基于CUMS大鼠逍遥散拆方药队抗抑郁作用及BDNF/HPA机制研究

Study on the antidepressant effects and mechanisms via BDNF/HPA of composition drug-group of Xiaoyao Powder based on CUMS rats

目的:以CUMS大鼠模型为载体,验证逍遥散拆方药队(柴胡、当归、薄荷,简称柴当薄组)的抗抑郁作用,探讨其抗抑郁作用的BDNF/HPA调节机制,为该药队的抗抑郁作用应用提供药理学依据。方法:慢性温和不可预知应激+孤养8周建立CUMS大鼠抑郁模型,造模第5周15.33、11.5g/kg柴当薄组、30 g/kg逍遥散全方及10mg/kg阿米替林灌胃给药,连续4周。以糖水偏好实验、旷场实验、强迫游泳及Morris水迷宫实验,观察柴当薄组对CUMS大鼠行为学的影响;测定HPA轴(肾上腺指数,血清、皮层、海马Cort水平,血清ACTH、CRH水平)和BDNF通路(血清、皮层、海马BDNF含量,血清TrkB、CREB水平)等指标,探讨其作用机制;采用Pearson分析评价CUMS大鼠抑郁样行为与其血清Cort水平、海马部位BDNF水平的相关性,揭示该模型的病理变化。结果:与模型对照组比较,柴当薄组11.5g/kg、15.33g/kg能提高CUMS大鼠的自主活动量、糖水偏好率及空间学习记忆能力,缩短强迫游泳不动时间,并能抑制肾上腺指数的增加,对抗模型大鼠血清、皮层与海马部位Cort水平和血清ACTH、CRH含量的异常升高,能提高模型大鼠血清、皮层与海马部位BDNF含量和血清TrkB、CREB水平;CUMS大鼠抑郁样行为程度与血清Cort水平呈正相关,与海马BDNF水平呈负相关。结论:逍遥散拆方功效研究所获得的柴当薄药组对CUMS大鼠具有与逍遥散全方类似的抗抑郁作用,作用机制与下调HPA轴功能亢进、上调BDNF-Trk、B-CREB水平有关。

Objective： To comfirm the antidepressant effect of the disassembled prescription drugs（Chai Hu,Dang Gui and Bo He,referred as Chai Dang Bo drug-group） from Xiaoyao Powder and investigate it＇s mechanism via BDNF/HPA signal pathway on CUMS model rats,so as to provide the pharmacology evidence for its antidepressant application. Methods： The depression model in rats was prepared by chronic unpredictable mild stress and isolated feeding for 8 weeks. At the fifth week,model rats were administered intragastrically with Xiaoyao Powder（30 g/kg）,Chai Dang Bo drug-group（15. 33 g/kg,11. 5 g/kg） and amitriptyline（10 mg/kg）,lasted for 4 weeks. The effect of Chai Dang Bo drug-group on behavior in CUMS rats were observed by experiments of sucrose preference test（SPT）,open field test（OFT）,forced swim test（FST）,spatial memory ability in Morris test. The index of HPA axis（adrenal gland index; levels of Cort in serum,cortex,hippocampus; levels of ACTH,CRH in serum） and BDNF pathway（levels of BDNF in serum,cortex,hippocampus; levels of TrkB,CREB in serum）was detected by ELISA,so as to explain the mechanism of its action. Pearson＇s correlation analysis was performed to evaluate the correlation of depressive-like behavior and the level of Cort in serum and BDNF in hippocampus of CUMS rats respectively,to reveal pathological changes of the model. Results： Compared with the model group,Chai Dang Bo drug-group（15. 33 g/kg,11. 5 g/kg） significantly increased the sucrose consumption and locomotor activity,improved the rats＇ learning and memorizing ability,as well as shortened immobility time in FTS.Chai Dang Bo drug-group（15. 33 g/kg,11. 5 g/kg） inhibited the increase of adrenal index,significantly decreased adrenal gland index,levels of Cort in serum,cortex and hippocampal and levels of ACTH,CRH in serum,and raised levels of BDNF in serum,cortex and hippocampus and levels of TrkB,CREB in serum. Depressive symptoms in CUMS rats were positively correlated with serum Cort level,but negatively correlated with hippocampal BDNF level. Conclusion： The Chai Dang Bo drug-group which were obtained by the antidepressant research of effective composition of Xiaoyao Powder showed the similar antidepressant effect in CUMS model rats to xiaoyao Powder. This mechanism is related to down-regulation of HPA axis hyperthyroidism and up-regulation of BDNF-TrkB-CREB levels.