galimberti D,Fenoglio C,Lovati C,et al. Serum MCP-1 levels are increased in mild cognitive impairment and mild Alzheimer's disease[J]. Neurobiol Aging,2006,27(12):1763-8.
[7] Dimitrijevic O B,Stamatovic S M,Keep R F,et al. Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice[J]. Stroke,2007,38(4):1345-53.
[8] Bose S,Cho J. Role of chemokine CCL2 and its receptor CCR2 in neurodegenerative diseases[J]. Arch Pharm Res,2013,36(9):1039-50.
[9] Liu S,Zhang L,Wu Q,et al. Chemokine CCL2 induces apoptosis in cortex following traumatic brain injury[J]. J Mol Neurosci,2013,51(3):1021-9.
[10] Kimura A,Yoshikura N,Hayashi Y,et al. Cerebrospinal fluid CC motif chemokine ligand 2 correlates with brain atrophy andcognitive impairment in Alzheimer's disease[J]. J Alzheimers Dis,2018,61(2):1-8.
[11]姜懿纳,陈乃宏. CCL2/MCP-1在其相关疾病的机制研究[J].中国药理学通报,2016,32(12):1634-8.[11] Jiang Y N,Chen N H. Mechanism of CCL2/MCP-1 in its relevant diseases[J]. Chin Pharmacol Bull,2016,32(12):1634-8.
[12] Zhou Y,Tang H,Xiong H. Chemokine CCL2 enhances NMDA receptor-mediated excitatory postsynaptic current in rat hippocampal slices-a potential mechanism for HIV-1-associated neuropathy[J]? J Neuroimmune Pharmacol,2016,11(2):306-15.
[13] Zhou Y,Tang H,Liu J,et al. Chemokine CCL2 modulation of neuronal excitability and synaptic transmission in rat hippocampal slices[J]. J Neurochem,2011,116(3):406-14.