逍遥抗癌解郁方对乳腺癌并发抑郁症小鼠海马NMDAR相关蛋白表达的影响
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摘要
目的:研究逍遥抗癌解郁方对乳腺癌并发抑郁小鼠海马中N-甲基-D-天冬氨酸受体(NMDAR)相关蛋白表达的影响。方法:构建乳腺癌并发抑郁症模型,设立空白组、模型组、紫杉醇组、逍遥抗癌解郁方组、紫杉醇联合氟西汀组和紫杉醇联合逍遥抗癌解郁方组。悬尾实验和强迫游泳实验检测各组小鼠抑郁样行为,免疫组化和实时荧光定量PCR检测小鼠海马NR2A,NR2B及cAMP结合蛋白(cAMP response element binding protein,CREB)与钙调蛋白激酶Ⅱ(calmodulin kinaseⅡ,CaMKⅡ)蛋白和mRNA的表达以及NR2A,NR2B在肿瘤组织中的相对表达量。结果:与空白组比较,模型组小鼠不动时间显著上升(P <0. 01或P <0. 05),海马中NR2A,NR2B,CaMKⅡ表达显著上升(P <0. 01),CREB表达显著下降(P <0. 01)。给予逍遥抗癌解郁方干预后小鼠不动时间显著下降(P <0. 01或P <0. 05),海马中NR2A,NR2B及CaMKⅡ表达显著降低(P <0. 01),CREB表达明显升高(P <0. 01)。与模型组相比,逍遥抗癌解郁方组小鼠肿瘤中NR2A,NR2B mRNA表达显著降低,肿瘤瘤重与瘤体积也显著减小(P <0. 01或P <0. 05)。结论:逍遥抗癌解郁方能明显改善乳腺癌并发抑郁小鼠抑郁样行为,在一定程度上抑制乳腺癌肿瘤生长,其作用机制与调节NMDAR相关蛋白表达及增强海马突触可塑性有关。
Objective: To investigate the effects of Xiaoyao Kangai Jieyu Formula on the expression of Nmethyl-D-aspartate receptor( NMDAR) related proteins in hippocampus of breast cancer related with depression mice. Methods: Construction of breast cancer related with depression model,and establishment control group,model group,paclitaxel group,Xiaoyao Kangai Jieyu Formula group,paclitaxel combined with fluoxetine group,and paclitaxel combined with Xiaoyao Kangai Jieyu Formula group. Tail suspension test and forced swimming tests were used to detect depressive behavior of mice. Immunohistochemistry and real-time quantitative PCR were used todetect the expression of NR2 A,NR2 B,cAMP response element binding protein( CREB) and calmodulin kinase Ⅱ( CaMKⅡ) protein and mRNA in hippocampus of mice,and the relative expression of NR2 A and NR2 B in tumor tissue. Results: Compared with the control group,the immobility time of the mice of model group increased significantly( P < 0. 01 or P < 0. 05),the expression of NR2 A,NR2 B,CaMK Ⅱ in hippocampus increased significantly( P < 0. 01),and the expression of CREB decreased significantly( P < 0. 01). The immobility time of mice was significantly decreased( P < 0. 01 or P < 0. 05),the expression of NR2 A,NR2 B and CaMK Ⅱ in hippocampus was significantly decreased( P < 0. 01),and the expression of CREB was significantly increased( P < 0. 01) after the intervention of Xiaoyao Kangai Jieyu Formula. Compared with the model group,the expression of NR2 A and NR2 B mRNA in tumor tissue of Xiaoyao Kangai Jieyu Formula group decreased significantly and the weight and volume of tumor were significantly decreased( P < 0. 01 or P < 0. 05). Conclusion: Xiaoyao Kangai Jieyu Formula can obviously improve the depression-like behavior of mice with breast cancer and depression,and inhibit the growth of breast cancer tumor to a certain extent. Its mechanism is related to regulating the expression of NMDAR related protein and enhancing the synaptic plasticity of hippocampus.
Objective: To investigate the effects of Xiaoyao Kangai Jieyu Formula on the expression of Nmethyl-D-aspartate receptor( NMDAR) related proteins in hippocampus of breast cancer related with depression mice. Methods: Construction of breast cancer related with depression model,and establishment control group,model group,paclitaxel group,Xiaoyao Kangai Jieyu Formula group,paclitaxel combined with fluoxetine group,and paclitaxel combined with Xiaoyao Kangai Jieyu Formula group. Tail suspension test and forced swimming tests were used to detect depressive behavior of mice. Immunohistochemistry and real-time quantitative PCR were used todetect the expression of NR2 A,NR2 B,cAMP response element binding protein( CREB) and calmodulin kinase Ⅱ( CaMKⅡ) protein and mRNA in hippocampus of mice,and the relative expression of NR2 A and NR2 B in tumor tissue. Results: Compared with the control group,the immobility time of the mice of model group increased significantly( P < 0. 01 or P < 0. 05),the expression of NR2 A,NR2 B,CaMK Ⅱ in hippocampus increased significantly( P < 0. 01),and the expression of CREB decreased significantly( P < 0. 01). The immobility time of mice was significantly decreased( P < 0. 01 or P < 0. 05),the expression of NR2 A,NR2 B and CaMK Ⅱ in hippocampus was significantly decreased( P < 0. 01),and the expression of CREB was significantly increased( P < 0. 01) after the intervention of Xiaoyao Kangai Jieyu Formula. Compared with the model group,the expression of NR2 A and NR2 B mRNA in tumor tissue of Xiaoyao Kangai Jieyu Formula group decreased significantly and the weight and volume of tumor were significantly decreased( P < 0. 01 or P < 0. 05). Conclusion: Xiaoyao Kangai Jieyu Formula can obviously improve the depression-like behavior of mice with breast cancer and depression,and inhibit the growth of breast cancer tumor to a certain extent. Its mechanism is related to regulating the expression of NMDAR related protein and enhancing the synaptic plasticity of hippocampus.
