
==== Front
Front Pharmacol
Front Pharmacol
Front. Pharmacol.
Frontiers in Pharmacology
1663-9812
Frontiers Media S.A.

1426769
10.3389/fphar.2024.1426769
Pharmacology
Review
The therapeutic potential of traditional Chinese medicine in depression: focused on the modulation of neuroplasticity
Lv et al.
10.3389/fphar.2024.1426769
Lv Shimeng 1

Yang Ni 1

Lu Yitong 1
Zhang Guangheng 1

Zhong Xia 2

Cui Yaru 3
Huang Yufei 4

Teng Jing 1

Sai Yanyan 5 *
1 Department of First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
2 Institute of Child and Adolescent Health, School of Public Health, Peking University, Beijing, China
3 Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
4 Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
5 University Town Hospital, Afiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
Edited by: Qi Liang, Air Force Medical University, China

Reviewed by: Wenzhi Hao, Jinan University, China

Dang Chun, Sichuan University, China

*Correspondence: Yanyan Sai, 50041450@qq.com
26 8 2024
2024
15 142676903 5 2024
06 8 2024
Copyright © 2024 Lv, Yang, Lu, Zhang, Zhong, Cui, Huang, Teng and Sai.
2024
Lv, Yang, Lu, Zhang, Zhong, Cui, Huang, Teng and Sai
https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Depression, a mood disorder characterized by a persistent low mood and lack of enjoyment, is considered the leading cause of non-fatal health losses worldwide. Neuroplasticity refers to the brain’s ability to adapt to external or internal stimuli, resulting in functional and structural changes. This process plays a crucial role in the development of depression. Traditional Chinese Medicine (TCM) shows significant potential as a complementary and alternative therapy for neurological diseases, including depression. However, there has been no systematic summary of the role of neuroplasticity in the pathological development of depression and TCM Interventions currently. This review systematically summarized recent literature on changes in neuroplasticity in depression and analyzed the regulatory mechanisms of active metabolites in TCM and TCM formulas on neuroplasticity in antidepressant treatment. Additionally, this review discussed the limitations of current research and the application prospects of TCM in regulating neuroplasticity in antidepressant research.

depression
major depressive disorder
antidepressant
traditional Chinese medicine
neuroplasticity
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Shandong Province Special Disease Prevention Project of Integrated Traditional Chinese and Western Medicine (YXH2019ZXY006) and Academic Project for College Students of Shandong Province Youth Education Science Planning Project (24BSH467).section-at-acceptanceEthnopharmacology
==== Body
pmc1 Introduction

Depression is a mood illness marked by enduring feelings of sadness and lack of enjoyment. The global average incidence rate is about 4.4%. By 2030, depression is expected to become the leading cause of disease burden worldwide, being the primary contributor to non-fatal health loss globally (Rehm and Shield, 2019; Bayes et al., 2020). Selective serotonin reuptake inhibitors (SSRIs) and other Western medicine therapies are the mainstays of treatment; however, most medications have delayed effects, high rates of non-responsiveness, and significant side effects such as headaches, nausea, weight gain, and chronic dysfunction (Wang et al., 2019; Qu et al., 2021; Wei et al., 2022).

Therefore, developing more effective and safer antidepressant drugs has become an urgent problem to be solved. Traditional Chinese Medicine (TCM) has a long history of understanding and treating depression. TCM is known for its multi metabolite, multi target, multi link, and multi pathway characteristics, which can act on multiple aspects of the disease and have high efficacy and low toxicity. This highlights the advantages and good prospects of TCM in treating depression. Importantly, compared to Western medicine, they have the advantages of easy use, good therapeutic effects, minimal dosage, and fewer side effects. Due to the shortcomings of existing antidepressants and the urgent market demand, research on the antidepressant mechanism of TCM has attracted much attention (Zhuang et al., 2023).

Neuroplasticity refers to the brain’s ability to respond to external or internal stimuli from the environment or organs, resulting in functional and structural changes (Vints et al., 2022). Neuroplasticity is closely related to depression (Tartt et al., 2022), and is a significant focus for the development of future antidepressant drugs (Duman et al., 2016). However, there remains a notable lack of a systematic overview regarding the role of neuroplasticity in the pathological development of depression and the intervention of TCM.

Based on the above findings, this review systematically summarized the changes in neuroplasticity observed in clinical and preclinical studies of depression by searching relevant literature from recent years. Furthermore, it explored into the pharmacological mechanisms through which TCM modulated neuroplasticity to treat depression, providing scientific basis for subsequent basic research and clinical applications.

2 Review methodology

To investigate how TCM exerted antidepressant effects by regulating neuroplasticity, we conducted a comprehensive search of articles in PubMed, Embase, Web of Science, and ScienceDirect databases. The search keywords included “Traditional Chinese Medicine,” “Chinese herbal medicine,” “herb,” “Traditional Chinese Medicine formulas,” “Traditional Chinese Medicine metabolites,” “depression,” “major depressive disorder,” “syntactic plasticity,” and “neuroplasticity.” The retrieved articles were reviewed by two independent reviewers based on their titles, abstracts, and full texts, adhering to specific inclusion and exclusion criteria. The inclusion criteria were: 1) Original articles written in English; 2) Articles that examined the relevant mechanisms of TCM in regulating neuroplasticity for the treatment of depression. Exclusion criteria were as follows: 1) Articles written in any language other than English; 2) Gray literature; 3) Editorials; 4) Review articles; 5) Duplicate publications.

3 Overview of neuroplasticity

3.1 Definition of neuroplasticity

Neuroplasticity is a crucial concept in life sciences, describing how the brain changes and adapts to environmental changes by continually forming new neural connections (Price and Duman, 2020). It represents the adaptability of the nervous system, enabling it to adjust to learning, memory, environmental changes, and rehabilitation following brain injury. The main mechanisms include the regulation of synaptic strength, structural remodeling, and the regulation of intrinsic neuronal properties. These processes are dynamic, involving changes in the number of brain nuclei and structures, various functions, and numerous interactions (Xing and Bai, 2020; Dzyubenko and Hermann, 2023). Neuroplasticity is essential for understanding brain development, learning, and the regulation of homeostasis in the central nervous system (CNS).

3.2 Classification of neuroplasticity

Neuroplasticity includes two primary types: structural plasticity and functional plasticity. Structural plasticity refers to changes in mechanisms that promote neurogenesis, the formation of dendritic spines, and the growth and repair of axons. It includes changes in the number and connectivity of synapses, the density of dendritic spines, and modifications in neural processes like axons and dendrites, as well as variations in the number of neuronal cells (De Paola et al., 2006; Knott et al., 2006). On the other hand, functional plasticity involves synaptic changes between neurons without modifying their physical structure, such as long-term potentiation (LTP) and long-term depression (LTD) effects (Castillo, 2012; Marsden, 2013; Diering and Huganir, 2018). LTP and LTD are crucial mechanisms that affect cognitive and emotional functions in depression patients. Intense and sustained stimulation leads to an increase in neuronal discharge, which in turn enhances the strength of synapses. This process facilitates learning and memory, thereby promoting LTP. In contrast, LTD is characterized by a decrease in the efficacy and connectivity of neuronal synapses (Figure 1 showed a schematic diagram of neurogenesis).

FIGURE 1 Schematic diagram of neurogenesis in structural plasticity.

Neuroplasticity is regulated by several key mechanisms, one of which is the brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling pathway. The synthesis of BDNF is triggered by the activation of cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB). CREB is pivotal in facilitating LTP and synaptic plasticity. When BDNF binds to TrkB receptors, it triggers various signaling cascades, such as the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phosphoinositide 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) pathways, which are responsible for spine enlargement and increased glutamate sensitivity (Figure 2 showed the regulatory mechanism) (Bourtchuladze et al., 1994; Tanaka et al., 2008; Tejeda and Díaz-Guerra, 2017).

FIGURE 2 Neuroplasticity regulatory mechanisms.

4 Neuroplasticity and depression

4.1 Changes in neuroplasticity in depression

4.1.1 Clinical studies

Meta-analysis is a prominent method for evaluating the effectiveness of public health interventions (Tanner-Smith and Grant, 2018). In the pathophysiology of depression, impaired neuroplasticity plays a crucial role, as indicated by a meta-analysis conducted on the cerebrospinal fluid of individuals with unipolar depression (Mousten et al., 2022). Studies have shown that the increase in motor evoked potential amplitude, induced by paired associative stimulation, weakens during severe depressive episodes and normalizes during remission. It suggests the presence of LTP deficits in individuals with depression (Player et al., 2013; Kuhn et al., 2016). Furthermore, compared to healthy subjects, patients with depression, particularly those with refractory depression, exhibit impaired neuroplasticity in the dorsolateral prefrontal cortex. Female patients with depression also demonstrate persistent LTD-like plasticity deficits (Noda et al., 2018; Yu et al., 2020; Kaneko et al., 2024). Abnormal changes in neuroplasticity-related proteins have been observed in depression patients (Hidese et al., 2020). The ratio of BDNF to leptin levels has been associated with treatment responses in depression and may also be related to the neuroplasticity of depression, as evidenced by a 12-week follow-up study (An et al., 2019).

4.1.2 Preclinical studies

4.1.2.1 Depression model induced by stress

Stress is recognized as a normal physiological and psychological response to both positive and negative situations. Chronic stress, in particular, plays a key role in the development of mental illnesses such as depression (Ray et al., 2017; Beurel et al., 2020; Monroe and Harkness, 2022). Prolonged exposure to chronic stress exacerbates the phagocytosis of synaptic elements and results in defects in neuroplasticity (Kokkosis et al., 2024). Synaptic pruning, as a developmental process, is closely related to synaptic plasticity. In models of depression induced by chronic unpredictable mild stress (CUMS), excessive activation of microglia leads to exaggerated synaptic pruning (Zhang et al., 2022a), accompanied by impairments in synaptic plasticity (Li et al., 2021a; Yan et al., 2021). Early-life stress increases susceptibility to depression in adolescent mice by regulating the miR-34c-5p/synaptotagmin-1 (SYT1) axis and disrupting hippocampal neuroplasticity (Yu et al., 2024). In a combined model, adult female rats subjected to maternal-infant separation (MS) and CUMS exhibited more severe depressive and anxiety-like behaviors, potentially linked to compromised synaptic plasticity (Huang et al., 2021). In a depression model where insomnia was induced by CUMS combined with sleep deprivation, dendritic spines in the hippocampal dentate gyrus (DG) region were damaged, neural networks were disrupted, and neuroplasticity was inhibited (Li et al., 2022). Studies have also demonstrated that the absence of bombesin receptor-activated protein homologous protein affects hippocampal synaptic plasticity and exacerbates CUMS-mediated behavioral changes (Yao et al., 2023). Mechanistic research has revealed that CUMS alters synaptic plasticity in the nucleus accumbens (NAc) by influencing Kv4.2 channels through glycogen synthase kinase 3β (GSK3β)-dependent mechanisms (Aceto et al., 2020). Additionally, CUMS can disrupt the synaptic plasticity of regenerating neurons in the hippocampus of ischemic rats via astrocytic glutamate transporter-1 (Yu et al., 2019).

4.1.2.2 Depression model induced by social isolation

Social isolation can induce fatigue, behavioral changes, substance abuse, and various mental illnesses. These effects can be sustained and irreversible, impacting both humans and animals and increasing the risk of developing mental illness (Jaremka et al., 2014; Hueston et al., 2017). Neuroplasticity-related signals play a crucial role in the impact of induced isolation on sexual and neurological behavioral deficits (Liu et al., 2020). Animals subjected to chronic social isolation (CSIS) displayed depressive-like behavior (Perić et al., 2021), accompanied by proteomic findings showing dysregulated expression of synaptic plasticity-related proteins (Filipović et al., 2023). Moreover, animals raised in isolation exhibited immature dendritic spines that appear small and thin, with impaired neuroplasticity observed through LTP testing (Medendorp et al., 2018). However, treatment with fluoxetine has been shown to alleviate depressive-like behavior induced by CSIS and regulate neuroplasticity-related proteins (Filipović et al., 2022).

4.1.2.3 Depression mode induced by corticosterone

The hypothalamic-pituitary-adrenal (HPA) axis is a vital metabolite of the neuroendocrine system. When active, the anterior pituitary gland releases adrenocorticotropin (ACTH) into the bloodstream. This signal is received by the paraventricular nucleus of the hypothalamus, which then produces corticotropin-releasing hormone. ACTH, in turn, stimulates the adrenal cortex to release cortisol (CORT) (Frankiensztajn et al., 2020). Excessive activation of the HPA axis correlates significantly with sustained elevation of CORT levels and depression. Elevated CORT levels observed in individuals with depression closely correlate with the severity of depressive symptoms and poor treatment outcomes (Karin et al., 2020). Chronic exposure to CORT reduces the structural plasticity of astrocytes in the hippocampus of mice, leading to hippocampal atrophy (Zhang et al., 2015). Mice treated with CORT exhibit depressive-like behavior accompanied by changes in synaptic plasticity (Crupi et al., 2013; Freitas et al., 2016). Mechanistic studies have shown that CORT reduces synaptic density and vesicle recycling by downregulating BNIP3 like (BNIP3L)/NIX, thereby inhibiting mitochondrial autophagy (Choi et al., 2021).

4.1.2.4 Lipopolysaccharide (LPS) induced depression model

LPS can be found in the outer wall of Gram-negative bacterial cells, consisting of lipids and polysaccharides. Mouse models induced with LPS to mimic depression-like symptoms are commonly used to study the mechanisms of inflammation-related depression and the therapeutic effects of various drugs (Yin et al., 2023). Early reports indicated that LPS administration could induce LTP and depression in the hippocampal CA1 area (Jo et al., 2001). Recent studies have found that LPS mediates depressive-like behavior by promoting neuroinflammation in the basolateral amygdala (BLA), enhancing glutamatergic synaptic transmission, and increasing the intrinsic excitability of BLA projection neurons (Zheng et al., 2021). Wu et al. (2019), through a combination of proteomics and metabolomics, found that LPS intervention in mice disrupts glutamatergic transmission and Ephrin receptor signaling, potentially leading to impaired hypothalamic synaptic plasticity and depressive-like behavior.

