化浊解毒疏肝方对慢性应激小鼠的抗抑郁作用及对BDNF-Rac1-cofilin通路的影响
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摘要
目的:探讨化浊解毒疏肝方对慢性应激小鼠的抗抑郁作用,并探讨治疗抑郁症的可能机制。方法:采用雄性ICR小鼠72只,随机分为正常组、模型组、西药组及中药高、中、低剂量组。建立慢性不可预见性应激模型,观察小鼠的抑郁程度,及海马神经元超微结构,免疫印迹法和实时定量PCR(qPCR)检测小鼠海马组织BDNF、TrkB、Rac1、p-cofilin蛋白水平。结果:①行为学测试显示模型组小鼠抑郁程度显著高于正常组(P<0.05),中药高中剂量组与模型组比较抑郁程度显著减轻(P<0.05)。②电镜显示模型组神经元细胞萎缩,膜结构欠清晰,突触融合,小泡减少,神经毡水肿。中药治疗后显著改善。③与正常组比较,模型组BDNF、TrkB、Rac1、p-cofilin表达显著减少(P<0.05);与模型组比较,中药高、中剂量组表达显著增加(P<0.05)。结论:化浊解毒疏肝方明显增加BDNF和受体的表达,从而激活Rac1-cofilin通路,进而影响突触可塑性,这可能是其发挥抗抑郁作用的机制之一。
Objective: To explore the anti-depression effect of Huazhuo Jiedu Shugan Formula(HJSF) on chronic mild stress mice and the expression of brain-derived neurotrophic factor(BDNF) protein and its receptor, and to discuss the possible mechanism of treating depression. Methods: Seventy-two male ICR mice were randomly divided into normal group, model group,western medicine group and high, medium and low dose groups. The model was established by chronic mild stress, and the degree of depression and the ultrastructure of hippocampal neurons in mice were observed. The levels of BDNF, TrkB, Rac1 and p-cofilin protein in hippocampus of mice were detected by western blot, and mRNA tested by qPCR. Results: ①Compared with the normal group, the depression degree of mice in model group was significantly higher(P<0.05), and the depression degree of the high dose group of traditional Chinese medicine was significantly reduced compared with the model group(P<0.05). ②Electron microscope showed atrophy of neurons, unclear membrane structure, synaptic fusion, decreased vesicles and neuropil edema in the model group, which were alleviated with HJSF treatment. ③The expression of BDNF, TrkB, Rac1 and p-cofilin protein and BDNF mRNA were significantly decreased in model group compared with normal group(P<0.05). Compared with the model group, the expression of TCM in the high and medium dose groups was significantly increased(P<0.05). Conclusion: HJSF could obviously improve the expression of BDNF and its receptors, activating the Rac1-cofilin pathway, and then affecting synaptic plasticity,which may be one of the mechanisms of anti-depression effect of HJSF.
Objective: To explore the anti-depression effect of Huazhuo Jiedu Shugan Formula(HJSF) on chronic mild stress mice and the expression of brain-derived neurotrophic factor(BDNF) protein and its receptor, and to discuss the possible mechanism of treating depression. Methods: Seventy-two male ICR mice were randomly divided into normal group, model group,western medicine group and high, medium and low dose groups. The model was established by chronic mild stress, and the degree of depression and the ultrastructure of hippocampal neurons in mice were observed. The levels of BDNF, TrkB, Rac1 and p-cofilin protein in hippocampus of mice were detected by western blot, and mRNA tested by qPCR. Results: ①Compared with the normal group, the depression degree of mice in model group was significantly higher(P<0.05), and the depression degree of the high dose group of traditional Chinese medicine was significantly reduced compared with the model group(P<0.05). ②Electron microscope showed atrophy of neurons, unclear membrane structure, synaptic fusion, decreased vesicles and neuropil edema in the model group, which were alleviated with HJSF treatment. ③The expression of BDNF, TrkB, Rac1 and p-cofilin protein and BDNF mRNA were significantly decreased in model group compared with normal group(P<0.05). Compared with the model group, the expression of TCM in the high and medium dose groups was significantly increased(P<0.05). Conclusion: HJSF could obviously improve the expression of BDNF and its receptors, activating the Rac1-cofilin pathway, and then affecting synaptic plasticity,which may be one of the mechanisms of anti-depression effect of HJSF.
引文
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[2]徐永著,盛慧.抑郁症发病机制研究进展.安徽医科大学学报,2012,47(3):323-326
[3]Larsen M H,Mikkelsen J D,Hay-Schmidt A,et al.Regulation of brain-derived neurotrophic factor(BDNF)in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment.J Psychiatr Res,2010,44(13):808-816
[4]Naranjoa C A,Tremblaye L K,Bustob U E.The role of the brain reward system in depression.Progress in Neuro-Psychopharmacology and Biological Psychiatry,2001,25(4):781-823
[5]Paoo M.Pharmacological validation of the chronic mild strss model of depression.European Neuropsychopharmacology,2001,11(Supp3):S166-S167
[6]McEwenBS,MagarinosAM.Stressandhippocampal plasticity:Implications for the pathophysiology of affective disorder.Hum Psychopharmacol,2001,16:S7-S19
[7]李婷婷,俞晓飞,李祥婷,等.归脾汤对抑郁模型大鼠行为学及海马CA3区BDNF水平的影响.中华中医药杂志,2018,33(7):2827-2831
[8]Castren E,Vodkar V,Rantarnaki T.Role of neurotrophic factors in depression.Current Opinion in Pharmacology,2007,7(1):18-21
[9]Castren E.Neurotrophic effects of antidepressant drugs.Curr Opin Pharmacol,2004,4:58-64
[10]Bi A L,Wang Y,Li B Q,et al.Region-specific involvement of actin rearrangement-related synaptic structure alterations in conditioned taste aversion memory.Learn Mem,2010,17:420-427
[11]Jiang H,Wang Z,Wang Y,et al.Antidepressant-like effects of curcumin in chronic mild stress of rats;Involvement of its antiinflammatory action.Prog Neuropsychopharmacol Biol Psychiatry,2013,47:33-39
[12]Lin T Y,Lu C W,Wang C C,et al.Curcumin inhibits glutamate release in nerve terminals from rat prefrontal cortex:Possible relevance to its antidepressant mechanism.Progress in NeuroPsychopharmacology&Biological Psychiatry,2011,35(7):1785-1793