解郁清心安神汤抗抑郁作用及机制研究
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摘要
目的：通过建立行为绝望抑郁小鼠模型、利血平诱导抑郁小鼠模型、慢性不可预知应激（chronic unpredictable stress, CUS）抑郁小鼠模型，观察解郁清心安神汤的抗抑郁作用，并探讨其相关机制。
方法：
1解郁清心安神汤对行为绝望抑郁模型小鼠的影响
①选择体重18-22g的SPF级雌性昆明种小鼠40只，随机分为4组：空白对照组、阳性药组、中药高、低剂量组，每组10只。②每日于08:00灌胃，空白对照组灌胃生理盐水，阳性药组灌胃盐酸氟西汀溶液，中药组灌胃相应浓度解郁清心安神汤浓缩煎剂，灌胃容量均为0.2ml/10g，连续8d。③第7d，进行悬尾实验，观察后5min内小鼠的不动时间④第8d，进行强迫游泳实验，观察后4min小鼠游泳不动时间。
2解郁清心安神汤对利血平诱导抑郁模型小鼠的影响
①选择体重18-22g的SPF级雌性昆明种小鼠50只，随机分为5组：空白对照组、模型组、阳性药组、中药高、低剂量组，每组10只。②每日于08:00灌胃，空白对照组和模型组灌胃生理盐水，阳性药组灌胃盐酸阿米替林溶液，中药组灌胃相应浓度解郁清心安神汤浓缩煎剂，灌胃容量均为0.2ml/10g，连续14d。③第14d，空白对照组腹腔注射生理盐水2.5mg/kg，其余各组腹腔注射利血平2.5mg/kg，。1h后观察小鼠眼睑下垂情况，3h后测肛温，计算小鼠出圈率。
3解郁清心安神汤对CUS抑郁模型小鼠的影响
①选择体重16-18g的SPF级雌性昆明种小鼠50只，适应性饲养一周后，随机分为5组：空白对照组、模型组、阳性药组、中药高、低剂量组，每组10只。②每日于08:00灌胃，空白对照组和模型组灌胃生理盐水，阳性药组灌胃盐酸氟西汀溶液，中药组灌胃相应浓度解郁清心安神汤浓缩煎剂，灌胃容量均为0.2ml/10g，连续60d。③除空白对照组外，其余各组通过慢性不可预知应激结合孤养建立慢性不可预知应激抑郁小鼠模型。④通过糖水偏好实验和旷场实验考察动物快感缺乏程度、焦虑水平、活动能力和活跃程度等行为；通过Morris水迷宫实验探讨抑郁小鼠对空间线索信息的学习和记忆能力。
4解郁清心安神汤对CUS抑郁模型小鼠海马单胺类神经递质影响
采用酶联免疫分析（ELISA）法测定模型小鼠海马5-HT、NA、DA含量，探讨解郁清心安神汤对CUS抑郁模型小鼠海马单胺类神经递质影响。
5解郁清心安神汤对CUS抑郁模型小鼠下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenocortical axis, HPA)轴的影响
采用酶联免疫分析（ELISA）法测定模型小鼠下丘脑CRF和血清ATCH含量，探讨解郁清心安神汤对CUS抑郁模型小鼠HPA轴的影响。
6解郁清心安神汤对CUS抑郁模型小鼠炎性损伤的影响
采用酶联免疫分析（ELISA）法测定模型小鼠血清IL-1β及IL-2含量，探讨解郁清心安神汤对CUS抑郁模型小鼠炎性损伤的影响。
7解郁清心安神汤对CUS抑郁模型小鼠海马BDNF的影响
采用酶联免疫分析（ELISA）法测定模型小鼠海马BDNF含量，探讨解郁清心安神汤对CUS抑郁模型小鼠海马神经可塑性的影响。
结果:
1与空白对照组比较，解郁清心安神汤可以明显缩短小鼠强迫游泳实验和悬尾实验的不动时间(p0.05)，表明解郁清心安神汤可以显著改善行为绝望小鼠的绝望状态。