4.2 Impact of antidepressant treatment on neuroplasticity

4.2.1 Chemicals acting on the CNS

Fluoxetine, a widely used SSRI in clinical practice, exerts its antidepressant effects by enhancing synaptic plasticity (Qian et al., 2024). It alos modified mood behaviors and hippocampal neuroplasticity by disrupting the nNOS-CAPON interaction that links postsynaptic 5-HT1AR activation (Shi et al., 2022). Additionally, fluoxetine enhances hippocampal neuroplasticity by promoting axonal formation induced by growth-associated protein 43 (GAP-43) (Zavvari et al., 2020). Pre-treatment with fluoxetine has been shown to prevent stress-induced LTD and spatial memory deficits in the hippocampus of rats (Han et al., 2015). Citalopram, another SSRI, is composed of two enantiomers, R-citalopram and S-citalopram, which inhibit serotonin (5-HT) reuptake in the brain, thereby exerting an antidepressant effect (Yan et al., 2023a). When combined with Punica granatum, citalopram can alleviate damage to dendritic spines in the hippocampal DG region (Vega-Rivera et al., 2023).

Agomelatine, a synthetic analogue of melatonin, exerts its antidepressant effects by stimulating melatonin receptors (MT1 and MT2) and antagonizing 5-HT2C receptors (Maddukuri et al., 2021). Research indicates that agomelatine improves pathological behavior in stressed mice by modulating BDNF signaling, synaptic plasticity, and epigenetic remodeling (Martin et al., 2017). It also demonstrates beneficial effects in mitigating stress-induced brain damage, as it restores the activity of hippocampal neurons affected by stress and promotes adult hippocampal neurogenesis (Dagyte et al., 2010).

Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, specifically inhibits GluN2B-containing NMDARs on inhibitory GABAergic interneurons (Sato et al., 2022). Its antidepressant mechanism involves modulating neuroplasticity (Clarke et al., 2017), and low concentrations of ketamine (20 μM) can induce postsynaptic enhancement in the hippocampal CA1 (Kim and Monteggia, 2020). Its antidepressant effects are mediated by increased neuroplasticity, including synaptic actions (Kopelman et al., 2023), and it can “reset the system” by participating in synaptic plasticity processes to reverse stress-induced loss of key neural circuit connections (Aleksandrova et al., 2020). In animal models with chronic pain and depression, TIAM1-mediated synaptic plasticity is a crucial factor in the antidepressant effect of ketamine (Ru et al., 2022). Ketamine may also exert rapid antidepressant effects by enhancing neuroplasticity, triggering autophagy, and preventing ferroptosis in the nucleus (Zhang et al., 2022b). Studies have found that ketamine-induced hippocampal synaptic plasticity during antidepressant treatment depends on 4E binding proteins (Aguilar-Valles et al., 2021).

4.2.2 Other types of chemicals

Metformin is the first-line treatment for type 2 diabetes, primarily acting by reducing liver gluconeogenesis and enhancing glucose metabolism. It also exhibits pleiotropic effects (LaMoia and Shulman, 2021). Beyond its antidiabetic role, metformin has been investigated for its potential in treating depression. Studies indicate that compared to other oral hypoglycemic drugs, metformin is associated with a lower risk of depression and demonstrates pleiotropic effects in depression management (Yu et al., 2022). Additionally, metformin can upregulate the expression of plasticity markers such as synapsin, sirtuin-1, AMP-activated protein kinase, and BDNF (Muñoz-Arenas et al., 2020). When combined with fluoxetine, metformin enhances the survival of NeuN-positive cells in the hippocampus and increases the number of BDNF-positive cells stimulated by fluoxetine, thereby enhancing its impact on neuroplasticity (Mendonça et al., 2022). Furthermore, metformin has been shown to mitigate synaptic plasticity damage induced by LPS in rats (Zhou et al., 2021) and improve the expression of synaptic plasticity markers [anti-microtubule-associated protein 2, synaptophysin (SYP), postsynaptic density protein 95], thereby alleviating depressive-like behavior in mice with allergic rhinitis (AR) (Lv et al., 2023). Hydrogen sulfide (H2S) is recognized as the third endogenous gas transmitter and can be produced in mammals through four enzyme pathways (Wu et al., 2018). H2S has been found to improve hippocampal synaptic plasticity in a Warburg-dependent manner, alleviating depression related to Parkinson’s disease (PD) (Liu et al., 2024) (Table 1).

TABLE 1 Regulation of antidepressant chemicals on neuroplasticity.

Chemical	Molecular formula	CAS NO.	Main mechanism of action	Reference	
Fluoxetine	C17H18F3NO	5410-89-3	Enhanced synaptic plasticity	Qian et al. (2024)	
Modified mood behaviors and hippocampal neuroplasticity by disrupting the nNOS-CAPON interaction that links postsynaptic 5-HT1AR activation	Shi et al. (2022)	
Enhanced hippocampal neuroplasticity by promoting axonal formation induced by GAP-43	Zavvari et al. (2020)	
Preventing LTD and spatial memory deficits caused by stress	Han et al. (2015)	
Citalopram	C20H21FN2O	59729-33-8	Combined use with Punica granatum can alleviate damage to dendritic spines in the DG region of the hippocampus	Vega-Rivera et al. (2023)	
Agomelatine	C15H17NO2	138112-76-2	Modulating BDNF signaling, synaptic plasticity, and epigenetic remodeling	Martin et al. (2017)	
Restored the activity of hippocampal neurons affected by stress and promotes adult hippocampal neurogenesis	Dagyte et al. (2010)	
Ketamine	C13H16ClNO	6740-88-1	Modulating neuroplasticity	Clarke et al. (2017)	
Inducing postsynaptic enhancement in the hippocampal CA1 region	Kim and Monteggia (2020)	
Increased neural plasticity, including synaptic interactions	Kopelman et al. (2023)	
Prevent the loss of critical neural circuit connections caused by stress	Aleksandrova et al. (2020)	
Metformin	C4H11N5	657-24-9	Upregulation of the expression of plasticity markers such as synaptic proteins, deacetylase-1, AMP activated protein kinase, and BDNF	Muñoz-Arenas et al. (2020)	
Improved the survival rate of hippocampal NeuN positive cells and increase the number of BDNF positive cells stimulated by fluoxetine, thereby enhancing its effect on neural plasticity	Mendonça et al. (2022)	
Improving synaptic plasticity damage	Zhou et al. (2021)	
Improving the expression of synaptic plasticity markers	Lv et al. (2023)	
H2S	H2S	7783-06-4	Improving synaptic plasticity in hippocampus	Liu et al. (2024)	

In summary, neuroplasticity undergoes alterations in patients with depression and is also impaired in stress-induced, social isolation-induced, CORT-induced, and LPS-induced depression models. Substances like fluoxetine, ketamine, and metformin can mitigate depressive symptoms by modulating neuroplasticity, suggesting that targeted manipulation of neuroplasticity offers potential for treating depression. However, fluoxetine carries specific adverse effects in therapeutic contexts, including the potential for hallucinations, hepatotoxicity, neurotoxicity, and addiction, which may restrict its clinical application.

5 Pharmacological mechanisms of TCM

At present, the treatment of depression is a major issue in the medical field, and neuroplasticity is closely related to depression. Regulation based on neuroplasticity is one of the potential important measures for the treatment of depression. However, the current Western medicine for treating depression is mainly developed based on the “monoamine neurotransmitter hypothesis” of depression, but drug dependence and withdrawal reactions are common. Therefore, the development of new antidepressant drugs has become a hot topic at present. TCM has unique advantages in preventing and treating depression, including its overall concept, syndrome differentiation, and treatment methods, as well as the specific characteristics of its multiple components and targets, which are beneficial to the overall internal environment while treating depression (Zhuang et al., 2023). Numerous studies have shown that the active metabolites and herbal formulas in TCM are involved in regulating neuroplasticity during the process of antidepressant treatment.

5.1 Active metabolites of TCM

5.1.1 Flavonoids

Engeletin, a flavonoid metabolite initially extracted from the leaves of Astragalus mongholicus Bunge (Huang et al., 2011), is a potent natural metabolite with antioxidant and anti-inflammatory properties (Fang et al., 2023). Recent research has shown that Engeletin exerts antidepressant effects by activating the BDNF/TrkB/mTORC1 signaling pathway and enhancing synaptic plasticity in the prefrontal cortex (Xu et al., 2023). Baicalein, an important flavonoid found in the roots Scutellaria baicalensis Georgi, is frequently used in Chinese medicine and herbal tea preparations to promote wellbeing (Chandrashekar and Pandi, 2022). In preclinical studies of antidepressant effects, baicalein has been found to activate the BDNF/TrkB/CREB signaling pathway and protect against synaptic plasticity damage in mice with depression related to PD (Zhao et al., 2021). It also increases the ratio of mature BDNF (mBDNF) to proBDNF, regulates neuronal survival and synaptic plasticity, and suppresses neuroinflammation, effectively alleviating LPS-induced depressive symptoms in mice (Liu et al., 2022). Baicalin, extracted from S. baicalensis Georgi, has significant biological activity, including anti-inflammatory properties (Guo et al., 2019). Its antidepressant effect involves regulating the expression of synaptophysin (SYP), PSD95, BDNF, and TrkB, activating the Rac1-cofilin pathway, and enhancing synaptic plasticity (Lu et al., 2019).

Quercitrin, a naturally occurring flavonoid found in various fruits and vegetables, is commonly used as a dietary metabolite and supplement (Chen et al., 2022a). In mice with LPS-induced depression, quercitrin intervention could improve hippocampal damage, restore the abnormal expression of the pCREB/BDNF/PSD95/Synapsin1 pathway, regulates the PI3K/AKT/NF-κB signaling pathway, and enhances neuroplasticity (Sun et al., 2021). Luteolin, another natural flavonoid found in plants such as Chrysanthemum indicum L., Capsicum annuum L., and Perilla frutescens (L.) Britton has been studied for its pharmacological mechanism in treating late-onset depression, involving the regulation of neuroplasticity-related proteins (Li et al., 2021b; Liu et al., 2023; Rauf et al., 2024).

Soy isoflavones (SI), essential metabolites of Glycine max (L.) Merr., have different biological functions. SI can upregulate the expression of phosphorylated SYP (p-SYP) and PSD95 in the hippocampus of mice, inhibit neuroinflammation, regulate tryptophan metabolism, and reverse LPS-induced depressive behavior (Lu et al., 2022). Additionally, S-equol, a metabolite of dietary soy isoflavones, has demonstrated antidepressant effects by increasing synaptic plasticity proteins and inhibiting neuroinflammation (Lu et al., 2021). Silibinin, a polymorphic flavonoid extracted from milk thistle [Silybum marianum (L.) Gaertn.] (Ma et al., 2023), exerts its antidepressant effects by improving neuroplasticity and increasing neurotransmitter levels (Yan et al., 2015).

5.1.2 Polyphenols

Polyphenols, metabolites widely distributed in a variety of plants, have garnered significant interest for their potential pharmacological actions, particularly their immune-stimulating and anticancer activities (Wang et al., 2022a). These metabolites have been found to enhance brain function by directly influencing cells and processes in the CNS (Grabska-Kobyłecka et al., 2023). Curcumin,a primary bioactive polyphenolic metabolite extracted from the rhizomes of Curcuma longa L., has been extensively studied for its therapeutic properties. In an ovariectomy-induced depression model, Curcumin was found to be a safe and effective regulator of 5-HT, similar to fluoxetine and neurotrophic E2, and was involved in regulating neuroplasticity (Abd-Rabo et al., 2019; Zia et al., 2021). Additionally, in the CUMS model, Curcumin was found to improve depressive-like behavior in animals by regulating the expression of synaptic plasticity proteins (Zhang et al., 2014).

5.1.3 Alkaloids

The defining characteristic uniting the diverse class of chemicals known as alkaloids is the presence of a nitrogen atom in a heterocyclic ring (Ziegler and Facchini, 2008). Berberine, an isoquinoline alkaloid derived from the Chinese botanical drug Coptis chinensis Franch. and related Berberis species, possesses a broad variety of pharmacological effects (Song et al., 2020). Studies have shown that Berberine effectively treats depression by inhibiting neuroinflammation and improving gut microbiota (Zhu et al., 2017; Yang et al., 2023a). Berberine has multi-target and multi-pathway antidepressant characteristics (Gao et al., 2024). Recent research has emphasized the impact of Berberine on neuroplasticity in the context of depression. In mouse models of depression treated with Berberine, an increase in neuronal and synaptic plasticity has been observed. Berberine targets enzymes such as tryptophan 5-hydroxylase one and indoleamine 2,3-dioxygenase one involved in tryptophan metabolism, thereby improving depressive symptoms in CUMS stimulated mice (Ge et al., 2023). Additionally, Berberine’s antidepressant effect is accompanied by a reduction in neuroinflammatory responses through the inhibition of NLRP3 inflammasome activation, promoting plasticity and neurogenesis to alleviate neuronal damage (Qin et al., 2023).

5.1.4 Saponins

Saponins, naturally occurring substances found in a wide range of plants, have garnered interest for their potential pharmacological properties (Zhang et al., 2023). Saikosaponin C, a metabolite purified from the traditional Chinese botanical drug Bupleurum chinense DC., has been studied for its effects on depression. Recent reports indicate that saikosaponin C reduces IL6 levels by inhibiting DNA methyltransferase one protein, leading to a decrease in IL6 expression. This metabolite promotes synaptic plasticity and alleviates depression-like behavior induced by chronic social defeat stress (Pan et al., 2019; Bai et al., 2023).

