基于CUMS大鼠逍遥散拆方药队抗抑郁作用的BDNF通路分子机制研究
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摘要
目的:以CUMS大鼠模型为载体,探讨逍遥散拆方药队(柴胡、当归等组成)抗抑郁作用的BDNF通路分子机制,为该药队的抗抑郁作用应用提供药理学依据。方法:通过4周慢性温和不可预知应激(CUMS)程序造模,建立CUMS大鼠抑郁模型。造模4周后开始灌胃给予相应药物,连续4周,同时持续造模程序。给药4周后取各组大鼠大脑皮层、海马部位,Real-Time PCR法测定BDNF、TrkB、CREB mRNA相对表达水平,Western-Blot法测定BDNF、TrkB、CREB、pCREB蛋白表达水平。结果:逍遥散拆方药队15.33、11.5 g﹒kg-1剂量与逍遥散全方可明显上调模型大鼠皮层与海马部位BDNF、TrkB、CREB mRNA和蛋白表达水平,促进CREB磷酸化。结论:逍遥散拆方药队对CUMS大鼠的抗抑郁作用发挥与上调BDNF-TrkB-CREB通路活性相关。
Objective: To study the antidepressant effects of BDNF pathways molecular mechanisms of the composition drug-group of Xiaoyaosan(Chaihu, Danggui and etc.) in CUMS model rats, and provide pharmacology basis for the antidepression effect in clinic application. Method: The depression rat model was established by chronic unpredictable mild stress(CUMS) for 4 weeks. Then the corresponding drugs were orally administered to different group for 4 weeks continually, and the process of model stimulation continued at the same time. The hippocampus and cerebral cortex of rats were isolated for detection after 4 weeks of administration. The mRNA expressions of BDNF, TrkB, and CREB in cortex and hippocampus were detected by Real-Time PCR. The protein expressions of BDNF, TrkB, CREB and pCREB in cortex and hippocampus were detected by Western-Blot. Result: Compared with the model group, Xiaoyaosan and the composition drug-group of Xiaoyaosan 15.33, 11.5 g﹒kg-1 could up-regulate the expressions of BDNF, TrkB, and CREB mRNA and protein in the cortex and hippocampus of CUMS rats, and promote the phosphorylation of CREB. Conclusion: The anti-depression effect of Xiaoyaosan and the composition druggroup of Xiaoyaosan on CUMS rats are related to the up-regulation of BDNF-TrkB-CREB pathway.
Objective: To study the antidepressant effects of BDNF pathways molecular mechanisms of the composition drug-group of Xiaoyaosan(Chaihu, Danggui and etc.) in CUMS model rats, and provide pharmacology basis for the antidepression effect in clinic application. Method: The depression rat model was established by chronic unpredictable mild stress(CUMS) for 4 weeks. Then the corresponding drugs were orally administered to different group for 4 weeks continually, and the process of model stimulation continued at the same time. The hippocampus and cerebral cortex of rats were isolated for detection after 4 weeks of administration. The mRNA expressions of BDNF, TrkB, and CREB in cortex and hippocampus were detected by Real-Time PCR. The protein expressions of BDNF, TrkB, CREB and pCREB in cortex and hippocampus were detected by Western-Blot. Result: Compared with the model group, Xiaoyaosan and the composition drug-group of Xiaoyaosan 15.33, 11.5 g﹒kg-1 could up-regulate the expressions of BDNF, TrkB, and CREB mRNA and protein in the cortex and hippocampus of CUMS rats, and promote the phosphorylation of CREB. Conclusion: The anti-depression effect of Xiaoyaosan and the composition druggroup of Xiaoyaosan on CUMS rats are related to the up-regulation of BDNF-TrkB-CREB pathway.
引文
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[2]杨靖,龚锡平,刘蓉,等.逍遥散及其功效拆方对CUMS抑郁模型大鼠行为学的影响[J].中国实验方剂学杂志,2013,11(22):191.
[3]何敏,武志强,阙昌田,等.逍遥散拆方药队的抗抑郁作用及部分机制研究[J].中药药理与临床,2014,30(6):5.
[4]王学,刘蓉,罗杰,等.基于CUMS大鼠逍遥散拆方药队抗抑郁作用及BDNF/HPA机制研究[J].中药药理与临床,2018,34(1):14.
[5]Machaalani R,Chen H.Brain derived neurotrophic factor(BDNF),its tyrosine kinase receptor B(TrkB)and nicotine[J].NeuroToxicology,2018,65:186.
[6]Bathina S,Das U N.Brain-derived neurotrophic factor and its clinical implications[J].Arch Med Sci,2015,11(6):164.
[7]Cohen-Cory S.The developing synapse:construction and modulation of synaptic structures and circuits[J].Science,2002,298(5594):770.
[8]Changeux J P.The nicotinic acetylcholine receptor:the founding father of the pentameric ligand-gated ion channel superfamily[J].J Biol Chem,2012,287(48):40207.
[9]Autry A E,Monteggia L M.Brain-derived neurotrophic factor and neuropsychiatric disorders[J].Pharmacological Rev,2012,64(2):238.
[10]Karege F,Vaudan G,Schwald M,et al.Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs[J].Brain Res Mol Brain Res,2005,136(1-2):29.
[11]Fuchs E,Czéh B,Kole M H,et al.Alterations of neuroplasticity in depression:the hippocampus and beyond[J].Eur Neuropsychopharmacol,2004,1 5(5):S481.
[12]De Vry J,Vanmierlo T,Martinez-Martinez P,et al.TrkB in the hippocampus and nucleus accumbens differentially modulates depression-like behavior in mice[J].Behav Brain Res,2016,296:15.
[13]Hashimoto K,Shimizu E,Iyo M.Critical role of brain derived neurotrophic factor in mood disorders[J].Brain Res Brain Res Rev,2004,45(2):104.
[14]Lin P P,Wang C,Xu B,et al.The VGF-derived peptide TLQP62 produces antidepressant-like effects in mice via the BDNF/TrkB/CREB signaling pathway[J].Pharmacol Biochem Behav,2014,120(5):140.
[15]Dwivedi Y,Rizavi HS,Roberts RC,et al.Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects[J].JNeurochem,2001,77(3):916.
[16]Coyle JT,Duman RS.Finding the intracellular signaling pathways affected by mood disorder treatments[J].Neuron,2003,38(2):157.
[17]王涵.帕罗西汀抗抑郁作用与BDNF、CORT、NET和5-HTT表达关系[D].重庆:重庆医科大学,2011.()