{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:15:58Z","timestamp":1790957758011,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Zhejiang Provincial Natural Science Foundation of China","award":["No.LD24H280001"],"award-info":[{"award-number":["No.LD24H280001"]}]},{"name":"College Students\u2019 Innovative Entrepreneurial Training Plan Program","award":["X202401134"],"award-info":[{"award-number":["X202401134"]}]},{"name":"the first batch of science and technology special mission projects in Anhui Province","award":["No: 2023tpt014"],"award-info":[{"award-number":["No: 2023tpt014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Baihe Dihuang Tang (BDT), a classical herbal formula from Zhang Zhongjing\u2019s Han Dynasty work Jin Gui Yao Lue, is widely used to treat depressive disorder by nourishing Yin, clearing heat, and tonifying the heart and lungs. However, its pharmacological mechanisms remain unclear. This study aims to explore BDT\u2019s antidepressant effects via MAOA-regulated serotonin (5-HT) metabolism and synaptic plasticity, supported by experimental validation, while using network pharmacology to predict MAOA-targeting active components. Methods: Active components and targets of BDT were screened using TCMSP, TCMID, and other databases, and then a component-target-pathway network was constructed. A chronic restraint stress (CRS)-induced depressive mouse model was established. Behavioral tests, including open field test (OFT), elevated plus maze (EPM), forced swimming test (FST) and tail suspension test (TST), were conducted to evaluate antidepressant effects. ELISA, qRT-PCR, and Western blot were employed to assess hippocampal 5-HT metabolism (MAOA, 5-HT\/5-HIAA ratio) neurotrophic signaling (BDNF, TrkB) and synaptic plasticity-related proteins (PSD-95, SYN1). Results: BDT significantly reduced FST\/TST immobility time and improved anxiety-like behaviors in OFT\/EPM. BDT treatment downregulated MAOA expression, elevated hippocampal 5-HT\/5-HIAA ratio, activated BDNF\/TrkB pathway, and upregulated PSD-95\/SYN1. Network pharmacology confirmed MAOA\u2019s central role, identifying MAOA\/serotonergic synapse modulation as BDT\u2019s main mechanism and pinpointing Ferulic acid, Caffeate, Stigmasterol, (\u2212)-nopinene, Eugenol, and cis-Anethol as MAOA-targeting bioactive components. Conclusions: BDT ameliorates depressive-like behaviors. This effect is mechanistically linked to suppression of MAOA-mediated 5-HT catabolism\u2014a key validated target. This suppression elevates hippocampal 5-HT bioavailability, thereby activating BDNF\/TrkB signaling and promoting synaptic plasticity. Network pharmacology confirmed MAOA as a primary target and identified specific modulatory bioactive components.<\/jats:p>","DOI":"10.3390\/ph18121786","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T14:59:04Z","timestamp":1763996344000},"page":"1786","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Baihe Dihuang Tang Exerts Antidepressant Effects via Modulation of MAOA-Mediated Serotonin Metabolism and Synaptic Plasticity"],"prefix":"10.3390","volume":"18","author":[{"given":"Defu","family":"Tie","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"School of Medicine, Hangzhou City University, Hangzhou 310015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine, Hangzhou City University, Hangzhou 310015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieru","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Medicine, Hangzhou City University, Hangzhou 310015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Medicine, Hangzhou City University, Hangzhou 310015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Ji","sequence":"additional","affiliation":[{"name":"School of Medicine, Hangzhou City University, Hangzhou 310015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Medicine, Hangzhou City University, Hangzhou 310015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haijun","family":"Han","sequence":"additional","affiliation":[{"name":"School of Medicine, Hangzhou City University, Hangzhou 310015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1158-5337","authenticated-orcid":false,"given":"Zheng","family":"Xiang","sequence":"additional","affiliation":[{"name":"School of Medicine, Hangzhou City University, Hangzhou 310015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7961-7975","authenticated-orcid":false,"given":"Wenlong","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1016\/S0140-6736(21)02143-7","article-title":"Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic","volume":"398","author":"Santomauro","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e019557","DOI":"10.1136\/bmjgh-2025-019557","article-title":"Mental health burden of persons living in Ukraine and Ukrainians displaced to Switzerland: The mental health assessment of the Ukrainian population (MAP) studies","volume":"10","author":"Yasenok","year":"2025","journal-title":"BMJ Glob. Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.pnpbp.2017.03.016","article-title":"The anti-inflammatory mechanism of antidepressants\u2014SSRIs, SNRIs","volume":"80","author":"Talarowska","year":"2018","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"115218","DOI":"10.1016\/j.jep.2022.115218","article-title":"Baihe Dihuang (Lilium Henryi Baker and Rehmannia Glutinosa) decoction attenuates somatostatin interneurons deficits in prefrontal cortex of depression via miRNA-144-3p mediated GABA synthesis and release","volume":"292","author":"Xue","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8559176","DOI":"10.1155\/2022\/8559176","article-title":"Evaluation of the Clinical Efficacy of the Classic Prescription \u201cBaihe Dihuang Decoction\u201d Based on Meta-Analysis","volume":"2022","author":"Peng","year":"2022","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"154991","DOI":"10.1016\/j.phymed.2023.154991","article-title":"Preclinical evidence evaluation of Xiaoyao san in treating chronic unpredictable mild stress model of depression based on meta-analysis","volume":"119","author":"Tong","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1016\/j.biopha.2018.12.141","article-title":"Modified Xiaoyao San ameliorates depressive-like behaviors by triggering autophagosome formation to alleviate neuronal apoptosis","volume":"111","author":"Wang","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_8","first-page":"10","article-title":"Antidepressant mechanism of Baihe Dihuang Decoction based on metabolomics and network pharmacology","volume":"50","author":"Hu","year":"2024","journal-title":"China J. Chin. Mater. Medica"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"156718","DOI":"10.1016\/j.phymed.2025.156718","article-title":"The microglial state transition as a novel mechanism by which fresh Baihe Dihuang decoction prevents depression by regulating SIRT1\/HMGB1 signaling","volume":"141","author":"Cao","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.2147\/DDDT.S458983","article-title":"Microbiome Metabolomic Analysis of the Anxiolytic Effect of Baihe Dihuang Decoction in a Rat Model of Chronic Restraint Stress","volume":"18","author":"Tang","year":"2024","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s00702-017-1709-8","article-title":"Type A monoamine oxidase and serotonin are coordinately involved in depressive disorders: From neurotransmitter imbalance to impaired neurogenesis","volume":"125","author":"Naoi","year":"2018","journal-title":"J. Neural Transm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/s41398-023-02506-2","article-title":"Impact of genetic variants within serotonin turnover enzymes on human cerebral monoamine oxidase A in vivo","volume":"13","author":"Spies","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_13","first-page":"36","article-title":"Metabonomics Study on the Intervention of Baihe Dihuang Decoction in Depressed rats","volume":"51","author":"Feng","year":"2023","journal-title":"Acta Chin. Med. Pharmacol."},{"key":"ref_14","first-page":"1955","article-title":"Mechanism of Baihe Dihuang Decoction activating AMPA receptor to improve anxiety and depression-like behavior in chronic unpredictability stress mice","volume":"38","author":"Zhao","year":"2023","journal-title":"China J. Tradit. Chin. Med. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"155510","DOI":"10.1016\/j.phymed.2024.155510","article-title":"Co-decoction of Lilii bulbus and Radix Rehmannia Recens and its key bioactive ingredient verbascoside inhibit neuroinflammation and intestinal permeability associated with chronic stress-induced depression via the gut microbiota-brain axis","volume":"129","author":"Mao","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"177063","DOI":"10.1016\/j.ejphar.2024.177063","article-title":"Escin ameliorates CUMS-induced depressive-like behavior via BDNF\/TrkB\/CREB and TLR4\/MyD88\/NF-\u03baB signaling pathways in rats","volume":"984","author":"Liu","year":"2024","journal-title":"Eur. J. Pharmacol."},{"key":"ref_17","first-page":"60","article-title":"Effects of the 5-HT1A receptor antagonist on synaptic plasticity in sevoflurane-induced cognitive dysfunction in aged rats and its mechanism","volume":"53","author":"Zou","year":"2024","journal-title":"J. China Med. Univ."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1007\/s00262-023-03622-0","article-title":"Targeting monoamine oxidase A: A strategy for inhibiting tumor growth with both immune checkpoint inhibitors and immune modulators","volume":"73","author":"Ma","year":"2024","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_19","first-page":"1677","article-title":"Experimental study on abnormal expression of TPH2,DDC and MAO-A involved in depression-like behaviors of rats induced by CUS","volume":"32","author":"Cui","year":"2016","journal-title":"Chin. Pharmacol. Bull."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/j.jad.2021.01.021","article-title":"Revisiting monoamine oxidase inhibitors for the treatment of depressive disorders: A systematic review and network meta-analysis","volume":"282","author":"Suchting","year":"2021","journal-title":"J. Affect. Disord."