Ginsenoside Rb1, one of the main ginsenosides found in Panax ginseng C.A.Mey., is known for its neuroprotective properties (Ni et al., 2022). Research has shown that ginsenoside Rb1 can alleviate depressive symptoms induced by CUMS by modulating hippocampal synaptic plasticity through the miR-134-mediated BDNF signaling pathway (Wang et al., 2022b). Additionally, ginsenoside Rb1 regulates mitochondrial autophagy and the NF-κB pathway to inhibit astrocyte apoptosis, thereby reducing neuroinflammation and enhancing synaptic plasticity to maintain nervous system homeostasis (Li et al., 2023a). Ginsenoside Rg1, another key metabolite of P. ginseng C.A.Mey., has gained attention for its potential in preventing neurological diseases, especially dementia and depression (Yang et al., 2023b). It has been found to synergize with exercise in treating depression by reducing inflammation and improving neuroplasticity (Wang et al., 2023a).

5.1.5 Terpenoids

The largest class of natural products is terpenoids, offering a plethora of potential therapeutic candidates (Huang et al., 2012). Gardenia jasminoides J. Ellis contains a type of iridoid glycoside called geniposide, which has various of biological benefits, including anti-neurodegenerative effects (Shen et al., 2020a). In a mouse model of postpartum depression, researchers observed excessive activation of the HPA axis and abnormal expression of proteins related to synaptic plasticity. Treatment with geniposide can alleviate these pathological phenomena and improve depressive-like behavior in mice (Ma et al., 2024). Xia et al. (2021) found that iridoids from Gardeniae fructus exerted antidepressant-like effects by stimulating AMPAR/mTOR signaling to enhance synaptic plasticity. For over a millennium, Paeonia lactiflora Pall. has been used in TCM to address ailments related to pain, inflammation, and the immune system (Zhang and Wei, 2020). Paeonia lactiflora Pall. produces a water-soluble monoterpene glycoside known as paeoniflorin (Cao et al., 2023), effectively reversing LTP damage induced by CUMS in the hippocampal CA1 region. Additionally, it can prevent CUMS-induced changes in dendritic spine density in the mouse hippocampus and downregulate BDNF and postsynaptic density protein 95 (PSD95) expression (Liu et al., 2019).

The pentacyclic triterpenoid chemical oleanolic acid (OA) is a naturally occurring substance extracted from various plants, including Olea europaea L. (Luo et al., 2024). Ursolic acid (UA) is another naturally occurring pentacyclic triterpenoid found in plants (Li et al., 2023b). Kong et al. (2023) conducted a study comparing the antidepressant effects of OA and UA, and found that in a depression model induced by CMS, OA was more effective than UA at reversing the depressive-like behavior induced by MS. In their mechanistic study, it was found that both OA and UA treatments reversed the decrease in synapsin expression levels caused by MS, but only OA upregulated the expression level of PSD-95 (Kong et al., 2023).

5.1.6 Polysaccharides

Polysaccharides are carbohydrate polymers composed of at least ten monosaccharides linked by glycosidic linkages (Yi et al., 2020). They are found in plants, microbes, bacteria, fungi, and seaweed all contain polysaccharides, playing crucial roles in various physiological processes (Chen et al., 2017). Post-traumatic stress disorder (PTSD) is a type of depression syndrome, and Xie et al. (2024) found that polysaccharides from Polygonatum cyrtonema Hua can improve PTSD-induced behavioral abnormalities and synaptic damage in mice by reducing oxidative stress and neuroinflammation, and by acting on the Nrf2/HO-1 signaling pathway. Inulin, a non-digestible fructan-type carbohydrate, was originally isolated from the roots of Inula helenium L. (Illippangama et al., 2022). Studies suggest that inulin improves neurogenesis and synaptic plasticity by enhancing CREB/BDNF signaling, prevents CUMS-induced reduction in blood-brain barrier permeability, reduces neuroinflammation, preserves intestinal barrier integrity, and promotes the production of short-chain fatty acids (SCFAs) (Wang et al., 2023b). Schisandra chinensis (Turcz.) Baill., belonging to the Magnoliaceae family and has been widely used as a medicinal plant in China for centuries. Modern pharmacological research has revealed the anti-inflammatory and anti-aging properties of S. chinensis and its active metabolites (Bian et al., 2022). Notably, studies have shown that the polysaccharide-rich fraction from S. chinensis (Turcz.) Baill. exhibits antidepressant effects in olfactory bulbectomized mice by enhancing abnormal synaptic plasticity (upregulating PSD95 expression), suppressing excessive activity of the HPA axis, and regulating gut microbiota (Zhu et al., 2024).

5.1.7 Botanical drugs extracts

Botanical drugs extracts are considered valuable for their comprehensive active properties, driven by complex biochemical interactions and synergistic effects among their natural metabolites (Pace and Martinelli, 2022). Saffron (Crocus sativus L.), a well-known natural product, has long been used to prevent and treat different disorders (Ghaffari and Roshanravan, 2019). In rats exposed to chronic mild stress (CMS), repeated administration of doses of 100 mg/kg and 200 mg/kg doses of Saffron Extract (Affron®) effectively normalized HPA axis dysregulation. Moreover, hypothalamic neuroplasticity showed a significant dose-dependent increase following treatment with Saffron Extract (Affron®) (Kim et al., 2023). Blueberry (Vaccinium spp.), a member of the Vaccinium genus, is recognized as one of the top five nutritious foods for humans and is often referred to as the “king of fruits.” This reputation has fueled considerable interest in the market for plant-based prebiotics (Duan et al., 2022). Blueberry Extract has demonstrated efficacy in alleviating depression-like behavior in LPS-induced mice. It also mitigates the increase in acetylcholinesterase (AChE) activity in the hippocampus induced by LPS and inhibits the mRNA expression of TNF-α, IL-1β, and IL-10 in the cerebral cortex following LPS administration, indicating a potential protective effect on neuroplasticity (Spohr et al., 2023).

5.1.8 Other types of active metabolites

Honokiol is a versatile lignan metabolites naturally occurring in plants like Magnolia grandiflora L., known for its anti-inflammatory and neuroprotective effects (Rauf et al., 2021; Hu et al., 2023). Fan et al. (2022) found that the antidepressant mechanism of Honokiol involved the activation of the HIF-1α/VEGF signaling pathway and the upregulation of synaptic protein one and PSD 95 expression levels. Salidroside, an active metabolites found in Rhodiola rosea L. used in TCM, has various pharmacological effects (Xue et al., 2019). It enhances BDNF expression, improve synaptic plasticity, and inhibits pyroptosis mediated by the P2X7/NF-κB/NLRP3 signaling pathway, thereby providing a treatment for depression (Chai et al., 2022).

Crocin is a hydrophilic carotenoid produced in the blooms of C. sativus L., has been associated with promoting new nerve cell generation in the adult hippocampus and exerting antidepressant effects by activating the Wnt/β-catenin signaling pathway (Boozari and Hosseinzadeh, 2022; Tao et al., 2023a), Neurogenesis plays a key role in the physiological mechanism of structural neuroplasticity. Wu et al. (2020) also found that crocin rapidly and persistently induced antidepressant effects in mice subjected to Prenatal stress (PNS), acting through the GHSR-PI3K signaling pathway and modulating the expression of hippocampal synaptic plasticity-related proteins. Panaxynol, commonly found in plants of the P. ginseng C.A.Mey., can alleviate HPA axis overactivity induced by CUMS, promote the release of 5-HT and dopamine (DA), enhance hippocampal synaptic plasticity, and improve neurotransmitter effectiveness (Table 2 showed the active metabolites of TCM information) (Sun et al., 2020).

TABLE 2 Information on the action of active metabolites in TCM.

Category	Active metabolites	Source information	In vivo/in vitro	Modeling method	Dosage	Behavioral testing evaluation	Main pharmacological mechanisms	References	
Flavonoids	Engeletin	Astragalus mongholicus Bunge	In vivo	CRS	2.5, 5, 10, 20 mg/kg	FST, TST, OFT, SPT	Activation of BDNF/TrkB/mTORC1 signaling pathway and regulation of PFC synaptic plasticity	Xu et al. (2023)	
Baicalein	Scutellaria baicalensis Georgi	In vivo	Rotenone	300 mg/kg	TST, SPT, OFT, Rotarod test	Activating the BDNF/TrkB/CREB signaling pathway to improve neural plasticity	Zhao et al. (2021)	
In vivo and in vitro	LPS	In vivo: 3 mg/kg	FST, TST	Increase the proportion of mBDNF/proBDNF to regulate neuronal survival and synaptic plasticity	Liu et al. (2022)	
Baicalin	Scutellaria baicalensis Georgi	In vivo	CMS	25, 50, 100 mg/kg	OFT, FST, SPT	Promote the expression of BDNF and CREB, regulate neuronal survival and synaptic plasticity	Lu et al. (2019)	
Quercitrin	Multiple fruits and vegetables	In vivo	LPS	10, 20, 30 mg/kg	FST, TST, OFT, SPT	Inhibiting Neuroinflammation PI3K/AKT/NF-κB Signal Transduction and Improving Damaged CREB/BDNF Neuroplastic Signal Transduction	Sun et al. (2021)	
luteolin	Chrysanthemum indicum L., Capsicum annuum L., and Perilla frutescens (L.) Britton	In vivo	CUMS	25 mg/kg	SPT, OFT, FST, MWM	Regulating Neuroplasticity Related Proteins	Liu et al. (2023)	
Soy isoflavones	soybeans	In vivo	LPS	10, 20, 40 mg/kg	FST, TST, OFT, SPT	Upregulation of hippocampal SYP phosphorylation and expression of PSD95	Lu et al. (2022)	
Polyphenols	Curcumin	Curcuma longa L	In vivo	Ovariectomised	100 mg/kg	FST	Regulating neural plasticity	Abd-Rabo et al. (2019)	
In vivo	CUMS	40 mg/kg	OFT, SPT, FST	Regulating neural plasticity related proteins (PSD95 and SYP)	Zhang et al. (2014)	
Alkaloids	Berberine	Coptis chinensis Franch	In vivo	CUMS	2.5, 5, 10 mg/kg	OFT, FST, Novelty-suppressed feeding test (NSFT)	Promote synaptic plasticity and regulate tryptophan metabolism by inhibiting IDO1 and activating TPH1	Ge et al. (2023)	
In vivo	CORT	100, 200 mg/kg	FST, TST, OFT, SPT	Inhibiting the activation of NLRP3 inflammasome to reduce neuroinflammatory response and promote synaptic plasticity and neurogenesis	Qin et al. (2023)	
Saponins	Saikosaponin C	Bupleurum chinense DC.	In vivo and in vitro	In vivo: CSDS
In vitro: LPS/ATP	In vivo: 0.5, 1 mg/kg	Social interaction TEST (SI), SPT, TST, FST, OFT	Inhibiting DNMT1 protein to reduce IL6 methylation, inducing decreased IL6 expression, and promoting synaptic plasticity	Bai et al. (2023)	
Ginsenoside Rb1	Panax ginseng C.A.Mey	In vivo	CUMS	20 mg/kg	FST, TST, OFT, SPT	Regulating hippocampal synaptic plasticity through the miR-134 mediated BDNF pathway	Wang et al. (2022b)	
In vivo and in vitro	In vivo: CUMS
In vitro: LPS-ATP stimulation	In vivo: 10 mg/kg	OFT, FST, SPT	Regulating mitophagy and NF-κB pathway to inhibit astrocyte pyroptosis, thereby inhibiting neuroinflammation and enhancing synaptic plasticity	Li et al. (2023a)	
Ginsenoside-Rg1	Panax ginseng C.A.Mey	In vivo	LPS	40 mg/kg	SPT, FST, OFT, EPM, MWM	It has a synergistic effect with volumetric running, with anti-inflammatory and improved neural plasticity functions	Wang et al. (2023a)	
Terpenoids	Geniposide	Gardenia jasminoides J.Ellis	In vivo	prenatal restraint stress	25, 50, 100 mg/kg	SPT, OFT, FST	Regulating the HPA axis and improving the expression of synaptic plasticity related proteins	Ma et al. (2024)	
Paeoniflorin	Paeonia lactiflora Pall	In vivo	CUMS	20 mg/kg	SPT, FST, TST, MWM	Improving LTP in hippocampal CA1 region and upregulating hippocampal dendritic spine density and expression levels of BDNF and PSD95	Liu et al. (2019)	
Oleanolic acid	Olea europaea L	In vivo	Maternal separation	30 mg/kg	OFT, EPM, Splash test, FST	Both OA and UA can upregulate synapsin levels, and OA can also upregulate the expression level of PSD95	Kong et al. (2023)	
Ursolic acid	Exists in various plants	
Polysaccharides	Polysaccharides from Polygonatum cyrtonema Hua	Polygonatum cyrtonema Hua	In vivo	Single prolonged stress	200, 400, 800 mg/kg	OFT, EPM, Fear conditioning task	Relieve oxidative stress and neuroinflammation, and act on the Nrf2/HO-1 signaling pathway to improve synaptic damage	Xie et al. (2024)	
Inulin	Inula helenium L	In vivo	CUMS	0.037 g of inulin/kcal	SPT, FST, OFT, TST, EPM	Enhancing CREB/BDNF signaling to improve neurogenesis and synaptic plasticity	Wang et al. (2023b)	
Polysaccharide-rich fraction from Schisandra chinensis (Turcz.) Baill	Schisandra chinensis (Turcz.) Baill	In vivo	Olfactory bulbectomy	50, 200, 800 mg/kg	FST, TST, Locomotor activity test	Improving abnormal synaptic plasticity (upregulating PSD95 expression), inhibiting excessive HPA axis activity, and regulating gut microbiota	Zhu et al. (2024)	
Botanical drugs extracts	Saffron Extract (Affron®)	Saffron (Crocus sativus L.)	In vivo	Unpredictable chronic mild stress	100, 200 mg/kg	SPT	Adjusting the HPA axis to increase hypothalamic neural plasticity	Kim et al. (2023)	
Blueberry Extract	Blueberry (Vaccinium spp.)	In vivo	LPS	100, 200 mg/kg	OFT, FST	Downregulation of hippocampal AChE activity, inhibition of neuroinflammation, and potential protection of neuroplasticity	Spohr et al. (2023)	
Other types	Honokiol	Magnolia grandiflora L	In vivo and in vitro	In vivo: CUMS	10 mg/kg	OFT, SPT	Activate the HIF-1α/VEGF signaling pathway and upregulate the protein expression levels of SYP 1 and PSD 95	Fan et al. (2022)	
Salidroside	Rhodiola rosea L	In vivo and in vitro	In vivo: CORT or LPS
In vitro: CORT or nigericin	20, 40 mg/kg	OFT, SPT, FST	Upregulation of BDNF expression, improvement of synaptic plasticity, and inhibition of P2X7/NF-κB/NLRP3 signaling pathway mediated pyroptosis	Chai et al. (2022)	
Crocin	Crocus sativus L	In vivo and in vitro	In vivo: CUMS	12.5, 25 mg/kg	SPT, TST, FST, OFT	Regulating the Wnt/β-catenin signaling pathway to promote adult hippocampal neurogenesis	Tao et al. (2023a)	
In vivo	Prenatal stress	10, 20, 40 mg/kg	OFT, TST, FST, SPT, NSFT	Regulating hippocampal synaptic plasticity related proteins	Wu et al. (2020)	
Panaxynol	Panax ginseng C.A.Mey	In vivo	CUMS	1.0 mg/kg	OFT, EPM, SPT	Regulating the HPA axis, promoting the release of 5-HT and DA, and improving hippocampal synaptic plasticity	Sun et al. (2020)	

5.2 TCM formulas

Zhi-Zi-Chi-Tang (ZZCT) is a potent traditional Chinese herbal remedy with a historical record in the “Shanghan Lun.” It consists of the dehydrated mature fruits of G. jasminoides J. Ellis and G. max (L.) Merr. In a rat depression model induced by CUMS, ZZCT enhances neuroplasticity through the 14–3–3ζ/GSK-3β/CREB/BDNF signaling pathway. It restores the expression of synaptic plasticity-related proteins like MAP2 and PSD95 in the hippocampal CA1 region, enhances LTP induction, and improves neuronal damage caused by CUMS (Tao et al., 2023b).

