Abstract
Introduction: Ding-Zhi-Xiao-Wan (DZXW) produces potential antidepressant-like effects. However, its antidepressant mechanisms are still unclear.
Objective: To analyze the antidepressant effects and the pharmacological mechanisms of DZXW, meta-analysis, network pharmacology, and molecular docking were selected in this study.
Methods: The compounds of DZXW and genes associated with compounds or depression were obtained from databases. The genes overlapping between DZXW compounds and depression were compared by Venn diagram. A network of medicine-ingredients-targets-disease was constructed, visualized, and analyzed. Protein-protein interaction, gene ontology, pathway enrichment, and molecular docking were performed to evaluate the potential mechanisms of DZXW for the treatment of depression.
Results: Meta-analysis showed that the antidepressant-like effects were produced by DZXW. The network pharmacology analysis showed that a total of 74 compound-related genes and 12607 PTSD-related genes were identified in the databases with 65 overlapping genes. The active ingredients derived from DZXW (i.e Beta-sitosterol, Stigmasterol, Fumarine, Hederagenin) elicited the antidepressant-like effects by targets, such as ACHE, HTR2A, and CHRM1. Moreover, the signaling pathways, like neuroactive ligand-receptor interaction, pathways in cancer, and cholinergic synapse, might play important roles in the treatment of depression by DZXW.
Conclusion: This study provides studies analysis and molecular evidence with the beneficial effects of DZXW for the treatment of depression.
Graphical Abstract
[1]
WHO. Depression Available From: https://www.who.int/news-room/fact-sheets/detail/ (accessed on 30 January 2020).
[2]
Jiang, C.Y.; Qin, X.Y.; Yuan, M.M.; Lu, G.J.; Cheng, Y. 2,3,5,4′-Tetrahydroxystilbene-2-O-beta-D-glucoside reverses stress-induced depression via inflammatory and oxidative stress pathways. Oxid. Med. Cell. Longev., 2018, 2018, 9501427.
[http://dx.doi.org/10.1155/2018/9501427] [PMID: 30327715]
[http://dx.doi.org/10.1155/2018/9501427] [PMID: 30327715]
[3]
Zhang, Y.W.; Cheng, Y.C. Challenge and prospect of traditional chinese medicine in depression treatment. Front. Neurosci., 2019, 13, 190.
[http://dx.doi.org/10.3389/fnins.2019.00190] [PMID: 30890916]
[http://dx.doi.org/10.3389/fnins.2019.00190] [PMID: 30890916]
[4]
Pothula, S.; Kato, T.; Liu, R.J.; Wu, M.; Gerhard, D.; Shinohara, R.; Sliby, A.N.; Chowdhury, G.M.; Behar, K.L.; Sanacora, G. Cell-Type specific modulation of NMDA receptors triggers antidepressant actions. Mol. Psychiatry, 2020, 26, 5097-5111.
[PMID: 32488125]
[PMID: 32488125]
[5]
Malhi, G.S.; Coulston, C.M.; Fritz, K.; Lampe, L.; Bargh, D.M.; Ablett, M.; Lyndon, B.; Sapsford, R.; Theodoros, M.; Woolfall, D.; van der Zypp, A.; Hopwood, M.; Mitchell, A.J. Unlocking the diagnosis of depression in primary care: Which key symptoms are GPs using to determine diagnosis and severity? Aust. N. Z. J. Psychiatry, 2014, 48(6), 542-547.
[http://dx.doi.org/10.1177/0004867413513342] [PMID: 24270311]
[http://dx.doi.org/10.1177/0004867413513342] [PMID: 24270311]
[6]
Qu, W.; Liu, S.; Zhang, W.; Zhu, H.; Tao, Q.; Wang, H.; Yan, H. Impact of traditional Chinese medicine treatment on chronic unpredictable mild stress-induced depression-like behaviors: Intestinal microbiota and gut microbiome function. Food Funct., 2019, 10(9), 5886-5897.
[http://dx.doi.org/10.1039/C9FO00399A] [PMID: 31464319]
[http://dx.doi.org/10.1039/C9FO00399A] [PMID: 31464319]
[7]
Li, C.; Huang, J.; Cheng, Y.C.; Zhang, Y.W. Traditional chinese medicine in depression treatment: From molecules to systems. Front. Pharmacol., 2020, 11, 586.