2与模型组比较，解郁清心安神汤可以明显拮抗利血平导致的体温下降(p0.05)、眼睑下垂(p0.05)及活动不能状态，表明解郁清心安神汤可以显著改善利血平所致的抑郁症状。
3与空白对照组比较，模型组小鼠糖水偏爱率降低(p0.05)，水平和垂直运动次数减少(p0.05)，水迷宫实验逃避潜伏期延长(p0.05)和穿越次数下降(p0.05)，表明慢性不可预知应激可以造成小鼠快感缺失，探究活动减少，学习记忆能力下降，提示造模成功；与模型组比较，解郁清心安神汤可以提高小鼠糖水偏爱率(p0.05)，增加水平和垂直运动次数(p0.05)，缩短逃避潜伏期(p0.05)和增加穿越次(p0.05)，表明解郁清心安神汤可以显著改善慢性应激抑郁小鼠抑郁症状，提高其学习记忆能力。
4与空白对照组比较，模型组小鼠海马5-HT、NA、DA含量均明显减少(均p0.05)，表明慢性不可预知应激可以使小鼠脑内单胺类神经递质含量下降，提示造模成功；与模型组比较，解郁清心安神汤高、低剂量组小鼠海马5-HT、NA、DA含量均明显升高(均p0.05)，表明解郁清心安神汤可以增加抑郁小鼠脑内单胺类神经递质的含量，提示提高中枢单胺类神经递质系统功能可能是解郁清心安神汤抗抑郁作用机制之一。
5与空白对照组比较，模型组小鼠下丘脑CRF含量明显增多(p0.05)、血清ACTH水平显著升高(p0.05)，表明慢性应激可以造成小鼠HPA轴功能亢进，提示造模成功；与模型组比较，解郁清心安神汤高、低剂量组小鼠下丘脑CRF及血清ACTH含量明显降低(均p0.05)，表明解郁清心安神汤可以抑制抑郁小鼠亢进的HPA轴，提示抑制HPA功能亢进可能是解郁清心安神汤抗抑郁作用机制之一。
6与空白对照组比较，模型组小鼠血清IL-1β及IL-2水平均明显升高(均p0.05)，提示慢性应激可以上调IL-1β及IL-2的表达，提示抑郁症可能存在炎性损伤；与模型组比较，解郁清心安神汤可以显著降低血清IL-1β及IL-2水平(均p0.05)，表明解郁清心安神汤可以下调IL-1β及IL-2的表达，提示减轻神经元的炎性损伤可能是解郁清心安神汤抗抑郁机制之一。
7与空白对照组比较，慢性应激模型小鼠海马BDNF含量明显减少(p0.05)，表明慢性应激可以使脑内BDNF表达减少，提示造模成功；与模型组比较，解郁清心安神汤高、低剂量组小鼠海马BDNF含量均明显升高(p0.05)，表明解郁清心安神汤可以增加抑郁小鼠脑内BDNF含量，提示促进中枢神经可塑性可能是其抗抑郁作用机制之一。
结论：
解郁清心安神汤具有显著的抗抑郁作用，可以改善抑郁小鼠的绝望状态和快感缺失症状，对抗利血平诱导的抑郁表现，提高CUS抑郁小鼠的学习记忆能力。
解郁清心安神汤的抗抑郁机制可能为以下几点：：①增加脑内5-HT、NA、DA单胺类递质含量，提高单胺类神经递质系统活性；②增加GR的敏感性，减弱GC抵抗，恢复GC对HPA轴的负反馈调节，下调HPA轴的活性；③下调IL-1β、IL-2致炎性细胞因子的表达，减轻神经元的炎性损伤；④上调脑内BDNF的表达，促进情绪中枢的神经可塑性。
Objective: To observe the effects of Jieyu Qingxin Anshen decoction (JYQXASD)and explore it’s possible antidepressant mechanism.