Zi-Shui-Qing-Gan-Yin (ZSQGY) is another traditional Chinese herbal remedy commonly used in China for depression symptoms. ZSQGY consists of 12 botanical drugs, including P. ginseng C.A.Mey et al. In a study conducted both in vivo and in vitro by Zhu et al. (2023), it was found that ZSQGY significantly improved depression-like behavior induced by monosodium glutamate (MSG) in rats. Further investigations revealed that ZSQGY improved synaptic ultrastructure by upregulating PGC-1α, regulating mitochondrial function, and inhibiting the expression of pro-inflammatory cytokines (Zhu et al., 2023).

The traditional remedy Danggui-Buxue Decoction (DBD), is taken from Li Dongyuan’s work on differentiating endogenous and exogenous diseases in the Jin and Yuan Dynasties (Shi et al., 2019). Studies suggest that DBD protects and reshapes hippocampal neurons by regulating the CREB/BDNF/TrkB pathway. It shows promise as a potential metabolite for preventing diabetes mellitus with depression (DD), with ferric acid potentially playing a crucial role in its effects (Wang et al., 2021). The Erzhi formula, composed of Ligustrum lucidum W.T.Aiton and Eclipta prostrata (L.) L., represents a TCM treatment (Peng et al., 2022). In an in vitro depression model, the Erzhi formula revealed the capacity to diminish dexamethasone-induced apoptosis in primary cultured cortical neurons and repair synaptic damage. Its neuroprotective effects were linked to the 11β-hydroxysteroid dehydrogenase 1 (HSD1)-glucocorticoids (GC)/glucocorticoid receptor (GR) signaling pathway (Han et al., 2023).

Xiaoyaosan, a TCM formula first introduced in the book “Prescriptions of the Bureau of Taiping People’s Welfare Pharmacy,” has a historical use in treating mental disorders, such as depression (Jiao et al., 2024). The ancient Chinese medicine pharmacopoeia also mentions Jiawei-Xiaoyao pill (JWX), a traditional Chinese medication, for the treatment of a variety of illnesses, including mood disorders. JWX consists of nine botanical drugs, including G. jasminoides J. Ellis et al. Studies have shown that JWX stimulates CaMKII signaling, leading to the activation of the mTOR/BDNF signaling pathway, Furthermore, it also enhances hippocampal neuroplasticity and triggering rapid antidepressant effects (Zhang et al., 2024a).

For more precise administration in patients with depression, Gao et al. (2018) introduced an empirical prescription called modified Xiaoshan (MXYS) based on Xiaoshan consisting of B. chinense DC et al. In a depression model induced by CUMS, MXYS was found to promote hippocampal neurogenesis and improve brain blood oxygen level-dependent signaling, indicating its potential therapeutic benefits for depression (Gao et al., 2018).

SiNiSan (SNS) is a TCM formula. Originally mentioned in the Treatise on Febrile Diseases for controlling liver qi (Cao et al., 2024), SNS has been shown to regulate neuroplasticity by activating the Calcium sensitive receptor (CaSR)-protein kinase C (PKC)-ERK signaling pathway. It also helps in regulating mitochondrial function and improving neuroplasticity (Shen et al., 2020b; Deng et al., 2022). Suanzaoren Decoction (SZRD), a TCM combination with a history of insomnia treatment (Dong et al., 2021; Yan et al., 2023b). Research by Du et al. (2024) using in vivo and in vitro experiments demonstrated that SZRD increases the expression levels of BDNF, SYP, and PSD95. It also inhibits the activation of the TLR4/MyD88/NF-κB and Wnt/β-catenin pathways, showing antidepressant effects, and SZRD could also adjust the CaMK signal system (Zhang et al., 2024b; Du et al., 2024).

Zhi-Zi Hou-Po Decoction (ZZHP), a TCM formula widely used in depression treatment (Feng et al., 2022). Studies suggest that ZZHP effectively reverses the decrease of monoamine neurotransmitters in the hippocampus, maintains their homeostasis, activates the BDNF/TrkB/CREB pathway, protects neuronal synaptic plasticity, promotes hippocampal neurogenesis, and alleviates depression-like symptoms in mice caused by CUMS (Ye et al., 2024). Kaiyu Zhishen Decoction (KZD) is composed of botanical drugs such as P. lactiflora Pall. Chen et al. (2024) found through network pharmacology and experimental verification that the antidepressant effect of KZD involves regulating the ERK-CREB-BDNF signaling pathway and promoting neuronal repair, potentially regulating neuroplasticity (Figure 3 showed the mechanism of TCM action and Table 3 showed the TCM formulas information).

FIGURE 3 The pharmacological mechanism of TCM regulation of neuroplasticity in the treatment of depression. The red arrow indicates changes caused by stress, while the green arrow indicates changes caused by TCM.

TABLE 3 Information on the action of TCM formulas.

TCM formulas	Main composition	In vivo/in vitro	Modeling method	Dosage	Behavioral testing evaluation	Main pharmacological mechanisms	References	
Zhi-Zi-Chi-Tang (ZZCT)	Gardenia jasminoides J.Ellis and Glycine max (L.) Merr	In vivo	CUMS	3, 6 g/kg	SPT, TST, FST, OFT	Regulating the 14–3–3ζ/GSK-3β/CREB/BDNF signaling pathway to enhance neural plasticity	Tao et al. (2023b)	
Zi-Shui-Qing-Gan-Yin (ZSQGY)	Panax ginseng C.A.Mey, Dioscorea oppositifolia L, Bupleurum chinense DC, Paeonia lactiflora Pall, Angelica sinensis (Oliv.) Diels, Anemarrhena asphodeloides Bunge, Cornus officinalis Siebold and Zucc, Paeonia × suffruticosa Andrews, Smilax glabra Roxb, Ziziphus jujuba Mill, Alisma plantago-aquatica L and Gardenia jasminoides J.Ellis	In vivo and in vitro	In vivo: monosodium glutamate
In vitro: CORT	12, 24, 48 g/kg	SFT, SPT, OFT	Upregulation of PGC-1α to improve pathological changes in synaptic ultrastructure, regulate mitochondrial function, and inhibit the expression level of pro-inflammatory cytokines	Zhu et al. (2023)	
Danggui-Buxue Decoction (DBD)	Astragalus mongholicus Bunge and Angelica sinensis (Oliv.) Diels	In vivo	CUMS	4, 8 g/kg	FST, OFT, TST	Regulating the CREB/BDNF/TrkB pathway to protect and reshape hippocampal neurons	Wang et al. (2021)	
Erzhi formula	Ligustrum lucidum W.T.Aiton and Eclipta prostrata (L.) L	In vitro	Dexamethasone	--	--	Reduce neuronal apoptosis and improve synaptic damage	Han et al. (2023)	
Jiawei-Xiaoyao pill (JWX)	Gardenia jasminoides J.Ellis, Paeonia × suffruticosa Andrews, Bupleurum chinense DC. , Paeonia lactiflora Pall., Angelica sinensis (Oliv.) Diels, Atractylodes macrocephala Koidz., Smilax glabra Roxb., Glycyrrhiza glabra L. and Mentha canadensis L	In vivo	CORT	0.7, 1, 1.4, 1.8 g/kg	OFT, TST, FST, SPT	Stimulation of CaMKII signaling pathway, followed by activation of mTOR/BDNF signaling pathway, enhances hippocampal neural plasticity	Zhang et al. (2024a)	
Modified Xiaoyaosan (MXYS)	Bupleurum chinense DC., Angelica sinensis (Oliv.) Diels, Paeonia lactiflora Pall., Atractylodes macrocephala Koidz., Acorus calamus L., Curcuma aromatica Salisb.,Reynoutria multiflora (Thunb.) Moldenke, Schisandra chinensis (Turcz.) Baill., Ziziphus jujuba Mill., and Periploca forrestii Schltr	In vivo	CUMS	0.4 g/kg	SPT, TST, FST	Promote hippocampal neurogenesis and improve BOLD signaling	Gao et al. (2018)	
SiNiSan (SNS)	Citrus × aurantium f. Aurantium, Paeonia lactiftora Pall., Glycyrrhiza glabra L., and Bupleurum chinense DC	In vivo	Maternal separation and CUMS	0.25, 0.5, 1 g/mL	SPT, OFT, FST	Activating the CaSR-PKC-ERK signaling pathway	Shen et al. (2020b)	
In vivo	Maternal separation	2.5, 5, 10 g/kg	SPT, OFT, FST	Regulating mitochondrial function, and improving neural plasticity	Deng et al. (2022)	
Suanzaoren Decoction (SZRD)	Ziziphus jujuba Mill., Smilax glabra Roxb., Anemarrhena asphodeloides Bunge, Oreocome striata (DC.) Pimenov and Kljuykov, and Glycyrrhiza glabra L	In vivo and in vitro	In vivo: CUMS
In vitro: LPS	15 g/kg	SPT, FST, OFT	Elevated the expression levels of BDNF, SYP, and PSD95, and inhibited the activation of TLR4/MyD88/NF-κB and Wnt/β-catenin pathways	Du et al. (2024)	
In vivo	CUMS	2.5, 5, 10 g/kg	SPT, OFT	Modulating CaMK signal system	Zhang et al. (2024b)	
Zhi-Zi Hou-Po Decoction (ZZHP)	Gardenia jasminoides J.Ellis, Citrus × aurantium f. Aurantium and Magnolia officinalis Rehder and E.H.Wilson	In vivo	CUMS	0, 30, 40 mg/kg	SPT, TST, FST, OFT	Activating the BDNF/TrkB/CREB pathway protects neuronal synaptic plasticity and promotes hippocampal neurogenesis	Ye et al. (2024)	
Kaiyu Zhishen Decoction (KZD)	Paeonia lactiflora Pall., Cyperus rotundus L., Smilax glabra Roxb., Angelica sinensis (Oliv.) Diels., Panax ginseng C.A.Mey., Gardenia jasminoides J.Ellis., Atractylodes macrocephala Koidz., Citrus reticulata Blanco., Glycyrrhiza glabra L., and Bupleurum chinense DC	In vivo and in vitro	In vivo: CUMS
In vitro: CORT	1.579, 4.73, 14.21 g/kg	SPT, FST, TST	Regulating the ERK-CREB-BDNF signaling pathway and enhancing neuronal repair	Chen et al. (2024)	

6 Conclusion and prospects

Depression is a common long-lasting mental disorder marked by enduring feelings of sadness, low self-esteem, and potentially dangerous suicidal ideation. Understanding the pathogenesis of depression remains a challenge in modern medicine, and there is a deficiency of therapeutic strategies that may effectively prevent or entirely reverse depression (Chen et al., 2022b; Xia et al., 2023). At now, great progress has been achieved in the study of depression, both at the preclinical level and at the fundamental research level. Multiple chemicals with antidepressant effects have been developed in some clinical treatments, but there are still certain side effects and insufficient efficacy. In addition, there is a lack of suitable and appropriate depression prediction tools in clinical practice. Currently, finding antidepressant drugs with multiple targets, high safety, good efficacy, and minimal adverse reactions is a major task.

In recent years, TCM has received attention and promotion, and has been vigorously developed in various aspects. In the research of antidepressants, TCM has gradually become the focus and hotspot of research. In the treatment of depression, it is crucial to explore how TCM can complement Western medicine approaches, leveraging the strengths of TCM’s multi-target effects and individualized treatments. Research in multi-target antidepressant therapies is essential to achieve outcomes comparable to modern medical “cocktail therapy.” TCM offers multiple advantages, including its emphasis on multiple targets and individualized treatment in line with the principles of precision medicine. Active metabolites in TCM, such as flavonoids, polyphenols, alkaloids, saponins, terpenes, polysaccharides, and TCM extracts, along with TCM formulas such as ZZCT, ZSQGY, DBD, Erzhi formula, JWX, MXYS, SNS, SZRD, KZD and ZZHP, play a role in regulating neuroplasticity through various targets and pathways when exerting antidepressant effects.

