Zhao Libin, Guo Rui, Cao Ningning, Lin Yingxian, Yang Wenjing, Pei Shuai, Ma Xiaowei, Zhang Yu, Li Yingpeng, Song Zhaohui, Du Wuxun, Xiao Xuefeng, Liu Changxiao
School of Graduate, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
Zhendong Research Institute, Shanxi Zhendong Pharmaceutical Co., Ltd, Beijing, China.
Front Pharmacol. 2021 Feb 15;11:590457. doi: 10.3389/fphar.2020.590457. eCollection 2020.
To evaluate the pharmacodynamical effects and pharmacological mechanism of Ginsenoside H dripping pills (GH) in chronic unpredictable mild stress (CUMS) model rats. First, the CUMS-induced rat model was established to assess the anti-depressant effects of GH (28, 56, and 112 mg/kg) by the changes of the behavioral indexes (sucrose preference, crossing score, rearing score) and biochemical indexes (serotonin, dopamine, norepinephrine) in Hippocampus. Then, the components of GH were identified by ultra-performance liquid chromatography-iron trap-time of flight-mass spectrometry (UPLC/IT-TOF MS). After network pharmacology analysis, the active ingredients of GH were further screened out based on OB and DL, and the PPI network of putative targets of active ingredients of GH and depression candidate targets was established based on STRING database. The PPI network was analyzed topologically to obtain key targets, so as to predict the potential pharmacological mechanism of GH acting on depression. Finally, some major target proteins involved in the predictive signaling pathway were validated experimentally. The establishment of CUMS depression model was successful and GH has antidepressant effects, and the middle dose of GH (56 mg/kg) showed the best inhibitory effects on rats with depressant-like behavior induced by CUMS. Twenty-eight chemical components of GH were identified by UPLC/IT-TOF MS. Subsequently, 20()-ginsenoside Rh2 was selected as active ingredient and the PPI network of the 43 putative targets of 20()-ginsenoside Rh2 containing in GH and the 230 depression candidate targets, was established based on STRING database, and 47 major targets were extracted. Further network pharmacological analysis indicated that the cAMP signaling pathway may be potential pharmacological mechanism regulated by GH acting on depression. Among the cAMP signaling pathway, the major target proteins, namely, cAMP, PKA, CREB, -CREB, BDNF, were used to verify in the CUMS model rats. The results showed that GH could activate the cAMP-PKA-CREB-BDNF signaling pathway to exert antidepressant effects. An integrative pharmacology-based pattern was used to uncover that GH could increase the contents of DA, NE and 5-HT, activate cAMP-PKA-CREB-BDNF signaling pathway exert antidepressant effects.
评估人参皂苷H滴丸（GH）在慢性不可预测性温和应激（CUMS）模型大鼠中的药效学作用及药理机制。首先，建立CUMS诱导的大鼠模型，通过行为学指标（蔗糖偏好、穿越得分、直立得分）和海马体中生化指标（5-羟色胺、多巴胺、去甲肾上腺素）的变化来评估GH（28、56和112mg/kg）的抗抑郁作用。然后，采用超高效液相色谱-离子阱-飞行时间质谱（UPLC/IT-TOF MS）鉴定GH的成分。经网络药理学分析，基于成药性（OB）和类药性（DL）进一步筛选出GH的活性成分，并基于STRING数据库构建GH活性成分潜在靶点与抑郁症候选靶点的蛋白质-蛋白质相互作用（PPI）网络。对PPI网络进行拓扑分析以获得关键靶点，从而预测GH作用于抑郁症的潜在药理机制。最后，对预测信号通路中涉及的一些主要靶蛋白进行实验验证。CUMS抑郁模型建立成功，GH具有抗抑郁作用，其中剂量GH（56mg/kg）对CUMS诱导的抑郁样行为大鼠的抑制作用最佳。通过UPLC/IT-TOF MS鉴定出GH的28种化学成分。随后，选择20（S）-人参皂苷Rh2作为活性成分，基于STRING数据库构建GH中含有的20（S）-人参皂苷Rh2的43个潜在靶点与230个抑郁症候选靶点的PPI网络，并提取出47个主要靶点。进一步的网络药理学分析表明，cAMP信号通路可能是GH作用于抑郁症所调控的潜在药理机制。在cAMP信号通路中，选用主要靶蛋白，即cAMP、蛋白激酶A（PKA）、环磷腺苷效应元件结合蛋白（CREB）、磷酸化环磷腺苷效应元件结合蛋白（p-CREB）、脑源性神经营养因子（BDNF），在CUMS模型大鼠中进行验证。结果表明，GH可激活cAMP-PKA-CREB-BDNF信号通路发挥抗抑郁作用。采用基于整合药理学的模式揭示，GH可增加多巴胺（DA）、去甲肾上腺素（NE）和5-羟色胺（5-HT）的含量，激活cAMP-PKA-CREB-BDNF信号通路发挥抗抑郁作用。
