Qu Shu-Yue, Li Xiao-Yue, Heng Xia, Qi Yi-Yu, Ge Ping-Yuan, Ni Sai-Jia, Yao Zeng-Ying, Guo Rui, Yang Nian-Yun, Cao Yi, Zhang Qi-Chun, Zhu Hua-Xu
Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, China.
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Front Pharmacol. 2021 Mar 4;12:619288. doi: 10.3389/fphar.2021.619288. eCollection 2021.
Depressive disorder is a common mental disorder characterized by depressed mood and loss of interest or pleasure. As the Herbal medicines are mainly used as complementary and alternative therapy for depression. This study aimed at exploring antidepressant activity of Huang-lian Jie-du Decoction (HLJDD), and evaluating active components and potential depression-associated targets. HLJDD was administered on chronic unpredictable mild stress-induced (CUMS) depressive mice. Behavior evaluation was performed through force swimming test (FST), novelty-suppressed feeding test (NSF), and open field test (OFT). Active components of HLJDD, potential targets, and metabolic pathways involved in depression were explored through systemic biology-based network pharmacology assay, molecular docking and metabonomics. FST assay showed that CUMS mice administered with HLJDD had significantly shorter immobility time compared with control mice. Further, HLJDD alleviated feeding latency of CUMS mice in NSFand increased moving distance and duration in OFT. In the following network pharmacology assay, thirty-eight active compounds in HLJDD were identified based on drug-like characteristics, and pharmacokinetics and pharmacodynamics profiles. Moreover, forty-eight molecular targets and ten biochemical pathways were uncovered through molecular docking and metabonomics. GRIN2B, DRD, PRKCA, HTR, MAOA, SLC6A4, GRIN2A, and CACNA1A are implicated in inhibition of depressive symptoms through modulating tryptophan metabolism, serotonergic and dopaminergic synaptic activities, cAMP signaling pathway, and calcium signaling pathway. Further network pharmacology-based analysis showed a correlation between HLJDD and tryptophan metabolism. A total of thirty-seven active compounds, seventy-six targets, and sixteen biochemical pathways were involved in tryptophan metabolism. These findings show that HLJDD acts on potential targets such as SLC6A4, HTR, INS, MAO, CAT, and FoxO, PI3K/Akt, calcium, HIF-1, and mTOR signaling pathways, and modulates serotoninergic and dopaminergic synaptic functions. In addition, metabonomics showed that tryptophan metabolism is the primary target for HLJDD in CUMS mice. The findings of the study show that HLJDD exhibited antidepressant effects. SLC6A4 and MAOA in tryptophan metabolism were modulated by berberine, baicalein, tetrahydroberberine, candicine and may be the main antidepressant targets for HLJDD.
抑郁症是一种常见的精神障碍，其特征为情绪低落以及兴趣或愉悦感丧失。由于草药主要用作抑郁症的补充和替代疗法。本研究旨在探索黄连解毒汤（HLJDD）的抗抑郁活性，并评估其活性成分和潜在的抑郁症相关靶点。将HLJDD给予慢性不可预测轻度应激诱导（CUMS）的抑郁小鼠。通过强迫游泳试验（FST）、新奇抑制摄食试验（NSF）和旷场试验（OFT）进行行为评估。通过基于系统生物学的网络药理学分析、分子对接和代谢组学探索HLJDD的活性成分、潜在靶点以及与抑郁症相关的代谢途径。FST试验表明，与对照小鼠相比，给予HLJDD的CUMS小鼠的不动时间显著缩短。此外，HLJDD减轻了CUMS小鼠在NSF中的摄食潜伏期，并增加了在OFT中的移动距离和持续时间。在接下来的网络药理学分析中，基于类药特性、药代动力学和药效学特征鉴定出HLJDD中的38种活性化合物。此外，通过分子对接和代谢组学发现了48个分子靶点和10条生化途径。GRIN2B、DRD、PRKCA、HTR、MAOA、SLC6A4、GRIN2A和CACNA1A通过调节色氨酸代谢、5-羟色胺能和多巴胺能突触活动、cAMP信号通路和钙信号通路参与抑制抑郁症状。基于网络药理学的进一步分析表明HLJDD与色氨酸代谢之间存在关联。共有37种活性化合物、76个靶点和16条生化途径参与色氨酸代谢。这些发现表明HLJDD作用于SLC6A4、HTR、INS、MAO、CAT和FoxO、PI3K/Akt、钙、HIF-1和mTOR信号通路等潜在靶点，并调节5-羟色胺能和多巴胺能突触功能。此外，代谢组学表明色氨酸代谢是HLJDD在CUMS小鼠中的主要靶点。该研究结果表明HLJDD具有抗抑郁作用。小檗碱、黄芩素、四氢小檗碱、坎地辛调节色氨酸代谢中的SLC6A4和MAOA，可能是HLJDD的主要抗抑郁靶点。