However, the causes and mechanisms of depression have not been fully elucidated, and there is a lack of unified and relatively authoritative methods for evaluating depression symptoms in clinical practice. There is no clear standard for the specific indicators of depression. More importantly, current research mostly focuses on the in vivo or in vitro levels, lacking high-quality clinical research on active metabolites and TCM formulas. Most studies only explore the mechanism of drug action, and the connection between TCM theory and neuroplasticity has not been thoroughly investigated. Furthermore, compared to the active metabolites of TCM, research on TCM formulas is relatively weak, and the diversity and depth of neuroplasticity-related signaling pathways explored are insufficient. There is no active substance in the world that not only exerts its pharmacological effects but also has non-specific off-target effects on normal tissues of the body (Guo et al., 2023). In current research on antidepressants, there has been insufficient exploration of the toxicology and side effects of TCM.

In addition, some Chinese herbal medicines lack clear quality control standards, compromising the stability and consistency of their chemical metabolites, limiting their clinical application and complicating the study of their pharmacological mechanisms. Furthermore, certain active metabolites of TCM face challenges such as poor stability, solubility issues, and difficulty in crossing the blood-brain barrier, which need further investigation to ascertain their efficacy in targeting CNS organs. The mechanism of neuroplasticity is complex, involving multiple signaling pathways and cell coordination. While TCM possesses the advantage of targeting multiple pathways, current research predominantly focuses on single signaling pathways with limited detection indicators. This approach fails to comprehensively elucidate the synergistic mechanisms underlying TCM’s multi-target and multi-pathway regulation of neuroplasticity.

Therefore, in future research, multicenter, large-sample clinical randomized controlled trials guided by TCM theory should be conducted to explore the efficacy and safety of TCM in treating depression, as well as the regulatory mechanisms of neuroplasticity, aiming to provide deeper insights into how TCM works in antidepressant treatment. Simultaneously, it is essential to enhance the quality control standards for TCM and strengthen the exploration of targeted delivery systems for TCM to increase the concentration and duration of TCM in target organs, thereby improving the therapeutic outcomes. Furthermore, focusing on cutting-edge technologies such as combined single-cell sequencing and spatial transcriptomics is necessary to further reveal the key regulatory targets of TCM and the regulatory mechanisms of neuroplasticity at different time points and cell types. This review systematically elucidated the role of neuroplasticity in the pathological development of depression and the regulatory role of TCM. In conclusion, substantial research efforts are still needed to fully explore the potential of TCM in modulating neuroplasticity for the prevention and treatment of depression.

Author contributions

SL: Writing–original draft. NY: Writing–review and editing. YL: Writing–review and editing. GZ: Writing–review and editing. XZ: Writing–review and editing. YC: Writing–review and editing. YH: Writing–review and editing. JT: Writing–review and editing. YS: Writing–review and editing.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Glossary

TCM	Traditional Chinese medicine	
MDD	Major depressive disorder	
SSRIs	Selective serotonin reuptake inhibitors	
LTP	Long-term potentiation	
LTD	long-term depression	
BDNF	Brain-derived neurotrophic factor	
TrkB	Tyrosine kinase receptor B	
cAMP	Cyclic adenosine monophosphate	
CREB	cAMP responsive element binding protein	
CUMS	Chronic unpredictable mild stress	
MS	maternal-infant separation	
DG	Dentate gyrus	
CSIS	Chronic social isolation	
HPA	Hypothalamic-pituitary-adrenal	
ACTH	Adrenocorticotropin	
CRH	Corticotropin-releasing hormone	
CORT	Cortisol	
BNIP3L	BNIP3 like	
LPS	Lipopolysaccharide	
PNs	Projection neurons	
CNS	Central nervous system	
BLA	Basolateral amygdala	
nNOS	neural nitric oxide synthase	
GAP-43	Growth associated protein 43	
5-HT	Serotonin	
NMDAR	N-methyl-D-aspartate receptor	
4E-BPs	4E binding proteins	
AR	Allergic rhinitis	
H 2 S	Hydrogen sulfide	
SI	Soy isoflavones	
p-SYP	Phosphorylated SYP	
OA	Oleanolic acid	
PTSD	Post-traumatic stress disorder	
SCFAs	Short-chain fatty acids	
AChE	Acetylcholinesterase	
PNS	Prenatal stress	
DA	Dopamine	
ZZCT	Zhi-Zi-Chi-Tang	
ZSQGY	Zi-Shui-Qing-Gan-Yin	
MSG	monosodium glutamate	
DBD	Danggui-Buxue Decoction	
AR	Astragali Radix	
ASR	Angelica Sinensis Radix	
DD	Diabetes mellitus with depression	
HSD1	11β-hydroxysteroid dehydrogenase 1	
GC	Glucocorticoids	
GR	Glucocorticoid receptor	
JWX	Jiawei-Xiaoyao pill	
MXYS	Modified Xiaoshan	
SNS	SiNiSan	
SZRD	Suanzaoren Decoction	
ZZHP	Zhi-Zi Hou-Po Decoction
==== Refs
References