Methods:
1. Force swimming test and tail suspension test.
①Select40female KM mice with18-22g, and divide them into4groups randomly:control group, Positive group, JYQXASD-H group and JYQXASD-L group,10in eachgroup.②Do the Intragastric administration for the mice every day at08:00,0.4ml salinefor control group,0.4ml fluoxertine hydrochloride saline liquor for positive group and0.4ml different concentrations of JYQXASD for different JYQXASD groups.③Record the accumulative immovability time in the late4minutes of the mice by theforced swimming test in each group on the7th day, and in the late5minutes of the mice bythe tail suspension on the8th day.
2. Effects of JYQXASD on the depression mice induced by reserpine.
①Select50female KM mice with18-22g, and divide them into5groups randomly:control group, model group, positive group, JYQXASD-H group and JYQXASD-L group,10in each group.②Do the intragastric administration for the mice every day at08:00,0.4ml saline for control group and model group,0.4ml amitrptyline saline liquor forpositive group and0.4ml different concentrations of JYQXASD for JYQXASD-H groupand JYQXASD-L group.③After the intragastric administration for14days, give reserpineto induce depression symptoms, and observe the body temperature, eye ptosis andakinese of mice.
3. Effects of JYQXASD on the depression mice made by unpredictable chronic stress.
①Select50female KM mice with16-18g, and divide them into5groups randomly: control group, model group, positive group, JYQXASD-H group and JYQXASD-L group,10in each group.②Do the intragastric administration for the mice every day at08:00,0.4ml saline for control group and model group,0.4ml fluoxertine hydrochloride salineliquor for positive group and0.4ml different concentrations of JYQXASD for differentJYQXASD groups. Except for the control group, The KM mice were subjected to10different stressors for60days to create the depression mouse model.③At the end ofexperiments, mice were analyzed with depression-related behavioral test. The body weightof all mice was recorded during the experiment process. Mood state was evaluated bysaccharin preference test and open-field test. The changes of cognitive processing weretested through Morris water maze.
4. Study on the mechanism of JYQXASD on depression mice induced by CUS
After the behavior tests, all mice were decapitated, and brains were rapidly removed.The levers of5-HT, NA, DA and BDNF in hippocampus, CRH in hypothalamus, ACTH,IL-1βand IL-2in blood of depression mice was measured all by ELISA.
Results:
1. Different dose groups of JYQXASD reduced significantly the immobility time ofthe mice during the forced swimming test and the tail test (p0.05).
2. Compared to the control mice, the reserpine induced eye ptosis and akinese of mice,and decreased body temperature significantly (p0.05). These behaviors could berecovered by administration of JYQXASD (p0.05).
3. The chronic unpredictable stress led to the slow increase of the weight of the mice,the inhibition of the excitation and reactivity of mice in open-field test, and induced theweakened abilities of exploration and memory in Morris water maze as compared to thecontrol (p0.05). Compared to the control mice, the depression model mice consumedsignificantly less cane sugar (p0.05). These behaviors could be recovered byadministration of JYQXASD (p0.05).
4.The level of5-HT, NA and DA in the hippocampus of depression mice was allsignificantly decreased as compared to the control(p0.05), and could be elevated bytreatment with JYQXASD(p0.05).
5. Compared to the control group, the level of CRH in hypothalamus and ACTH inthe blood of depression mice was significantly increased (p0.05); And JYQXASD coulddecrease the level of CRH and ACTH(p0.05).
6. The level of L-1βand IL-2in the blood of depression mice was all significantlyincreased as compared to the control(p0.05), and JYQXASD could decrease the level ofIL-1βand IL-2(p0.05).
7. The chronic unpredictable stress could decrease the level of BDNF in thehippocampus, as compared to thud control (p0.05), and JYQXASD could significantlyelevate the level of BDNF (p0.05).
Conclusion: Jieyu Qingxin Anshen decoction could reduce the immobility time of themice in the forced swimming test and the tail test, at the same time could reverse the ptosis,akinesia, hypothermia induced by Reserpine. Furthermore, JYQXASD could reverse thesymptom of depression induced by the chronic unpredictable stress. Chronic psychologicalstress can injure function of hippocampus which can be declined by JYQXASD.Ourstudies indicated that JYQXASD can enhance the function of monoamine neurotransmitter,regulate HPA axis hypoglycemia, strengthen the immunity ability, and at the same timereverse the decline of the lever of BDNF.