[http://dx.doi.org/10.3389/fphar.2020.00586] [PMID: 32457610]
[http://dx.doi.org/10.3389/fphar.2020.00586] [PMID: 32457610]
[8]
Qing-Jia, H.U.A.N.G.; Lin, W.U.; Wei, C.H.E.N. Overview on etiology and pathogenesis of traditional chinese medicine of depression. Journal of Sichuan of Tradition-al Chinese Medicine, 2017, 35(11), 212-214.
[9]
Xin-Qing, Q.I.; Xue-Mei, Q.I.; Tian-meng, L.I.U. Prescriptions for treating depression by tonifying deficiency: A Review. Zhongguo Shiyan Fangjixue Zazhi, 2021, 27(17), 217-226.
[10]
Jin, Z.; Gao, N.; Zhang, J.; Li, X.; Chen, H.; Xiong, J.; Li, Y.; Tang, Y. The discovery of Yuanzhi-1, a triterpenoid saponin derived from the traditional Chinese medicine, has antidepressant-like activity. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2014, 53, 9-14.
[http://dx.doi.org/10.1016/j.pnpbp.2014.02.013] [PMID: 24614095]
[http://dx.doi.org/10.1016/j.pnpbp.2014.02.013] [PMID: 24614095]
[11]
Xu, J.; Chen, L.; Su, J.; Liu, Z.; Chen, J.; Lin, Q.; Mao, W.; Shen, D. The anxiolytic-like effects of ginsenoside Rg3 on chronic unpredictable stress in rats. Sci. Rep., 2018, 8(1), 7741.
[http://dx.doi.org/10.1038/s41598-018-26146-5] [PMID: 29773855]
[http://dx.doi.org/10.1038/s41598-018-26146-5] [PMID: 29773855]
[12]
Zhu, X.; Gao, R.; Liu, Z.; Cheng, Z.; Qi, Y.; Fan, C.; Yu, S.Y. Ginsenoside Rg1 reverses stress-induced depression-like behaviours and brain-derived neurotrophic factor expression within the prefrontal cortex. Eur. J. Neurosci., 2016, 44(2), 1878-1885. a
[http://dx.doi.org/10.1111/ejn.13255] [PMID: 27062560]
[http://dx.doi.org/10.1111/ejn.13255] [PMID: 27062560]
[13]
Yu, H.; Fan, C.; Yang, L.; Yu, S.; Song, Q.; Wang, P.; Mao, X. Ginsenoside Rg1 Prevents Chronic Stress-Induced Depression-Like Behaviors and Neuronal Structural Plasticity in Rats. Cell. Physiol. Biochem., 2018, 48(6), 2470-2482.
[http://dx.doi.org/10.1159/000492684] [PMID: 30121663]
[http://dx.doi.org/10.1159/000492684] [PMID: 30121663]
[14]
Xu, D.; Wang, C.; Zhao, W.; Gao, S.; Cui, Z. Antidepressant-like effects of ginsenoside Rg5 in mice: Involving of hippocampus BDNF signaling pathway. Neurosci. Lett., 2017, 645, 97-105. a
[http://dx.doi.org/10.1016/j.neulet.2017.02.071] [PMID: 28257788]
[http://dx.doi.org/10.1016/j.neulet.2017.02.071] [PMID: 28257788]
[15]
Drevets, W.C.; Zarate, C.A., Jr; Furey, M.L. Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine: A review. Biol. Psychiatry, 2013, 73(12), 1156-1163.
[http://dx.doi.org/10.1016/j.biopsych.2012.09.031] [PMID: 23200525]
[http://dx.doi.org/10.1016/j.biopsych.2012.09.031] [PMID: 23200525]
[16]
Fogaça, M.V.; Fukumoto, K.; Franklin, T.; Liu, R.J.; Duman, C.H.; Vitolo, O.V.; Duman, R.S. N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects. Neuropsychopharmacology, 2019, 44(13), 2230-2238.
[http://dx.doi.org/10.1038/s41386-019-0501-x] [PMID: 31454827]
[http://dx.doi.org/10.1038/s41386-019-0501-x] [PMID: 31454827]
[17]
Zhang, Y.; Long, Y.; Yu, S.; Li, D.; Yang, M.; Guan, Y.; Zhang, D.; Wan, J.; Liu, S.; Shi, A.; Li, N.; Peng, W. Natural volatile oils derived from herbal medicines: A promising therapy way for treating depressive disorder. Pharmacol. Res., 2021, 164, 105376.
[http://dx.doi.org/10.1016/j.phrs.2020.105376] [PMID: 33316383]
[http://dx.doi.org/10.1016/j.phrs.2020.105376] [PMID: 33316383]
[18]
He-Hua, C.H.E.N.; Yue, W.A.N.G.; Xiao-ming, S.H.E.N. clinical observation of ding-zhi xiaowan combined with fluoxetine hydrochloride capsules in treating senile depression. Guide of China Medicine, 2014, 12(8), 274-275.