Abd-Rabo M. M. Georgy G. S. Saied N. M. Hassan W. A. (2019). Involvement of the serotonergic system and neuroplasticity in the antidepressant effect of curcumin in ovariectomized rats: comparison with oestradiol and fluoxetine. Phytother. Res. 33 (2 ), 387–396. 10.1002/ptr.6232 30575146
Aceto G. Colussi C. Leone L. Fusco S. Rinaudo M. Scala F. (2020). Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels. Proc. Natl. Acad. Sci. U. S. A. 117 (14 ), 8143–8153. 10.1073/pnas.1917423117 32209671
Aguilar-Valles A. De Gregorio D. Matta-Camacho E. Eslamizade M. J. Khlaifia A. Skaleka A. (2021). Antidepressant actions of ketamine engage cell-specific translation via eIF4E. Nature 590 (7845 ), 315–319. 10.1038/s41586-020-03047-0 33328636
Aleksandrova L. R. Wang Y. T. Phillips A. G. (2020). Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression. Mol. Brain. 13 (1 ), 92. 10.1186/s13041-020-00627-z 32546197
An J. H. Jang E. H. Kim A. Y. Fava M. Mischoulon D. Papakostas G. I. (2019). Ratio of plasma BDNF to leptin levels are associated with treatment response in major depressive disorder but not in panic disorder: a 12-week follow-up study. J. Affect. Disord. 259 , 349–354. 10.1016/j.jad.2019.08.021 31465895
Bai Z. Gao T. Zhang R. Lu Y. Tian J. Wang T. (2023). Inhibition of IL-6 methylation by Saikosaponin C regulates neuroinflammation to alleviate depression. Int. Immunopharmacol. 118 , 110043. 10.1016/j.intimp.2023.110043 36965369
Bayes J. Schloss J. Sibbritt D. (2020). Effects of polyphenols in a mediterranean diet on symptoms of depression: a systematic literature review. Adv. Nutr. 11 (3 ), 602–615. 10.1093/advances/nmz117 31687743
Beurel E. Toups M. Nemeroff C. B. (2020). The bidirectional relationship of depression and inflammation: double trouble. Neuron 107 (2 ), 234–256. 10.1016/j.neuron.2020.06.002 32553197
Bian Z. Qin Y. Li L. Su L. Fei C. Li Y. (2022). Schisandra chinensis (Turcz.) Baill. Protects against DSS-induced colitis in mice: involvement of TLR4/NF-κB/NLRP3 inflammasome pathway and gut microbiota. J. Ethnopharmacol. 298 , 115570. 10.1016/j.jep.2022.115570 35868549
Boozari M. Hosseinzadeh H. (2022). Crocin molecular signaling pathways at a glance: a comprehensive review. Phytother. Res. 36 (10 ), 3859–3884. 10.1002/ptr.7583 35989419
Bourtchuladze R. Frenguelli B. Blendy J. Cioffi D. Schutz G. Silva A. J. (1994). Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell. 79 (1 ), 59–68. 10.1016/0092-8674(94)90400-6 7923378
Cao K. Zhong J. Wang S. Shi Y. Bai S. Zhao J. (2024). SiNiSan exerts antidepressant effects by modulating serotonergic/GABAergic neuron activity in the dorsal raphe nucleus region through NMDA receptor in the adolescent depression mouse model. J. Ethnopharmacol. 328 , 118040. 10.1016/j.jep.2024.118040 38479542
Cao Y. Xiong J. Guan X. Yin S. Chen J. Yuan S. (2023). Paeoniflorin suppresses kidney inflammation by regulating macrophage polarization via KLF4-mediated mitophagy. Phytomedicine 116 , 154901. 10.1016/j.phymed.2023.154901 37247587
Castillo P. E. (2012). Presynaptic LTP and LTD of excitatory and inhibitory synapses. Cold. Spring. Harb. Perspect. Biol. 4 (2 ), a005728. 10.1101/cshperspect.a005728 22147943
Chai Y. Cai Y. Fu Y. Wang Y. Zhang Y. Zhang X. (2022). Salidroside ameliorates depression by suppressing NLRP3-mediated pyroptosis via P2X7/NF-κB/NLRP3 signaling pathway. Front. Pharmacol. 13 , 812362. 10.3389/fphar.2022.812362 35496273
Chandrashekar N. Pandi A. (2022). Baicalein: a review on its anti-cancer effects and mechanisms in lung carcinoma. J. Food. Biochem. 46 (9 ), e14230. 10.1111/jfbc.14230 35543192
Chen J. Lei C. Li X. Wu Q. Liu C. Ma Q. (2022b). Research progress on classical traditional Chinese medicine formula xiaoyaosan in the treatment of depression. Front. Pharmacol. 13 , 925514. 10.3389/fphar.2022.925514 35991880
Chen J. Li G. Sun C. Peng F. Yu L. Chen Y. (2022a). Chemistry, pharmacokinetics, pharmacological activities, and toxicity of Quercitrin. Phytother. Res. 36 , 1545–1575. 10.1002/ptr.7397 35253930
Chen Q. Shao X. Ling P. Liu F. Han G. Wang F. (2017). Recent advances in polysaccharides for osteoarthritis therapy. Eur. J. Med. Chem. 139 , 926–935. 10.1016/j.ejmech.2017.08.048 28881287
Chen Y. Chen X. Zhang J. Wang D. Lu N. (2024). Network pharmacology and experimental evidence: ERK/CREB/BDNF signaling pathway is involved in the antidepressive roles of Kaiyu Zhishen decoction. J. Ethnopharmacol. 329 , 118098. 10.1016/j.jep.2024.118098 38582152
Choi G. E. Lee H. J. Chae C. W. Cho J. H. Jung Y. H. Kim J. S. (2021). BNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects. Nat. Commun. 12 (1 ), 487. 10.1038/s41467-020-20679-y 33473105
Clarke M. Razmjou S. Prowse N. Dwyer Z. Litteljohn D. Pentz R. (2017). Ketamine modulates hippocampal neurogenesis and pro-inflammatory cytokines but not stressor induced neurochemical changes. Neuropharmacology 112 (Pt A ), 210–220. 10.1016/j.neuropharm.2016.04.021 27106168
Crupi R. Paterniti I. Ahmad A. Campolo M. Esposito E. Cuzzocrea S. (2013). Effects of palmitoylethanolamide and luteolin in an animal model of anxiety/depression. CNS. Neurol. Disord. Drug. Targets. 12 (7 ), 989–1001. 10.2174/18715273113129990084 23844686
Dagyte G. Trentani A. Postema F. Luiten P. G. Den Boer J. A. Gabriel C. (2010). The novel antidepressant agomelatine normalizes hippocampal neuronal activity and promotes neurogenesis in chronically stressed rats. CNS. Neurosci. Ther. 16 (4 ), 195–207. 10.1111/j.1755-5949.2009.00125.x 20236141
Deng D. Cui Y. Gan S. Xie Z. Cui S. Cao K. (2022). Sinisan alleviates depression-like behaviors by regulating mitochondrial function and synaptic plasticity in maternal separation rats. Phytomedicine 106 , 154395. 10.1016/j.phymed.2022.154395 36103769
De Paola V. Holtmaat A. Knott G. Song S. Wilbrecht L. Caroni P. (2006). Cell type-specific structural plasticity of axonal branches and boutons in the adult neocortex. Neuron 49 (6 ), 861–875. 10.1016/j.neuron.2006.02.017 16543134
Diering G. H. Huganir R. L. (2018). The AMPA receptor code of synaptic plasticity. Neuron 100 (2 ), 314–329. 10.1016/j.neuron.2018.10.018 30359599
Dong Y. J. Jiang N. H. Zhan L. H. Teng X. Fang X. Lin M. Q. (2021). Soporific effect of modified Suanzaoren Decoction on mice models of insomnia by regulating Orexin-A and HPA axis homeostasis. Biomed. Pharmacother. 143 , 112141. 10.1016/j.biopha.2021.112141 34509822
Du Y. Yan T. Wu B. He B. Jia Y. (2024). Research on the mechanism of antidepressive effect of Suanzaoren Decoction through TLR4/MyD88/NF-κB pathway and Wnt/β-catenin pathway. J. Ethnopharmacol. 319 (Pt 1 ), 117190. 10.1016/j.jep.2023.117190 37739105
Duan Y. Tarafdar A. Chaurasia D. Singh A. Bhargava P. C. Yang J. (2022). Blueberry fruit valorization and valuable constituents: a review. Int. J. Food. Microbiol. 381 , 109890. 10.1016/j.ijfoodmicro.2022.109890 36095867
Duman R. S. Aghajanian G. K. Sanacora G. Krystal J. H. (2016). Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat. Med. 22 (3 ), 238–249. 10.1038/nm.4050 26937618
Dzyubenko E. Hermann D. M. (2023). Role of glia and extracellular matrix in controlling neuroplasticity in the central nervous system. Semin. Immunopatho. 45 (3 ), 377–387. 10.1007/s00281-023-00989-1
Fan X. X. Sun W. Y. Li Y. Tang Q. Li L. N. Yu X. (2022). Honokiol improves depression-like behaviors in rats by HIF-1α- VEGF signaling pathway activation. Front. Pharmacol. 13 , 968124. 10.3389/fphar.2022.968124 36091747
Fang Z. Liu Z. Tao B. Jiang X. (2023). Engeletin mediates antiarrhythmic effects in mice with isoproterenol-induced cardiac remodeling. Biomed. Pharmacother. 161 , 114439. 10.1016/j.biopha.2023.114439 36848751
Feng X. Bi Y. Wang J. Li T. Yu G. Zhang T. (2022). Discovery of the potential novel pharmacodynamic substances from zhi-zi-hou-Po decoction based on the concept of Co-decoction reaction and analysis strategy. Front. Pharmacol. 12 , 830558. 10.3389/fphar.2021.830558 35095537
Filipović D. Novak B. Xiao J. Yan Y. Bernardi R. E. Turck C. W. (2023). Chronic fluoxetine treatment in socially-isolated rats modulates the prefrontal cortex synaptoproteome. J. Proteomics. 282 , 104925. 10.1016/j.jprot.2023.104925 37164273
Filipović D. Novak B. Xiao J. Yan Y. Yeoh K. Turck C. W. (2022). Chronic fluoxetine treatment of socially isolated rats modulates prefrontal cortex proteome. Neuroscience 501 , 52–71. 10.1016/j.neuroscience.2022.08.011 35963583
Frankiensztajn L. M. Elliott E. Koren O. (2020). The microbiota and the hypothalamus-pituitary-adrenocortical (HPA) axis, implications for anxiety and stress disorders. Curr. Opin. Neurobiol. 62 , 76–82. 10.1016/j.conb.2019.12.003 31972462
Freitas A. E. Egea J. Buendia I. Gómez-Rangel V. Parada E. Navarro E. (2016). Agmatine, by improving neuroplasticity markers and inducing Nrf2, prevents corticosterone-induced depressive-like behavior in mice. Mol. Neurobiol. 53 (5 ), 3030–3045. 10.1007/s12035-015-9182-6 25966970
Gao L. Huang P. Dong Z. Gao T. Huang S. Zhou C. (2018). Modified xiaoyaosan (MXYS) exerts anti-depressive effects by rectifying the brain blood oxygen level-dependent fMRI signals and improving hippocampal neurogenesis in mice. Front. Pharmacol. 9 , 1098. 10.3389/fphar.2018.01098 30323763
Gao Y. Nie K. Wang H. Dong H. Tang Y. (2024). Research progress on antidepressant effects and mechanisms of berberine. Front. Pharmacol. 15 , 1331440. 10.3389/fphar.2024.1331440 38318145
Ge P. Y. Qu S. Y. Ni S. J. Yao Z. Y. Qi Y. Y. Zhao X. (2023). Berberine ameliorates depression-like behavior in CUMS mice by activating TPH1 and inhibiting Ido1-associated with tryptophan metabolism. Phytother. Res. 37 (1 ), 342–357. 10.1002/ptr.7616 36089660
Ghaffari S. Roshanravan N. (2019). Saffron; an updated review on biological properties with special focus on cardiovascular effects. Biomed. Pharmacother. 109 , 21–27. 10.1016/j.biopha.2018.10.031 30391705
Grabska-Kobyłecka I. Szpakowski P. Król A. Książek-Winiarek D. Kobyłecki A. Głąbiński A. (2023). Polyphenols and their impact on the prevention of neurodegenerative diseases and development. Nutrients 15 (15 ), 3454. 10.3390/nu15153454 37571391
Guo C. Huang Q. Wang Y. Yao Y. Li J. Chen J. (2023). Therapeutic application of natural products: NAD+ metabolism as potential target. Phytomedicine 114 , 154768. 10.1016/j.phymed.2023.154768 36948143
Guo L. T. Wang S. Q. Su J. Xu L. X. Ji Z. Y. Zhang R. Y. (2019). Baicalin ameliorates neuroinflammation-induced depressive-like behavior through inhibition of toll-like receptor 4 expression via the PI3K/AKT/FoxO1 pathway. J. Neuroinflammation 16 (1 ), 95. 10.1186/s12974-019-1474-8 31068207
Han H. Dai C. Dong Z. (2015). Single fluoxetine treatment before but not after stress prevents stress-induced hippocampal long-term depression and spatial memory retrieval impairment in rats. Sci. Rep. 5 , 12667. 10.1038/srep12667 26218751
Han R. Han G. Yan Y. Han L. Li L. Zhang H. (2023). Protective effects and mechanisms of the Erzhi formula on glucocorticoid induced primary cortical neuron injury. Front. Pharmacol. 14 , 1038492. 10.3389/fphar.2023.1038492 36923359
Hidese S. Hattori K. Sasayama D. Tsumagari T. Miyakawa T. Matsumura R. (2020). Cerebrospinal fluid neuroplasticity-associated protein levels in patients with psychiatric disorders: a multiplex immunoassay study. Transl. Psychiatry. 10 (1 ), 161. 10.1038/s41398-020-0843-5 32439851
Hu M. Jiang W. Ye C. Hu T. Yu Q. Meng M. (2023). Honokiol attenuates high glucose-induced peripheral neuropathy via inhibiting ferroptosis and activating AMPK/SIRT1/PGC-1α pathway in Schwann cells. Phytother. Res. 37 (12 ), 5787–5802. 10.1002/ptr.7984 37580045
Huang H. Cheng Z. Shi H. Xin W. Wang T. T. Yu L. L. (2011). Isolation and characterization of two flavonoids, engeletin and astilbin, from the leaves of Engelhardia roxburghiana and their potential anti-inflammatory properties. J. Agric. Food. Chem. 59 (9 ), 4562–4569. 10.1021/jf2002969 21476602
Huang J. Shen C. Ye R. Shi Y. Li W. (2021). The effect of early maternal separation combined with adolescent chronic unpredictable mild stress on behavior and synaptic plasticity in adult female rats. Front. Psychiatry. 12 , 539299. 10.3389/fpsyt.2021.539299 33746787
Huang M. Lu J. J. Huang M. Q. Bao J. L. Chen X. P. Wang Y. T. (2012). Terpenoids: natural products for cancer therapy. Expert. Opin. Investig. Drugs. 21 (12 ), 1801–1818. 10.1517/13543784.2012.727395
Hueston C. M. Cryan J. F. Nolan Y. M. (2017). Adolescent social isolation stress unmasks the combined effects of adolescent exercise and adult inflammation on hippocampal neurogenesis and behavior. Neuroscience 365 , 226–236. 10.1016/j.neuroscience.2017.09.020 28939260
Illippangama A. U. Jayasena D. D. Jo C. Mudannayake D. C. (2022). Inulin as a functional ingredient and their applications in meat products. Carbohydr. Polym. 275 , 118706. 10.1016/j.carbpol.2021.118706 34742431
Jaremka L. M. Andridge R. R. Fagundes C. P. Alfano C. M. Povoski S. P. Lipari A. M. (2014). Pain, depression, and fatigue: loneliness as a longitudinal risk factor. Health. Psychol. 33 (9 ), 948–957. 10.1037/a0034012 23957903
Jiao H. Fan Y. Gong A. Li T. Fu X. Yan Z. (2024). Xiaoyaosan ameliorates CUMS-induced depressive-like and anorexia behaviors in mice via necroptosis related cellular senescence in hypothalamus. J. Ethnopharmacol. 318 (Pt A ), 116938. 10.1016/j.jep.2023.116938 37495029
Jo J. H. Park E. J. Lee J. K. Jung M. W. Lee C. J. (2001). Lipopolysaccharide inhibits induction of long-term potentiation and depression in the rat hippocampal CA1 area. Eur. J. Pharmacol. 422 (1-3 ), 69–76. 10.1016/s0014-2999(01)01075-5 11430915
Kaneko N. Wada M. Nakajima S. Takano M. Taniguchi K. Honda S. (2024). Neuroplasticity of the left dorsolateral prefrontal cortex in patients with treatment-resistant depression as indexed with paired associative stimulation: a TMS-EEG study. Cereb. Cortex 34 (2 ), bhad515. 10.1093/cercor/bhad515 38204301