方法：
1解郁清心安神汤对行为绝望抑郁模型小鼠的影响
①选择体重18-22g的SPF级雌性昆明种小鼠40只，随机分为4组：空白对照组、阳性药组、中药高、低剂量组，每组10只。②每日于08:00灌胃，空白对照组灌胃生理盐水，阳性药组灌胃盐酸氟西汀溶液，中药组灌胃相应浓度解郁清心安神汤浓缩煎剂，灌胃容量均为0.2ml/10g，连续8d。③第7d，进行悬尾实验，观察后5min内小鼠的不动时间④第8d，进行强迫游泳实验，观察后4min小鼠游泳不动时间。
2解郁清心安神汤对利血平诱导抑郁模型小鼠的影响
①选择体重18-22g的SPF级雌性昆明种小鼠50只，随机分为5组：空白对照组、模型组、阳性药组、中药高、低剂量组，每组10只。②每日于08:00灌胃，空白对照组和模型组灌胃生理盐水，阳性药组灌胃盐酸阿米替林溶液，中药组灌胃相应浓度解郁清心安神汤浓缩煎剂，灌胃容量均为0.2ml/10g，连续14d。③第14d，空白对照组腹腔注射生理盐水2.5mg/kg，其余各组腹腔注射利血平2.5mg/kg，。1h后观察小鼠眼睑下垂情况，3h后测肛温，计算小鼠出圈率。
3解郁清心安神汤对CUS抑郁模型小鼠的影响
①选择体重16-18g的SPF级雌性昆明种小鼠50只，适应性饲养一周后，随机分为5组：空白对照组、模型组、阳性药组、中药高、低剂量组，每组10只。②每日于08:00灌胃，空白对照组和模型组灌胃生理盐水，阳性药组灌胃盐酸氟西汀溶液，中药组灌胃相应浓度解郁清心安神汤浓缩煎剂，灌胃容量均为0.2ml/10g，连续60d。③除空白对照组外，其余各组通过慢性不可预知应激结合孤养建立慢性不可预知应激抑郁小鼠模型。④通过糖水偏好实验和旷场实验考察动物快感缺乏程度、焦虑水平、活动能力和活跃程度等行为；通过Morris水迷宫实验探讨抑郁小鼠对空间线索信息的学习和记忆能力。
4解郁清心安神汤对CUS抑郁模型小鼠海马单胺类神经递质影响
采用酶联免疫分析（ELISA）法测定模型小鼠海马5-HT、NA、DA含量，探讨解郁清心安神汤对CUS抑郁模型小鼠海马单胺类神经递质影响。
5解郁清心安神汤对CUS抑郁模型小鼠下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenocortical axis, HPA)轴的影响
采用酶联免疫分析（ELISA）法测定模型小鼠下丘脑CRF和血清ATCH含量，探讨解郁清心安神汤对CUS抑郁模型小鼠HPA轴的影响。
6解郁清心安神汤对CUS抑郁模型小鼠炎性损伤的影响
采用酶联免疫分析（ELISA）法测定模型小鼠血清IL-1β及IL-2含量，探讨解郁清心安神汤对CUS抑郁模型小鼠炎性损伤的影响。
7解郁清心安神汤对CUS抑郁模型小鼠海马BDNF的影响
采用酶联免疫分析（ELISA）法测定模型小鼠海马BDNF含量，探讨解郁清心安神汤对CUS抑郁模型小鼠海马神经可塑性的影响。
结果:
1与空白对照组比较，解郁清心安神汤可以明显缩短小鼠强迫游泳实验和悬尾实验的不动时间(p0.05)，表明解郁清心安神汤可以显著改善行为绝望小鼠的绝望状态。
2与模型组比较，解郁清心安神汤可以明显拮抗利血平导致的体温下降(p0.05)、眼睑下垂(p0.05)及活动不能状态，表明解郁清心安神汤可以显著改善利血平所致的抑郁症状。
3与空白对照组比较，模型组小鼠糖水偏爱率降低(p0.05)，水平和垂直运动次数减少(p0.05)，水迷宫实验逃避潜伏期延长(p0.05)和穿越次数下降(p0.05)，表明慢性不可预知应激可以造成小鼠快感缺失，探究活动减少，学习记忆能力下降，提示造模成功；与模型组比较，解郁清心安神汤可以提高小鼠糖水偏爱率(p0.05)，增加水平和垂直运动次数(p0.05)，缩短逃避潜伏期(p0.05)和增加穿越次(p0.05)，表明解郁清心安神汤可以显著改善慢性应激抑郁小鼠抑郁症状，提高其学习记忆能力。
