We searched for CSS about depressive disorders using the terms described below to obtain data from several electronic databases from the inception of each database to October 2023. Specifically, we searched using PubMed, Web of Science, Google Scholar, Cochrane Library, Chinese National Knowledge Infrastructure, VIP Information, and Wanfang Database. We used the search strategy of combining words (“Depression” OR “Depressive Symptoms” OR “Symptom, Depressive”) AND (“Chaihushugansan” OR “Chai Hu Shu Gan San” OR “Chai-Hu-Shu-Gan-San” OR “Chaihu Shugan San” OR “Chai Hu Shu Gan formula” OR “Chai Hu Shu Gan powder”).

The inclusion criteria were defined as follows: 1) Studies, both in vivo and in vitro, that evaluated the effects of CSS in the treatment of depression; 2) Any intervention in the experimental group that involved the use of an CSS prescription for depression, comprising the seven botanical drugs mentioned earlier, at any dosage, frequency, or administration method; 3) No restrictions on the species, sex, age, or weight of animals, and the species of cells under investigation; and 4) Studies that focused on depression. The exclusion criteria were as follows: 1) The use of CSS as an adjuvant drug in the intervention group; 2) Duplicate studies; 3) Inadequate outcome measures or incomplete data in the studies.

Multiple meta-analyses have demonstrated that when CSS is used in conjunction with antidepressant drugs such as fluoxetine, venlafaxine, paroxetine, etc., the efficacy in treating depression significantly surpasses that of using antidepressants alone, indicating that the combination of CSS with antidepressants effectively enhances the treatment outcomes (Zeng et al., 2017; Sun et al., 2020). In a study involving 40 postpartum depression patients who received 4 weeks of CSS treatment, it was found that the patients experienced a reduction in their postpartum depression scores, as measured by the Edinburgh Postartum Depression Scale (EPDS) and the Hamilton Depression Scale (HAMD). Simultaneously, their hormone levels, including luteotropic hormone (LH), estradiol (E2), and follicular stimulating hormone (FSH), increased. This suggests that CSS can effectively ameliorate clinical symptoms of depression and regulate hormone levels. In a clinical study involving 120 geriatric depression patients, after CSS treatment, it was observed that HAMD scores, Pittsburgh Sleep Quality Index (PSQI) scores, and Quality of Life (QOL) scores all improved. This indicates that CSS can effectively reduce the severity of depression, improve sleep quality and life quality of patients (Xiong et al., 2019).

When CSS was used as the primary treatment, a network meta-analysis of seven traditional Chinese medicines as adjunctive therapy for post-stroke depression revealed that CSS has unique advantages in enhancing clinical efficacy compared to some other traditional Chinese medicines (Yu et al., 2022). In a clinical randomized controlled trial involving 86 patients, CSS demonstrated a significantly higher clinical effectiveness rate compared to the control group (97.67% vs. 81.40%) and substantially alleviated depression levels of patients (Zhang, 2016). Results from a clinical study indicated that, when used as an adjunctive medication, clinical effectiveness of CSS (overall efficacy rate of 97.20%) was significantly better than the control group receiving only psychotherapy (overall efficacy rate of 91.42%) (Chen et al., 2021).

In a systematic review and meta-analysis assessing the safety and efficacy of CSS in treating depression, it was observed that the adverse reaction rate of CSS combined with antidepressants was lower than that of the group receiving antidepressants alone (Zeng et al., 2017; Sun et al., 2020). An analysis of a randomized controlled trial involving 66 patients treated with CSS for post-stroke depression showed that CSS significantly improved scores on related scales, including the Hamilton Anxiety Rating Scale, and that CSS in combination with antidepressants effectively treated post-stroke depression with lower side effects compared to the control group (6.06% vs. 27.27%) (Tao et al., 2023). These studies suggest that the likelihood of CSS interacting with other medications is quite low.

However, further investigation is needed to assess the safety of using CSS alone. In a meta-analysis involving CSS for Parkinson’s disease patients, data from 11 trials showed no adverse reactions, indicating that CSS could be a potential treatment option for patients with comorbid depression (Huber et al., 2023). A meta-analysis of 24 studies using CSS or its modified formulas for treating depression reported neurological symptoms such as dizziness, headache, sleep disturbances, hyperactivity, blurred vision, and fatigue, as well as gastrointestinal symptoms including dry mouth, diarrhea, anorexia, nausea, vomiting, and constipation. However, the incidence of adverse reactions was lower than in the control group (Zhao et al., 2023b).