Karin O. Raz M. Tendler A. Bar A. Korem Kohanim Y. Milo T. (2020). A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks. Mol. Syst. Biol. 16 (7 ), e9510. 10.15252/msb.20209510 32672906
Kim C. Y. Ko K. Choi S. H. Jo M. Kim J. Yoon S. (2023). Effects of Saffron extract (Affron®) with 100 mg/kg and 200 mg/kg on hypothalamic-pituitary-adrenal Axis and stress resilience in chronic mild stress-induced depression in wistar rats. Nutrients 15 (23 ), 4855. 10.3390/nu15234855 38068714
Kim J. W. Monteggia L. M. (2020). Increasing doses of ketamine curtail antidepressant responses and suppress associated synaptic signaling pathways. Behav. Brain. Res. 380 , 112378. 10.1016/j.bbr.2019.112378 31760154
Knott G. W. Holtmaat A. Wilbrecht L. Welker E. Svoboda K. (2006). Spine growth precedes synapse formation in the adult neocortex in vivo . Nat. Neurosci. 9 (9 ), 1117–1124. 10.1038/nn1747 16892056
Kokkosis A. G. Madeira M. M. Hage Z. Valais K. Koliatsis D. Resutov E. (2024). Chronic psychosocial stress triggers microglial-/macrophage-induced inflammatory responses leading to neuronal dysfunction and depressive-related behavior. Glia 72 (1 ), 111–132. 10.1002/glia.24464 37675659
Kong C. H. Park K. Kim D. Y. Kim J. Y. Kang W. C. Jeon M. (2023). Effects of oleanolic acid and ursolic acid on depression-like behaviors induced by maternal separation in mice. Eur. J. Pharmacol. 956 , 175954. 10.1016/j.ejphar.2023.175954 37541369
Kopelman J. Keller T. A. Panny B. Griffo A. Degutis M. Spotts C. (2023). Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression. Transl. Psychiatry. 13 (1 ), 159. 10.1038/s41398-023-02451-0 37160885
Kuhn M. Mainberger F. Feige B. Maier J. G. Wirminghaus M. Limbach L. (2016). State-dependent partial occlusion of cortical LTP-like plasticity in major depression. Neuropsychopharmacology 41 (6 ), 1521–1529. 10.1038/npp.2015.310 26442602
LaMoia T. E. Shulman G. I. (2021). Cellular and molecular mechanisms of metformin action. Endocr. Rev. 42 (1 ), 77–96. 10.1210/endrev/bnaa023 32897388
Li B. Du P. Du Y. Zhao D. Cai Y. Yang Q. (2021b). Luteolin alleviates inflammation and modulates gut microbiota in ulcerative colitis rats. Life. Sci. 269 , 119008. 10.1016/j.lfs.2020.119008 33434535
Li J. Tian S. Wang H. Wang Y. Du C. Fang J. (2021a). Protection of hUC-MSCs against neuronal complement C3a receptor-mediated NLRP3 activation in CUMS-induced mice. Neurosci. Lett. 741 , 135485. 10.1016/j.neulet.2020.135485 33161108
Li Y. Li J. Yang L. Ren F. Dong K. Zhao Z. (2023a). Ginsenoside Rb1 protects hippocampal neurons in depressed rats based on mitophagy-regulated astrocytic pyroptosis. Phytomedicine 121 , 155083. 10.1016/j.phymed.2023.155083 37722244
Li Y. Zhao L. Zhao Q. Zhou Y. Zhou L. Song P. (2023b). Ursolic acid nanoparticles for glioblastoma therapy. Nanomedicine 50 , 102684. 10.1016/j.nano.2023.102684 37100267
Li Z. R. Liu D. G. Xie S. Wang Y. H. Han Y. S. Li C. Y. (2022). Sleep deprivation leads to further impairment of hippocampal synaptic plasticity by suppressing melatonin secretion in the pineal gland of chronically unpredictable stress rats. Eur. J. Pharmacol. 930 , 175149. 10.1016/j.ejphar.2022.175149 35878808
Liu F. Tian Q. Tang H. L. Cheng X. Zou W. Zhang P. (2024). Hydrogen sulfide attenuates depression-like behaviours in Parkinson's disease model rats by improving synaptic plasticity in a hippocampal Warburg effect-dependent manner. Pharmacol. Biochem. Behav. 234 , 173677. 10.1016/j.pbb.2023.173677 37967673
Liu H. T. Lin Y. N. Tsai M. C. Wu Y. C. Lee M. C. (2022). Baicalein exerts therapeutic effects against endotoxin-induced depression-like behavior in mice by decreasing inflammatory cytokines and increasing brain-derived neurotrophic factor levels. Antioxidants (Basel) 11 (5 ), 947. 10.3390/antiox11050947 35624812
Liu K. Li H. Zeng N. Li B. Yao G. Wu X. (2023). Exploration of the core pathways and potential targets of luteolin treatment on late-onset depression based on cerebrospinal fluid proteomics. Int. J. Mol. Sci. 24 (4 ), 3485. 10.3390/ijms24043485 36834894
Liu N. Wang Y. An A. Y. Banker C. Qian Y. H. O'Donnell J. M. (2020). Single housing-induced effects on cognitive impairment and depression-like behavior in male and female mice involve neuroplasticity-related signaling. Eur. J. Neurosci. 52 (1 ), 2694–2704. 10.1111/ejn.14565 31471985
Liu S. C. Hu W. Y. Zhang W. Y. Yang L. Li Y. Xiao Z. C. (2019). Paeoniflorin attenuates impairment of spatial learning and hippocampal long-term potentiation in mice subjected to chronic unpredictable mild stress. Psychopharmacol. Berl. 236 (9 ), 2823–2834. 10.1007/s00213-019-05257-5
Lu C. Gao R. Zhang Y. Jiang N. Chen Y. Sun J. (2021). S-equol, a metabolite of dietary soy isoflavones, alleviates lipopolysaccharide-induced depressive-like behavior in mice by inhibiting neuroinflammation and enhancing synaptic plasticity. Food. Funct. 12 (13 ), 5770–5778. 10.1039/d1fo00547b 34038497
Lu C. Wei Z. Wang Y. Li S. Tong L. Liu X. (2022). Soy isoflavones alleviate lipopolysaccharide-induced depressive-like behavior by suppressing neuroinflammation, mediating tryptophan metabolism and promoting synaptic plasticity. Food. Funct. 13 (18 ), 9513–9522. 10.1039/d2fo01437h 35993820
Lu Y. Sun G. Yang F. Guan Z. Zhang Z. Zhao J. (2019). Baicalin regulates depression behavior in mice exposed to chronic mild stress via the Rac/LIMK/cofilin pathway. Biomed. Pharmacother. 116 , 109054. 10.1016/j.biopha.2019.109054 31176122
Luo Q. Wei Y. Lv X. Chen W. Yang D. Tuo Q. (2024). The effect and mechanism of oleanolic acid in the treatment of metabolic syndrome and related cardiovascular diseases. Molecules 29 (4 ), 758. 10.3390/molecules29040758 38398510
Lv H. Gao Z. Wang Y. Chen S. Liu P. Xie Y. (2023). Metformin improves comorbid depressive symptoms in mice with allergic rhinitis by reducing olfactory bulb damage. Neurochem. Res. 48 (12 ), 3639–3651. 10.1007/s11064-023-04012-9 37574530
Ma X. Xie Y. Gong Y. Hu C. Qiu K. Yang Y. (2023). Silibinin prevents tgfβ-induced EMT of RPE in proliferative vitreoretinopathy by inhibiting Stat3 and Smad3 phosphorylation. Invest. Ophthalmol. Vis. Sci. 64 (13 ), 47. 10.1167/iovs.64.13.47
Ma Y. Li S. X. Zhou R. Y. Deng L. J. le He W. Guo L. L. (2024). Geniposide improves depression-like behavior in prenatal stress male offspring through restoring HPA axis- and glucocorticoid receptor-associated dysfunction. Life. Sci. 340 , 122434. 10.1016/j.lfs.2024.122434 38232800
Maddukuri R. K. Hema C. Sri Tejaswi K. Venkata Mounika M. Vegesana B. P. (2021). Antidepressant efficacy of Agomelatine: meta-analysis of placebo controlled and active comparator studies. Asian. J. Psychiatr. 65 , 102866. 10.1016/j.ajp.2021.102866 34592623
Marsden W. N. (2013). Synaptic plasticity in depression: molecular, cellular and functional correlates. Prog. Neuropsychopharmacol. Biol. Psychiatry 43 , 168–184. 10.1016/j.pnpbp.2012.12.012 23268191
Martin V. Allaïli N. Euvrard M. Marday T. Riffaud A. Franc B. (2017). Effect of agomelatine on memory deficits and hippocampal gene expression induced by chronic social defeat stress in mice. Sci. Rep. 8 , 45907. 10.1038/srep45907 28374847
Medendorp W. E. Petersen E. D. Pal A. Wagner L. M. Myers A. R. Hochgeschwender U. (2018). Altered behavior in mice socially isolated during adolescence corresponds with immature dendritic spine morphology and impaired plasticity in the prefrontal cortex. Front. Behav. Neurosci. 12 , 87. 10.3389/fnbeh.2018.00087 29867388
Mendonça I. P. Paiva I. H. R. Duarte-Silva E. P. Melo M. G. Silva R. S. D. Oliveira W. H. (2022). Metformin and fluoxetine improve depressive-like behavior in a murine model of Parkinsońs disease through the modulation of neuroinflammation, neurogenesis and neuroplasticity. Int. Immunopharmacol. 102 , 108415. 10.1016/j.intimp.2021.108415 34890997
Monroe S. M. Harkness K. L. (2022). Major depression and its recurrences: life course matters. Annu. Rev. Clin. Psychol. 18 , 329–357. 10.1146/annurev-clinpsy-072220-021440 35216520
Mousten I. V. Sørensen N. V. Christensen R. H. B. Benros M. E. (2022). Cerebrospinal fluid biomarkers in patients with unipolar depression compared with healthy control individuals: a systematic review and meta-analysis. JAMA. Psychiatry. 79 (6 ), 571–581. 10.1001/jamapsychiatry.2022.0645 35442429
Muñoz-Arenas G. Pulido G. Treviño S. Vázquez-Roque R. Flores G. Moran C. (2020). Effects of metformin on recognition memory and hippocampal neuroplasticity in rats with metabolic syndrome. Synapse 74 (9 ), e22153. 10.1002/syn.22153 32190918
Ni X. C. Wang H. F. Cai Y. Y. Yang D. Alolga R. N. Liu B. (2022). Ginsenoside Rb1 inhibits astrocyte activation and promotes transfer of astrocytic mitochondria to neurons against ischemic stroke. Redox. Biol. 54 , 102363. 10.1016/j.redox.2022.102363 35696763
Noda Y. Zomorrodi R. Vila-Rodriguez F. Downar J. Farzan F. Cash R. F. H. (2018). Impaired neuroplasticity in the prefrontal cortex in depression indexed through paired associative stimulation. Depress. Anxiety. 35 (5 ), 448–456. 10.1002/da.22738 29637656
Pace R. Martinelli E. M. (2022). The phytoequivalence of herbal extracts: a critical evaluation. Fitoterapia 162 , 105262. 10.1016/j.fitote.2022.105262 35940385
Pan Y. Ke Z. Ye H. Sun L. Ding X. Shen Y. (2019). Saikosaponin C exerts anti-HBV effects by attenuating HNF1α and HNF4α expression to suppress HBV pgRNA synthesis. Inflamm. Res. 68 (12 ), 1025–1034. 10.1007/s00011-019-01284-2 31531682
Peng M. Xia T. Zhong Y. Zhao M. Yue Y. Liang L. (2022). Integrative pharmacology reveals the mechanisms of Erzhi Pill, a traditional Chinese formulation, against diabetic cardiomyopathy. J. Ethnopharmacol. 296 , 115474. 10.1016/j.jep.2022.115474 35716918
Perić I. Costina V. Djordjević S. Gass P. Findeisen P. Inta D. (2021). Tianeptine modulates synaptic vesicle dynamics and favors synaptic mitochondria processes in socially isolated rats. Sci. Rep. 11 (1 ), 17747. 10.1038/s41598-021-97186-7 34493757
Player M. J. Taylor J. L. Weickert C. S. Alonzo A. Sachdev P. Martin D. (2013). Neuroplasticity in depressed individuals compared with healthy controls. Neuropsychopharmacology 38 (11 ), 2101–2108. 10.1038/npp.2013.126 23676792
Price R. B. Duman R. (2020). Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Mol. Psychiatry. 25 (3 ), 530–543. 10.1038/s41380-019-0615-x 31801966
Qian X. Zhong Z. D. Zhang Y. Qiu L. Q. Tan H. J. (2024). Fluoxetine mitigates depressive-like behaviors in mice via anti-inflammation and enhancing neuroplasticity. Brain. Res. 1825 , 148723. 10.1016/j.brainres.2023.148723 38101693
Qin Z. Shi D. D. Li W. Cheng D. Zhang Y. D. Zhang S. (2023). Berberine ameliorates depression-like behaviors in mice via inhibiting NLRP3 inflammasome-mediated neuroinflammation and preventing neuroplasticity disruption. J. Neuroinflammation 20 (1 ), 54. 10.1186/s12974-023-02744-7 36859349
Qu S. Y. Li X. Y. Heng X. Qi Y. Y. Ge P. Y. Ni S. J. (2021). Analysis of antidepressant activity of huang-lianie Jie-du decoction through network pharmacology and metabolomics. Front. Pharmacol. 12 , 619288. 10.3389/fphar.2021.619288 33746756
Rauf A. Olatunde A. Imran M. Alhumaydhi F. A. Aljohani A. S. M. Khan S. A. (2021). Honokiol: a review of its pharmacological potential and therapeutic insights. Phytomedicine 90 , 153647. 10.1016/j.phymed.2021.153647 34362632
Rauf A. Wilairatana P. Joshi P. B. Ahmad Z. Olatunde A. Hafeez N. (2024). Revisiting luteolin: an updated review on its anticancer potential. Heliyon 10 (5 ), e26701. 10.1016/j.heliyon.2024.e26701 38455556
Ray A. Gulati K. Rai N. (2017). Stress, anxiety, and immunomodulation: a pharmacological analysis. Vitam. Horm. 103 , 1–25. 10.1016/bs.vh.2016.09.007 28061967
Rehm J. Shield K. D. (2019). Global burden of disease and the impact of mental and addictive disorders. Curr. Psychiatry. Rep. 21 (2 ), 10. 10.1007/s11920-019-0997-0 30729322
Ru Q. Lu Y. Saifullah A. B. Blanco F. A. Yao C. Cata J. P. (2022). TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain. J. Clin. Invest. 132 (24 ), e158545. 10.1172/JCI158545 36519542
Sato S. Bunney B. Mendoza-Viveros L. Bunney W. Borrelli E. Sassone-Corsi P. (2022). Rapid-acting antidepressants and the circadian clock. Neuropsychopharmacology 47 (4 ), 805–816. 10.1038/s41386-021-01241-w 34837078
Shen B. Feng H. Cheng J. Li Z. Jin M. Zhao L. (2020a). Geniposide alleviates non-alcohol fatty liver disease via regulating Nrf2/AMPK/mTOR signalling pathways. J. Cell. Mol. Med. 24 (9 ), 5097–5108. 10.1111/jcmm.15139 32293113
Shen C. Cao K. Cui S. Cui Y. Mo H. Wen W. (2020b). SiNiSan ameliorates depression-like behavior in rats by enhancing synaptic plasticity via the CaSR-PKC-ERK signaling pathway. Biomed. Pharmacother. 124 , 109787. 10.1016/j.biopha.2019.109787 31958763
Shi H. J. Wu D. L. Chen R. Li N. Zhu L. J. (2022). Requirement of hippocampal DG nNOS-CAPON dissociation for the anxiolytic and antidepressant effects of fluoxetine. Theranostics 12 (8 ), 3656–3675. 10.7150/thno.70370 35664081
Shi X. Q. Yue S. J. Tang Y. P. Chen Y. Y. Zhou G. S. Zhang J. (2019). A network pharmacology approach to investigate the blood enriching mechanism of Danggui buxue Decoction. J. Ethnopharmacol. 235 , 227–242. 10.1016/j.jep.2019.01.027 30703496
Song D. Hao J. Fan D. (2020). Biological properties and clinical applications of berberine. Front. Med. 14 (5 ), 564–582. 10.1007/s11684-019-0724-6 32335802
Spohr L. de Aguiar M. S. S. Bona N. P. Luduvico K. P. Alves A. G. Domingues W. B. (2023). Blueberry extract modulates brain enzymes activities and reduces neuroinflammation: promising effect on lipopolysaccharide-induced depressive-like behavior. Neurochem. Res. 48 (3 ), 846–861. 10.1007/s11064-022-03813-8 36357747
Sun X. Zhang T. Zhao Y. Cai E. Zhu H. Liu S. (2020). Panaxynol attenuates CUMS-induced anxiety and depressive-like behaviors via regulating neurotransmitters, synapses and the HPA axis in mice. Food. Funct. 11 (2 ), 1235–1244. 10.1039/c9fo03104a 32048672