4与空白对照组比较，模型组小鼠海马5-HT、NA、DA含量均明显减少(均p0.05)，表明慢性不可预知应激可以使小鼠脑内单胺类神经递质含量下降，提示造模成功；与模型组比较，解郁清心安神汤高、低剂量组小鼠海马5-HT、NA、DA含量均明显升高(均p0.05)，表明解郁清心安神汤可以增加抑郁小鼠脑内单胺类神经递质的含量，提示提高中枢单胺类神经递质系统功能可能是解郁清心安神汤抗抑郁作用机制之一。
5与空白对照组比较，模型组小鼠下丘脑CRF含量明显增多(p0.05)、血清ACTH水平显著升高(p0.05)，表明慢性应激可以造成小鼠HPA轴功能亢进，提示造模成功；与模型组比较，解郁清心安神汤高、低剂量组小鼠下丘脑CRF及血清ACTH含量明显降低(均p0.05)，表明解郁清心安神汤可以抑制抑郁小鼠亢进的HPA轴，提示抑制HPA功能亢进可能是解郁清心安神汤抗抑郁作用机制之一。
6与空白对照组比较，模型组小鼠血清IL-1β及IL-2水平均明显升高(均p0.05)，提示慢性应激可以上调IL-1β及IL-2的表达，提示抑郁症可能存在炎性损伤；与模型组比较，解郁清心安神汤可以显著降低血清IL-1β及IL-2水平(均p0.05)，表明解郁清心安神汤可以下调IL-1β及IL-2的表达，提示减轻神经元的炎性损伤可能是解郁清心安神汤抗抑郁机制之一。
7与空白对照组比较，慢性应激模型小鼠海马BDNF含量明显减少(p0.05)，表明慢性应激可以使脑内BDNF表达减少，提示造模成功；与模型组比较，解郁清心安神汤高、低剂量组小鼠海马BDNF含量均明显升高(p0.05)，表明解郁清心安神汤可以增加抑郁小鼠脑内BDNF含量，提示促进中枢神经可塑性可能是其抗抑郁作用机制之一。
结论：
解郁清心安神汤具有显著的抗抑郁作用，可以改善抑郁小鼠的绝望状态和快感缺失症状，对抗利血平诱导的抑郁表现，提高CUS抑郁小鼠的学习记忆能力。
解郁清心安神汤的抗抑郁机制可能为以下几点：：①增加脑内5-HT、NA、DA单胺类递质含量，提高单胺类神经递质系统活性；②增加GR的敏感性，减弱GC抵抗，恢复GC对HPA轴的负反馈调节，下调HPA轴的活性；③下调IL-1β、IL-2致炎性细胞因子的表达，减轻神经元的炎性损伤；④上调脑内BDNF的表达，促进情绪中枢的神经可塑性。
Objective: To observe the effects of Jieyu Qingxin Anshen decoction (JYQXASD)and explore it’s possible antidepressant mechanism.
Methods:
1. Force swimming test and tail suspension test.
①Select40female KM mice with18-22g, and divide them into4groups randomly:control group, Positive group, JYQXASD-H group and JYQXASD-L group,10in eachgroup.②Do the Intragastric administration for the mice every day at08:00,0.4ml salinefor control group,0.4ml fluoxertine hydrochloride saline liquor for positive group and0.4ml different concentrations of JYQXASD for different JYQXASD groups.③Record the accumulative immovability time in the late4minutes of the mice by theforced swimming test in each group on the7th day, and in the late5minutes of the mice bythe tail suspension on the8th day.