引文
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[11] PEREZRANDO M,CASTILLOGMEZ E,GUIRADO R,et al.NMDA receptors regulate the structural plasticity of spines and axonal boutons in hippocampal interneurons[J]. Front Cell Neurosci,2017,11(1):166-179.
[12] ZANOS P,THOMPSON SM,DUMAN RS,et al. Convergent mechanisms underlying rapid antidepressant action[J]. CNS Drugs,2018,32(3):197-227.
[13] JIANG T,WANG X,DING C,et al. Genistein attenuates isoflurane-induced neurotoxicity and improves impaired spatial learning and memory by regulating c AMP/CREB and BDNF-TrkB-PI3K/Akt signaling[J]. Korean J Physiol Pharmacol,2017,21(6):579-589.
[14] REN X,DWIVEDI Y,MONDAL AC,et al. Cyclic-AMP response element binding protein(CREB)in the neutrophils of depressed patients[J]. Psychiatry Res,2010,185(1-2):108-112.
[15] WANG H,PENG RY. Basic roles of key molecules connected with NMDAR signaling pathway on regulating learning and memory and synaptic plasticity[J]. Mil Med Res,2016,3(4):212-218.
[2]陈万青,郑荣寿.中国女性乳腺癌发病死亡和生存状况[J].中国肿瘤临床,2015,42(13):668-674.
[3] LIM CC,DEVI MK,ANG E. Anxiety in women with breast cancer undergoing treatment:a systematic review[J]. Int J Qual Health C,2011,9(3):215-235.
[4] ROBINSON HPC,LI L. Autocrine,paracrine and necrotic NMDA receptor signalling in mouse pancreatic neuroendocrine tumour cells[J]. Open Biol,2017,7(12):170221-170234.
[5] GUO H,CAMARGO LM,YEBOAH F,et al. A NMDA-receptor calcium influx assay sensitive to stimulation by glutamate and glycine/D-serine[J]. Sci Rep,2017,7(1):11608-11620.
[6]李兴宇,高灿.突触上与突触外的NMDA受体及其与阿尔茨海默病关系的研究进展[J].生物化学与生物物理进展,2014,41(9):823-829.
[7] D'SOUZA V,DAUDT H,KAZANJIAN A. Survivorship care plans for breast cancer patients:understanding the quality of the available evidence[J]. Curr Oncol,2017,24(6):446-465.
[8]程熙,印国兵,李霞,等.乌司他丁联合去氧氟尿苷对乳腺癌肿瘤微环境的影响[J].中国新药杂志,2017,26(14):1696-1705.
[9] ZHAN H,HUANG F,YAN F,et al. Alterations in splenic function and gene expression in mice with depressive-like behavior induced by exposure to corticosterone[J]. Int J of Mol Med,2017,39(2):327-336.
[10] NORTH WG,GAO G,MEMOLI VA,et al. Breast cancer expresses functional NMDA receptors[J]. Breast Cancer Res Treat,2009,122(2):307-314.
[11] PEREZRANDO M,CASTILLOGMEZ E,GUIRADO R,et al.NMDA receptors regulate the structural plasticity of spines and axonal boutons in hippocampal interneurons[J]. Front Cell Neurosci,2017,11(1):166-179.
[12] ZANOS P,THOMPSON SM,DUMAN RS,et al. Convergent mechanisms underlying rapid antidepressant action[J]. CNS Drugs,2018,32(3):197-227.
[13] JIANG T,WANG X,DING C,et al. Genistein attenuates isoflurane-induced neurotoxicity and improves impaired spatial learning and memory by regulating c AMP/CREB and BDNF-TrkB-PI3K/Akt signaling[J]. Korean J Physiol Pharmacol,2017,21(6):579-589.
[14] REN X,DWIVEDI Y,MONDAL AC,et al. Cyclic-AMP response element binding protein(CREB)in the neutrophils of depressed patients[J]. Psychiatry Res,2010,185(1-2):108-112.
[15] WANG H,PENG RY. Basic roles of key molecules connected with NMDAR signaling pathway on regulating learning and memory and synaptic plasticity[J]. Mil Med Res,2016,3(4):212-218.