Sun Y. Zhang H. Wu Z. Yu X. Yin Y. Qian S. (2021). Quercitrin rapidly alleviated depression-like behaviors in lipopolysaccharide-treated mice: the involvement of PI3K/AKT/NF-κB signaling suppression and CREB/BDNF signaling restoration in the Hippocampus. Acs. Chem. Neurosci. 12 (18 ), 3387–3396. 10.1021/acschemneuro.1c00371 34469122
Tanaka J. Horiike Y. Matsuzaki M. Miyazaki T. Ellis-Davies G. C. Kasai H. (2008). Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319 (5870 ), 1683–1687. 10.1126/science.1152864 18309046
Tanner-Smith E. E. Grant S. (2018). Meta-analysis of complex interventions. Annu. Rev. Public. Health. 39 , 135–151. 10.1146/annurev-publhealth-040617-014112 29328876
Tao W. Ruan J. Wu R. Zhao M. Zhao T. Qi M. (2023a). A natural carotenoid crocin exerts antidepressant action by promoting adult hippocampal neurogenesis through Wnt/β-catenin signaling. J. Adv. Res. 43 , 219–231. 10.1016/j.jare.2022.02.015 36585110
Tao W. Yao G. Yue Q. Xu C. Hu Y. Cheng X. (2023b). 14-3-3ζ Plays a key role in the modulation of neuroplasticity underlying the antidepressant-like effects of Zhi-Zi-Chi-Tang. Phytomedicine 116 , 154888. 10.1016/j.phymed.2023.154888 37257329
Tartt A. N. Mariani M. B. Hen R. Mann J. J. Boldrini M. (2022). Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications. Mol. Psychiatry. 27 (6 ), 2689–2699. 10.1038/s41380-022-01520-y 35354926
Tejeda G. S. Díaz-Guerra M. (2017). Integral characterization of defective BDNF/TrkB signalling in neurological and psychiatric disorders leads the way to new therapies. Int. J. Mol. Sci. 18 (2 ), 268. 10.3390/ijms18020268 28134845
Vega-Rivera N. M. González-Trujano M. E. Luna-Angula A. Sánchez-Chapul L. Estrada-Camarena E. (2023). Antidepressant-like effects of the Punica granatum and citalopram combination are associated with structural changes in dendritic spines of granule cells in the dentate gyrus of rats. Front. Pharmacol. 14 , 1211663. 10.3389/fphar.2023.1211663 37900157
Vints W. A. J. Levin O. Fujiyama H. Verbunt J. Masiulis N. (2022). Exerkines and long-term synaptic potentiation: mechanisms of exercise-induced neuroplasticity. Front. Neuroendocrinol. 66 , 100993. 10.1016/j.yfrne.2022.100993 35283168
Wang G. An T. Lei C. Zhu X. Yang L. Zhang L. (2022b). Antidepressant-like effect of ginsenoside Rb1 on potentiating synaptic plasticity via the miR-134-mediated BDNF signaling pathway in a mouse model of chronic stress-induced depression. J. Ginseng. Res. 46 (3 ), 376–386. 10.1016/j.jgr.2021.03.005 35600767
Wang L. Wang Z. Lan Y. Tuo Y. Ma S. Liu X. (2023b). Inulin attenuates blood-brain barrier permeability and alleviates behavioral disorders by modulating the TLR4/MyD88/NF-κB pathway in mice with chronic stress. J. Agric. Food. Chem. 71 (36 ), 13325–13337. 10.1021/acs.jafc.3c03568 37642581
Wang Q. Yang B. Wang N. Gu J. (2022a). Tumor immunomodulatory effects of polyphenols. Front. Immunol. 13 , 1041138. 10.3389/fimmu.2022.1041138 36505462
Wang W. Wang L. Wang L. Li Y. Lan T. Wang C. (2023a). Ginsenoside-Rg1 synergized with voluntary running exercise protects against glial activation and dysregulation of neuronal plasticity in depression. Food. Funct. 14 (15 ), 7222–7239. 10.1039/d3fo00496a 37464840
Wang W. K. Zhou Y. Fan L. Sun Y. Ge F. Xue M. (2021). The antidepressant-like effects of Danggui Buxue Decoction in GK rats by activating CREB/BDNF/TrkB signaling pathway. Phytomedicine 89 , 153600. 10.1016/j.phymed.2021.153600 34130073
Wang Y. S. Shen C. Y. Jiang J. G. (2019). Antidepressant active ingredients from herbs and nutraceuticals used in TCM: pharmacological mechanisms and prospects for drug discovery. Pharmacol. Res. 150 , 104520. 10.1016/j.phrs.2019.104520 31706012
Wei Y. Chang L. Hashimoto K. (2022). Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor. Mol. Psychiatry. 27 (1 ), 559–573. 10.1038/s41380-021-01121-1 33963284
Wu D. Wang H. Teng T. Duan S. Ji A. Li Y. (2018). Hydrogen sulfide and autophagy: a double edged sword. Pharmacol. Res. 131 , 120–127. 10.1016/j.phrs.2018.03.002 29514056
Wu R. Xiao D. Shan X. Dong Y. Tao W. W. (2020). Rapid and prolonged antidepressant-like effect of crocin is associated with GHSR-mediated hippocampal plasticity-related proteins in mice exposed to prenatal stress. Acs. Chem. Neurosci. 11 (8 ), 1159–1170. 10.1021/acschemneuro.0c00022 32203651
Wu Y. Wei Z. Li Y. Wei C. Li Y. Cheng P. (2019). Perturbation of Ephrin receptor signaling and glutamatergic transmission in the hypothalamus in depression using proteomics integrated with metabolomics. Front. Neurosci. 13 , 1359. 10.3389/fnins.2019.01359 31920518
Xia B. Huang X. Sun G. Tao W. (2021). Iridoids from Gardeniae fructus ameliorates depression by enhancing synaptic plasticity via AMPA receptor-mTOR signaling. J. Ethnopharmacol. 268 , 113665. 10.1016/j.jep.2020.113665 33307051
Xia C. Y. Guo Y. X. Lian W. W. Yan Y. Ma B. Z. Cheng Y. C. (2023). The NLRP3 inflammasome in depression: potential mechanisms and therapies. Pharmacol. Res. 187 , 106625. 10.1016/j.phrs.2022.106625 36563870
Xie P. Chen L. Wang J. Wang X. Yang S. Zhu G. (2024). Polysaccharides from Polygonatum cyrtonema Hua prevent post-traumatic stress disorder behaviors in mice: mechanisms from the perspective of synaptic injury, oxidative stress, and neuroinflammation. J. Ethnopharmacol. 319 (Pt 1 ), 117165. 10.1016/j.jep.2023.117165 37696440
Xing Y. Bai Y. (2020). A review of exercise-induced neuroplasticity in ischemic stroke: pathology and mechanisms. Mol. Neurobiol. 57 (10 ), 4218–4231. 10.1007/s12035-020-02021-1 32691303
Xu Y. Zhang J. Yu L. Zhang W. Zhang Y. Shi Y. (2023). Engeletin alleviates depression-like phenotype by increasing synaptic plasticity via the BDNF-TrkB-mTORC1 signalling pathway. J. Cell. Mol. Med. 27 (23 ), 3928–3938. 10.1111/jcmm.17975 37799103
Xue H. Li P. Luo Y. Wu C. Liu Y. Qin X. (2019). Salidroside stimulates the Sirt1/PGC-1α axis and ameliorates diabetic nephropathy in mice. Phytomedicine 54 , 240–247. 10.1016/j.phymed.2018.10.031 30668374
Yan L. Ai Y. Xing Y. Wang B. Gao A. Xu Q. (2023a). Citalopram in the treatment of elderly chronic heart failure combined with depression: a systematic review and meta-analysis. Front. Cardiovasc. Med. 10 , 1107672. 10.3389/fcvm.2023.1107672 36818339
Yan W. J. Tan Y. C. Xu J. C. Tang X. P. Zhang C. Zhang P. B. (2015). Protective effects of silibinin and its possible mechanism of action in mice exposed to chronic unpredictable mild stress. Biomol. Ther. Seoul. 23 (3 ), 245–250. 10.4062/biomolther.2014.138 25995823
Yan Y. Li J. Zhang Y. Wang H. Qin X. Zhai K. (2023b). Screening the effective components of Suanzaoren decoction on the treatment of chronic restraint stress induced anxiety-like mice by integrated chinmedomics and network pharmacology. Phytomedicine 115 , 154853. 10.1016/j.phymed.2023.154853 37156059
Yan Y. Xu X. Chen R. Wu S. Yang Z. Wang H. (2021). Down-regulation of MST1 in hippocampus protects against stress-induced depression-like behaviours and synaptic plasticity impairments. Brain. Behav. Immun. 94 , 196–209. 10.1016/j.bbi.2021.02.007 33607238
Yang L. Huang Y. Chen F. Wang Y. Su K. Zhao M. (2023a). Berberine attenuates depression-like behavior by modulating the hippocampal NLRP3 ubiquitination signaling pathway through Trim65. Int. Immunopharmacol. 123 , 110808. 10.1016/j.intimp.2023.110808 37595491
Yang S. J. Wang J. J. Cheng P. Chen L. X. Hu J. M. Zhu G. Q. (2023b). Ginsenoside Rg1 in neurological diseases: from bench to bedside. Acta. Pharmacol. Sin. 44 (5 ), 913–930. 10.1038/s41401-022-01022-1 36380226
Yao X. Qin X. Wang H. Zheng J. Peng Z. Wang J. (2023). Lack of bombesin receptor-activated protein homologous protein impairs hippocampal synaptic plasticity and promotes chronic unpredictable mild stress induced behavioral changes in mice. Stress 26 (1 ), 1–14. 10.1080/10253890.2022.2155513 36520154
Ye Z. Wang J. Fang F. Wang Y. Liu Z. Shen C. (2024). Zhi-Zi-Hou-Po decoction alleviates depressive-like behavior and promotes hippocampal neurogenesis in chronic unpredictable mild stress induced mice via activating the BDNF/TrkB/CREB pathway. J. Ethnopharmacol. 319 (Pt 3 ), 117355. 10.1016/j.jep.2023.117355 37890805
Yi Y. Xu W. Wang H. X. Huang F. Wang L. M. (2020). Natural polysaccharides experience physiochemical and functional changes during preparation: a review. Carbohydr. Polym. 234 , 115896. 10.1016/j.carbpol.2020.115896 32070516
Yin R. Zhang K. Li Y. Tang Z. Zheng R. Ma Y. (2023). Lipopolysaccharide-induced depression-like model in mice: meta-analysis and systematic evaluation. Front. Immunol. 14 , 1181973. 10.3389/fimmu.2023.1181973 37359525
Yu C. Li A. Li X. Chen Z. Wang P. Dong Z. (2020). Impaired LTD-like motor cortical plasticity in female patients with major depression disorder. Neuropharmacology 179 , 108268. 10.1016/j.neuropharm.2020.108268 32791084
Yu D. Cheng Z. Ali A. I. Wang J. Le K. Chibaatar E. (2019). Chronic unexpected mild stress destroys synaptic plasticity of neurons through a glutamate transporter, GLT-1, of astrocytes in the ischemic stroke rat. Neural. Plast. 2019 , 1615925. 10.1155/2019/1615925 31019528
Yu H. Yang R. Wu J. Wang S. Qin X. Wu T. (2022). Association of metformin and depression in patients with type 2 diabetes. J. Affect. Disord. 318 , 380–385. 10.1016/j.jad.2022.09.015 36108876
Yu S. Zhao Y. Luo Q. Gu B. Wang X. Cheng J. (2024). Early life stress enhances the susceptibility to depression and interferes with neuroplasticity in the hippocampus of adolescent mice via regulating miR-34c-5p/SYT1 axis. J. Psychiatr. Res. 170 , 262–276. 10.1016/j.jpsychires.2023.12.030 38181539
Zavvari F. Nahavandi A. Goudarzi M. (2020). Fluoxetine attenuates stress-induced depressive-like behavior through modulation of hippocampal GAP43 and neurogenesis in male rats. Jj. Chem. Neuroanat. 103 , 101711. 10.1016/j.jchemneu.2019.101711
Zhang H. Sun Y. Huang Z. Wu Z. Ying Y. Liu R. (2024a). Jiawei-Xiaoyao pill elicits a rapid antidepressant effect, dependent on activating CaMKII/mTOR/BDNF signaling pathway in the hippocampus. J. Ethnopharmacol. 318 (Pt B ), 117016. 10.1016/j.jep.2023.117016 37567427
Zhang H. Zhao Y. Wang Z. (2015). Chronic corticosterone exposure reduces hippocampal astrocyte structural plasticity and induces hippocampal atrophy in mice. Neurosci. Lett. 592 , 76–81. 10.1016/j.neulet.2015.03.006 25748318
Zhang L. Luo J. Zhang M. Yao W. Ma X. Yu S. Y. (2014). Effects of curcumin on chronic, unpredictable, mild, stress-induced depressive-like behaviour and structural plasticity in the lateral amygdala of rats. Int. J. Neuropsychopharmacol. 17 (5 ), 793–806. 10.1017/S1461145713001661 24405689
Zhang L. Wei W. (2020). Anti-inflammatory and immunoregulatory effects of paeoniflorin and total glucosides of paeony. Pharmacol. Ther. 207 , 107452. 10.1016/j.pharmthera.2019.107452 31836457
Zhang M. Lyu D. Wang F. Shi S. Wang M. Yang W. (2022b). Ketamine may exert rapid antidepressant effects through modulation of neuroplasticity, autophagy, and ferroptosis in the habenular nucleus. Neuroscience 506 , 29–37. 10.1016/j.neuroscience.2022.10.015 36280022
Zhang M. M. Huo G. M. Cheng J. Zhang Q. P. Li N. Z. Guo M. X. (2022a). Gypenoside XVII, an active ingredient from gynostemma pentaphyllum, inhibits C3aR-associated synaptic pruning in stressed mice. Nutrients 14 (12 ), 2418. 10.3390/nu14122418 35745148
Zhang R. Zeng M. Zhang X. Zheng Y. Lv N. Wang L. (2023). Therapeutic candidates for alzheimer's disease: saponins. Int. J. Mol. Sci. 24 (13 ), 10505. 10.3390/ijms241310505 37445682
Zhang X. Guo J. Zhang C. Wang W. Du S. Tian X. (2024b). Suanzaoren decoction exerts its antidepressant effect via the CaMK signaling pathway. Transl. Neurosci. 15 (1 ), 20220341. 10.1515/tnsci-2022-0341 38736723
Zhao X. Kong D. Zhou Q. Wei G. Song J. Liang Y. (2021). Baicalein alleviates depression-like behavior in rotenone-induced Parkinson's disease model in mice through activating the BDNF/TrkB/CREB pathway. Biomed. Pharmacother. 140 , 111556. 10.1016/j.biopha.2021.111556 34087694
Zheng Z. H. Tu J. L. Li X. H. Hua Q. Liu W. Z. Liu Y. (2021). Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala. Brain. Behav. Immun. 91 , 505–518. 10.1016/j.bbi.2020.11.007 33161163
Zhou C. Peng B. Qin Z. Zhu W. Guo C. (2021). Metformin attenuates LPS-induced neuronal injury and cognitive impairments by blocking NF-κB pathway. Bmc. Neurosci. 22 (1 ), 73. 10.1186/s12868-021-00678-5 34836498
Zhu S. M. Luo F. Y. Peng J. Luo L. Y. Xue R. Yang Y. (2024). The physicochemical characteristics and antidepressant-like effects of a polysaccharide-rich fraction from Schisandra chinensis (Turcz.) Baill in behavioral despair mice and olfactory bulbectomy-induced depression-like mice. J. Ethnopharmacol. 320 , 117464. 10.1016/j.jep.2023.117464 37992879
Zhu W. Zhang W. Yang F. Cai M. Li X. Xiang Y. (2023). Role of PGC-1α mediated synaptic plasticity, mitochondrial function, and neuroinflammation in the antidepressant effect of Zi-Shui-Qing-Gan-Yin. Front. Neurol. 14 , 1108494. 10.3389/fneur.2023.1108494 37251232
Zhu X. Sun Y. Zhang C. Liu H. (2017). Effects of berberine on a rat model of chronic stress and depression via gastrointestinal tract pathology and gastrointestinal flora profile assays. Mol. Med. Rep. 15 (5 ), 3161–3171. 10.3892/mmr.2017.6353 28339024
Zhuang W. Liu S. L. Xi S. Y. Feng Y. N. Wang K. Abduwali T. (2023). Traditional Chinese medicine decoctions and Chinese patent medicines for the treatment of depression: efficacies and mechanisms. J. Ethnopharmacol. 307 , 116272. 10.1016/j.jep.2023.116272 36791924
Zia A. Farkhondeh T. Pourbagher-Shahri A. M. Samarghandian S. (2021). The role of curcumin in aging and senescence: molecular mechanisms. Biomed. Pharmacother. 134 , 111119. 10.1016/j.biopha.2020.111119 33360051
Ziegler J. Facchini P. J. (2008). Alkaloid biosynthesis: metabolism and trafficking. Annu. Rev. Plant. Biol. 59 , 735–769. 10.1146/annurev.arplant.59.032607.092730 18251710