2. Effects of JYQXASD on the depression mice induced by reserpine.
①Select50female KM mice with18-22g, and divide them into5groups randomly:control group, model group, positive group, JYQXASD-H group and JYQXASD-L group,10in each group.②Do the intragastric administration for the mice every day at08:00,0.4ml saline for control group and model group,0.4ml amitrptyline saline liquor forpositive group and0.4ml different concentrations of JYQXASD for JYQXASD-H groupand JYQXASD-L group.③After the intragastric administration for14days, give reserpineto induce depression symptoms, and observe the body temperature, eye ptosis andakinese of mice.
3. Effects of JYQXASD on the depression mice made by unpredictable chronic stress.
①Select50female KM mice with16-18g, and divide them into5groups randomly: control group, model group, positive group, JYQXASD-H group and JYQXASD-L group,10in each group.②Do the intragastric administration for the mice every day at08:00,0.4ml saline for control group and model group,0.4ml fluoxertine hydrochloride salineliquor for positive group and0.4ml different concentrations of JYQXASD for differentJYQXASD groups. Except for the control group, The KM mice were subjected to10different stressors for60days to create the depression mouse model.③At the end ofexperiments, mice were analyzed with depression-related behavioral test. The body weightof all mice was recorded during the experiment process. Mood state was evaluated bysaccharin preference test and open-field test. The changes of cognitive processing weretested through Morris water maze.
4. Study on the mechanism of JYQXASD on depression mice induced by CUS
After the behavior tests, all mice were decapitated, and brains were rapidly removed.The levers of5-HT, NA, DA and BDNF in hippocampus, CRH in hypothalamus, ACTH,IL-1βand IL-2in blood of depression mice was measured all by ELISA.
Results:
1. Different dose groups of JYQXASD reduced significantly the immobility time ofthe mice during the forced swimming test and the tail test (p0.05).
2. Compared to the control mice, the reserpine induced eye ptosis and akinese of mice,and decreased body temperature significantly (p0.05). These behaviors could berecovered by administration of JYQXASD (p0.05).
3. The chronic unpredictable stress led to the slow increase of the weight of the mice,the inhibition of the excitation and reactivity of mice in open-field test, and induced theweakened abilities of exploration and memory in Morris water maze as compared to thecontrol (p0.05). Compared to the control mice, the depression model mice consumedsignificantly less cane sugar (p0.05). These behaviors could be recovered byadministration of JYQXASD (p0.05).
4.The level of5-HT, NA and DA in the hippocampus of depression mice was allsignificantly decreased as compared to the control(p0.05), and could be elevated bytreatment with JYQXASD(p0.05).
5. Compared to the control group, the level of CRH in hypothalamus and ACTH inthe blood of depression mice was significantly increased (p0.05); And JYQXASD coulddecrease the level of CRH and ACTH(p0.05).
6. The level of L-1βand IL-2in the blood of depression mice was all significantlyincreased as compared to the control(p0.05), and JYQXASD could decrease the level ofIL-1βand IL-2(p0.05).
7. The chronic unpredictable stress could decrease the level of BDNF in thehippocampus, as compared to thud control (p0.05), and JYQXASD could significantlyelevate the level of BDNF (p0.05).
Conclusion: Jieyu Qingxin Anshen decoction could reduce the immobility time of themice in the forced swimming test and the tail test, at the same time could reverse the ptosis,akinesia, hypothermia induced by Reserpine. Furthermore, JYQXASD could reverse thesymptom of depression induced by the chronic unpredictable stress. Chronic psychologicalstress can injure function of hippocampus which can be declined by JYQXASD.Ourstudies indicated that JYQXASD can enhance the function of monoamine neurotransmitter,regulate HPA axis hypoglycemia, strengthen the immunity ability, and at the same timereverse the decline of the lever of BDNF.
引文
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