[19]
Ji-yan, C.H.A.I.; De-hong, S.H.A.N.; De-shan, W.A.N.G. Effect of dingzhixiaowan on nest in expression in depression model rats. Chinese Journal of Information on TCM [J], 2005, 12(4), 29-30.
[20]
Ming, C.; Ying, J.; Shan, D. Effect of Dingzhi Xiaowan on the structure and function of hippocampus and the secretion of estradiol in rat models of depression. Chinese Journal of Clinical Rechabilitation [J], 2005, 9(16), 120-121.
[21]
Shan, D.; Chai, J-Y.; Wang, C. Effect of dingzhixiaowan on neural stem cells of dentate gyrus and learning memory in depression model rats. Chinese archives of traditional chinese medicine, 2005, 23(8), 1426-1427.
[22]
Xing-yu, YAN.; De-shan, WANG. De-hong, SHAN Effect of dingzhixiaowan on E2 and dentate gyrus neural stem cell of female depressed rats. Chinese Journal of Experimental Traditional Medical Formulae, 2007, 13(6), 43-45.
[23]
Dong, X.Z.; Li, Z.L.; Zheng, X.L.; Mu, L.H.; Zhang, G.; Liu, P. A representative prescription for emotional disease, Ding-Zhi-Xiao-Wan restores 5-HT system deficit through interfering the synthesis and transshipment in chronic mild stress-induced depressive rats. J. Ethnopharmacol., 2013, 150(3), 1053-1061.
[http://dx.doi.org/10.1016/j.jep.2013.10.018] [PMID: 24184266]
[http://dx.doi.org/10.1016/j.jep.2013.10.018] [PMID: 24184266]
[24]
Liu, W.W.; Xu, L.; Dong, X.Z.; Tan, X.; Wang, S.; Zhu, W.Y.; Liu, P. [Effects of Kaixin San formulas on behavioristics and central monoamine neurotransmitters of chronic stress rats] Zhongguo Zhongyao Zazhi, 2015, 40(11), 2180-2185.
[PMID: 26552177]
[PMID: 26552177]
[25]
Tian-yi, Z.H.A.N.G.; Xian-zhe, D.O.N.G.; Xia, F.E.N.G. Study on the intervention of 5-HT level by Dingzhi Xiaowan regulation oxidation-reduction system. Chinese Journal of Drug Application and Monitoring [J], 2018, 15(3), 140-144.
[26]
Zhu, W.Y.; Feng, X.; Wang, J.; Lu, Y.P.; Dong, X.Z.; Liu, P. Effect of dingzhi xiaowan on miR-16 expression and 5-HT reuptake. Zhongguo Zhongyao Zazhi, 2018, 43(17), 3513-3518.
[PMID: 30347920]
[PMID: 30347920]
[27]
Li, Y.A.N.G.; Wanwan, L.I.U.; Xiaojiang, Z.H.O.U. Antidepressant effects and mechanism of dingzhixiaowan and kaixinwan on CUMS model rats. Chinese Journal of Pharmacovigilance, 2021. Available From: https://kns.cnki.net/kcms/detail/11.5219.R.20210520.1647.012.html
[28]
Wang, X.X.; Tao, Z.P.; Li, Y.; Li, C.W.; Fan, M.R.; Liu, W.H.; Wei, G.N.; Gao, P.F. Study advance of depressive animal models and its application in traditional Chinese medicines. Zhongguo Zhongyao Zazhi, 2020, 45(11), 2473-2480.
[PMID: 32627477]
[PMID: 32627477]
[29]
Katz, R.J.; Roth, K.A.; Carroll, B.J. Acute and chronic stress effects on open field activity in the rat: Implications for a model of depression. Neurosci. Biobehav. Rev., 1981, 5(2), 247-251.
[http://dx.doi.org/10.1016/0149-7634(81)90005-1] [PMID: 7196554]
[http://dx.doi.org/10.1016/0149-7634(81)90005-1] [PMID: 7196554]
[30]
Pothion, S.; Bizot, J.C.; Trovero, F.; Belzung, C. Strain differences in sucrose preference and in the consequences of unpredictable chronic mild stress. Behav. Brain Res., 2004, 155(1), 135-146.
