Li Zhiping, Liang Shimin, Cui Xulan, Shen Chongkun, Xu Zaibin, Chen Wei, Wu Mingan, Liang Chao, Liu Jinman, Huang Jiawen, Li Weirong
Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China.
Front Psychiatry. 2024 Aug 23;15:1414242. doi: 10.3389/fpsyt.2024.1414242. eCollection 2024.
The incidence rate of adolescent depression and anxiety has been increasing since the outbreak of COVID-19, which there are no effective therapeutic drugs available. Si-ni San is commonly used in traditional Chinese medicine for the treatment of depression-like as well as anxiety-like behavior, but its mechanism for treating depression combined with anxiety during adolescence is not yet clear.
Network pharmacology was used to explore potential drug molecules and related targets, molecular docking and molecular dynamics (MD) simulation were used to evaluate the interaction between the potential drug molecules and related targets, and a model of anxiety combined with depression in adolescent rats as well as the following behavioral tests and molecular biology tests were used to verify the results from network pharmacology and molecular docking.
As a result, 256 active ingredients of Si-ni San and 1128 potential targets were screened out. Among them, quercetin, Luteolin, kaempferol, 7-Methoxy-2-methyl isoflavone, formononetin showed to be the most potential ingredients; while STAT3, IL6, TNF, AKT1, AKT1, TP53, IL1B, MAPK3, VEGFA, CASP3, MMP9 showed to be the most potential targets. AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, HIF-1 signaling pathway, PI3K-Akt signaling pathway and TNF signaling pathway, which are involved in anti-inflammation processes, showed to be the most probable pathways regulated by Si-ni San. Molecular docking and MD simulation between the compounds to inflammation-associated targets revealed good binding abilities of quercetin, Luteolin, kaempferol, nobiletin and formononetin to PTGS2 and PPARγ. In the experiment with adolescent rats, Si-ni San markedly suppressed early maternal separation (MS) combined with adolescent chronic unpredictable mild stress (CUMS)-induced depression combined with anxiety. The qPCR results further indicated that Si-ni San regulated the oxidative stress and inflammatory response.
This study demonstrates that adolescent anxiety- and depression-like behavior induced by MS combined CUMS can be ameliorated by Si-ni San by improved inflammation in hippocampus via targeting TNF pathway and Nrf2 pathway, helping to reveal the mechanism of Si-ni San in treating adolescent depression combined with anxiety.
自新冠疫情爆发以来，青少年抑郁和焦虑的发病率一直在上升，且目前尚无有效的治疗药物。四逆散是中医常用的治疗抑郁样和焦虑样行为的方剂，但其治疗青少年抑郁合并焦虑的机制尚不清楚。
采用网络药理学探索潜在药物分子和相关靶点，运用分子对接和分子动力学（MD）模拟评估潜在药物分子与相关靶点之间的相互作用，并通过青少年大鼠焦虑合并抑郁模型及后续行为学测试和分子生物学测试验证网络药理学和分子对接的结果。
筛选出四逆散的256种活性成分和1128个潜在靶点。其中，槲皮素、木犀草素、山奈酚、7-甲氧基-2-甲基异黄酮、芒柄花素显示为最具潜力的成分；而信号转导和转录激活因子3（STAT3）、白细胞介素6（IL6）、肿瘤坏死因子（TNF）、蛋白激酶B1（AKT1）、蛋白激酶B1（AKT1）、肿瘤蛋白53（TP53）、白细胞介素1β（IL1B）、丝裂原活化蛋白激酶3（MAPK3）、血管内皮生长因子A（VEGFA）、半胱天冬酶3（CASP3）、基质金属蛋白酶9（MMP9）显示为最具潜力的靶点。参与抗炎过程的糖尿病并发症中的晚期糖基化终末产物受体（AGE-RAGE）信号通路、白细胞介素17信号通路、缺氧诱导因子1信号通路、磷脂酰肌醇-3激酶-蛋白激酶B信号通路和肿瘤坏死因子信号通路显示为四逆散最可能调节的通路。化合物与炎症相关靶点之间的分子对接和MD模拟显示，槲皮素、木犀草素、山奈酚、川陈皮素和芒柄花素与环氧合酶2（PTGS2）和过氧化物酶体增殖物激活受体γ（PPARγ）具有良好的结合能力。在青少年大鼠实验中，四逆散显著抑制了早期母婴分离（MS）联合青少年慢性不可预测温和应激（CUMS）诱导的抑郁合并焦虑。定量聚合酶链反应（qPCR）结果进一步表明，四逆散调节了氧化应激和炎症反应。
本研究表明，MS联合CUMS诱导的青少年焦虑和抑郁样行为可通过四逆散改善，其机制可能是通过靶向肿瘤坏死因子（TNF）通路和核因子E2相关因子2（Nrf2）通路减轻海马体炎症，这有助于揭示四逆散治疗青少年抑郁合并焦虑的机制。