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.bbr.2013.10.011","article-title":"Increased oxidative stress in prefrontal cortex and hippocampus is related to depressive-like behavior in streptozotocin-diabetic rats","volume":"258","author":"Ferreira","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.bbi.2012.11.011","article-title":"Dysregulated relationship of inflammation and oxidative stress in major depression","volume":"31","author":"Rawdin","year":"2013","journal-title":"Brain Behav. Immun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"129108","DOI":"10.1016\/j.foodchem.2021.129108","article-title":"Evaluation of the inhibition of monoamine oxidase A by bioactive coffee compounds protecting serotonin degradation","volume":"348","author":"Grzelczyk","year":"2021","journal-title":"Food Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4777","DOI":"10.1016\/j.bmc.2005.04.081","article-title":"Eugenol and its structural analogs inhibit monoamine oxidase A and exhibit antidepressant-like activity","volume":"13","author":"Tao","year":"2005","journal-title":"Bioorg. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.lfs.2018.08.050","article-title":"Serotonin receptors in depression and anxiety: Insights from animal studies","volume":"210","author":"Sapa","year":"2018","journal-title":"Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41392-024-01738-y","article-title":"Major depressive disorder: Hypothesis, mechanism, prevention and treatment","volume":"9","author":"Cui","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.neulet.2016.12.011","article-title":"5-HT1A receptor (HTR1A) 5\u2032 region haplotypes significantly affect protein expression in vitro","volume":"638","author":"Wu","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s13041-017-0306-y","article-title":"The role of 5-HT receptors in depression","volume":"10","author":"Yohn","year":"2017","journal-title":"Mol. Brain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1007\/s00213-024-06586-w","article-title":"5-HT 2A and 5-HT 2C receptor antagonism differentially modulate reinforcement learning and cognitive flexibility: Behavioural and computational evidence","volume":"241","author":"Hervig","year":"2024","journal-title":"Psychopharmacology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/s41594-018-0180-z","article-title":"Structures of the 5-HT2A receptor in complex with the antipsychotics risperidone and zotepine","volume":"26","author":"Kimura","year":"2019","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Parenti, I., Leit\u00e3o, E., Kuechler, A., Villard, L., Goizet, C., Courdier, C., Bayat, A., Rossi, A., Julia, S., and Bruel, A.-L. (2022). The different clinical facets of SYN1-related neurodevelopmental disorders. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.1019715"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Gu, Y., Pope, A., Smith, C., Carmona, C., Johnstone, A., Shi, L., Chen, X., Santos, S., Bacon-Brenes, C.C., and Shoff, T. (2024). BDNF and TRiC-inspired reagent rescue cortical synaptic deficits in a mouse model of Huntington\u2019s disease. Neurobiol. Dis., 195.","DOI":"10.1016\/j.nbd.2024.106502"},{"key":"ref_33","first-page":"235","article-title":"Research Progress and Quality Marker Prediction of Famous Classical Formula Baihe Dihuangtang","volume":"30","author":"Liu","year":"2024","journal-title":"Chin. J. Exp. Tradit. Med. Formulae"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.jare.2024.10.025","article-title":"Neural and molecular investigation into the paraventricular thalamus for chronic restraint stress induced depressive-like behaviors","volume":"75","author":"He","year":"2024","journal-title":"J. Adv. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2316","DOI":"10.1038\/s41380-020-0692-x","article-title":"Programmed cell death 4 as an endogenous suppressor of BDNF translation is involved in stress-induced depression","volume":"26","author":"Li","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"16188","DOI":"10.1021\/acs.jafc.2c06318","article-title":"Nelumbinis Stamen Ameliorates Chronic Restraint Stress-Induced Muscle Dysfunction and Fatigue in Mice by Decreasing Serum Corticosterone Levels and Activating Sestrin2","volume":"70","author":"Wang","year":"2022","journal-title":"J. Agric. Food Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.jare.2023.06.001","article-title":"CRISPR\/Cas9 based gene editing of Frizzled class receptor 6 (FZD6) reveals its role in depressive symptoms through disrupting Wnt\/\u03b2-catenin signaling pathway","volume":"58","author":"Han","year":"2024","journal-title":"J. Adv. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R Package for Comparing Biological Themes Among Gene Clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS A J. Integr. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Sasikumar, D.S.N., Thiruselvam, P., Sundararajan, V., Ravindran, R., Gunasekaran, S., Madathil, D., Kaliamurthi, S., Peslherbe, G.H., Selvaraj, G., and Sudhakaran, S.L. (2024). Insights into dietary phytochemicals targeting Parkinson\u2019s disease key genes and pathways: A network pharmacology approach. Comput. Biol. Med., 172.","DOI":"10.1016\/j.compbiomed.2024.108195"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/12\/1786\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T05:15:32Z","timestamp":1764134132000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/12\/1786"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,24]]},"references-count":39,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ph18121786"],"URL":"https:\/\/doi.org\/10.3390\/ph18121786","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,24]]}}}