[http://dx.doi.org/10.1016/j.bbr.2004.04.008] [PMID: 15325787]
[http://dx.doi.org/10.1016/j.bbr.2004.04.008] [PMID: 15325787]
[31]
Katz, R.J. Animal model of depression: Pharmacological sensitivity of a hedonic deficit. Pharmacol. Biochem. Behav., 1982, 16(6), 965-968.
[http://dx.doi.org/10.1016/0091-3057(82)90053-3] [PMID: 7202217]
[http://dx.doi.org/10.1016/0091-3057(82)90053-3] [PMID: 7202217]
[32]
Mitchell, P.; Redfern, P. Animal models of depressive illness: The importance of chronic drug treatment. Curr. Pharm. Des., 2005, 11(2), 171-203.
[http://dx.doi.org/10.2174/1381612053382250] [PMID: 15638757]
[http://dx.doi.org/10.2174/1381612053382250] [PMID: 15638757]
[33]
Hasler, G.; Drevets, W.C.; Manji, H.K.; Charney, D.S. Discovering endophenotypes for major depression. Neuropsychopharmacology, 2004, 29(10), 1765-1781.
[http://dx.doi.org/10.1038/sj.npp.1300506] [PMID: 15213704]
[http://dx.doi.org/10.1038/sj.npp.1300506] [PMID: 15213704]
[34]
Planchez, B.; Surget, A.; Belzung, C. Animal models of major depression: Drawbacks and challenges. J. Neural Transm., 2019, 126(11), 1383-1408.
[http://dx.doi.org/10.1007/s00702-019-02084-y] [PMID: 31584111]
[http://dx.doi.org/10.1007/s00702-019-02084-y] [PMID: 31584111]
[35]
Horiuchi, Y.; Nakayama, J.; Ishiguro, H.; Ohtsuki, T.; Detera-Wadleigh, S.D.; Toyota, T.; Yamada, K.; Nankai, M.; Shibuya, H.; Yoshikawa, T.; Arinami, T. Possible association between a haplotype of the GABA-A receptor alpha 1 subunit gene (GABRA1) and mood disorders. Biol. Psychiatry, 2004, 55(1), 40-45.
[http://dx.doi.org/10.1016/S0006-3223(03)00689-9] [PMID: 14706423]
[http://dx.doi.org/10.1016/S0006-3223(03)00689-9] [PMID: 14706423]
[36]
Shiah, I.S.; Yatham, L.N. GABA function in mood disorders: An update and critical review. Life Sci., 1998, 63(15), 1289-1303.
[http://dx.doi.org/10.1016/S0024-3205(98)00241-0] [PMID: 9768867]
[http://dx.doi.org/10.1016/S0024-3205(98)00241-0] [PMID: 9768867]
[37]
Sun, Y.; He, Y.; Liu, S. Comparative pharmacokinetics of Ding-Zhi-Xiao-Wan preparation and its single herbs in rats by using a putative multiple-reaction monitoring UPLC-MS/MS method. Phytochem. Anal., 2021, 32(3), 362-374.
[PMID: 32896044]
[PMID: 32896044]
[38]
Xiang-peng, K.O.N.G.; Zhi-cong, C.H.E.N.; Ying-jie, X.I.A. Optimization of AChE extraction and determination in mouse brain and inhibitory activity of isoquinoline alkaloids on AChE. Journal of liaoning university of TCM, 2021, 23(7), 35-39.
[39]
Kao, C.F.; Kuo, P.H.; Yu, Y.W.; Yang, A.C.; Lin, E.; Liu, Y.L.; Tsai, S.J. Gene-based association analysis suggests association of HTR2A with antidepressant treatment response in depressed patients. Front. Pharmacol., 2020, 11, 559601.
[40]
W.; Yuan-sheng, Z.; Xue-Jia, Tan.; Hong-Ai, A.; You-Sheng, Z. Li-Bo, Associations between the 1438A/G, 102T/C, and rs7997012G/A polymorphisms of HTR2A and the safety and effi-cacy of antidepressants in depression: A meta-analysis. The Pharmacogenomics Journal, 2021, (2), 200-215.
[41]
Martin, V.; Riffaud, A.; Marday, T.; Brouillard, C.; Franc, B.; Tassin, J.P.; Sevoz-Couche, C.; Mongeau, R.; Lanfumey, L. Response of Htr3a knockout mice to antidepressant treatment and chronic stress. Br. J. Pharmacol., 2017, 174(15), 2471-2483.
[http://dx.doi.org/10.1111/bph.13857] [PMID: 28493335]
[http://dx.doi.org/10.1111/bph.13857] [PMID: 28493335]