Damage to the monoaminergic neurotransmission and the accompanying decrease in 5-HT and NE concentrations are major factors in the pathogenesis of depression and are the targets of most antidepressants (Perez-Caballero et al., 2019). Currently, most antidepressants work by inhibiting the reuptake of monoamines, thereby increasing monoamine levels in the synaptic cleft (Lee et al., 2010). However, selective serotonin reuptake inhibitors may lead to withdrawal symptoms such as nausea, vomiting, and diarrhea, limiting their clinical use (Lee et al., 2010). As shown in Figure 2, After treatment with CSS, the content of 5-HT, 5-HIAA, and DA in the hippocampus and hypothalamus of rats increased, while the NE content decreased. This suggests that CSS exerts its antidepressant effects by regulating levels of monoaminergic neurotransmitters like 5-HT and DA in the rat brain (Yufeng et al., 2016). Furthermore, earlier research has also yielded the same conclusion (Wang et al., 2014). MAO-A is involved in the metabolism of 5-HT and NE, and some antidepressants can exert their effects by inhibiting MAO activity (Jahanabadi et al., 2023). Studies have shown that CSS effectively reduces the activity of MAO enzymes, regulating the expression of 5-HT and NE, thereby achieving its antidepressant effects (Haiying et al., 2011).

Tryptophan (Trp) is an essential amino acid taken in by the human body from external sources. It serves as the primary metabolic precursor for the production of serotonin (5-HT) and kynurenine (KYN), which regulate various metabolic activities (Zádori et al., 2018). Under normal physiological conditions, the activity of indoleamine-2,3-dioxygenase (IDO) is low, and Trp is primarily metabolized by tryptophan-2,3-dioxygenase (TDO) in the liver. However, in the presence of inflammation or stress, proinflammatory cytokines can induce a significant increase in IDO activity, and elevated glucocorticoids further activate TDO, directing Trp toward the kynurenine pathway (KP), resulting in a decrease in central and peripheral 5-HT levels (Murakami et al., 2016). In normal mammals, approximately 40% of brain KYN comes from central metabolism, while the remaining 60% originates from the periphery. Therefore, peripheral KYN levels may to some extent represent the levels of central KP metabolites (Li et al., 2020a). In 72 untreated depressive patients, it was found that the levels of KP metabolites in cerebrospinal fluid were closely correlated with those in plasma, with the KYN/Trp ratio being the most correlated indicator (Haroon et al., 2020). In mice after treatment with CSS, the ratio of 5-HT/TRP in the liver significantly increased, while the ratio of KYN/TRP in tissues such as the liver, colon, and brain significantly decreased (Mengyu et al., 2021). Additionally, CSS reduced the activity and expression levels of TDO in the liver, leading to an increase in mouse 5-HT expression levels and the alleviation of depression-like behavior.

One prominent feature of depression is the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis (Menke, 2023). HPA axis hyperactivity is particularly common in individuals with depression and can affect their cognitive functions (Cherian et al., 2019). Excessive stress stimuli to the brain result in cortical impact, triggering the release of signals from the hypothalamus. This leads to increased secretion of corticotropin-releasing factor (CRF) in the HPA axis. Excess CRF is transported through the portal venous system to the pituitary, where it stimulates the synthesis of adrenocorticotropic hormone (ACTH). This, in turn, promotes the production of cortisol (CORT) by the adrenal cortex (Dwyer et al., 2020). CRF is a key regulator of the body’s stress response and is closely associated with various psychiatric disorders, including depression. Overproduction of CRF is a mechanism that activates the HPA axis (Montgomery et al., 2023). Furthermore, cortisol (CORT), which acts downstream of the HPA axis, plays a significant role in the pathogenesis of depression. The CORT levels in individuals with depression are closely related to their clinical symptoms (Holloway et al., 2023). In a study involving perimenopausal depression rats treated with CSS for 21 days, both CRH and CORT levels significantly increased, indicating that CSS can regulate CRH and CORT levels to restore HPA axis function (Shengqiang et al., 2015). Similarly, in the case of CUMS combined with social isolation-induced depression in rats, CSS exhibited the same antidepressant effects (Yunhui et al., 2009).

During stress, corticotropin-releasing hormone (CRH) secreted by the paraventricular nucleus (PVN) of the hypothalamus stimulates the secretion of ACTH and glucocorticoids (GC); corticosterone in rodents (Kim et al., 2019). Receptors for glucocorticoids primarily include mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). During stress, the expression of GC increases dramatically. After crossing the blood-brain barrier, GC acts on hippocampal GR. The GC-GR complex formed in response to high GC concentrations inhibits CRH transcription in the hypothalamus, providing negative feedback regulation on the HPA axis, thus suppressing HPA axis hyperactivity (de Kloet and Joëls, 2023). GC levels are crucial indicators for evaluating HPA axis function. The hippocampus, as the central regulator of the HPA axis, is rich in GR and mineralocorticoid receptors (MR). It is highly susceptible to the influence of high concentrations of glucocorticoids during stress (Gong et al., 2023). As illustrated in Figure 3, when CSS was orally administered to CUMS rats continuously for 21 days, it was found that CRH levels increased and GR levels decreased in the hippocampus compared to the depression model group. This indicates that CSS can effectively weaken the negative feedback effect of GC on the HPA axis, alleviating HPA axis hyperactivity. Thus, CSS may regulate HPA axis hyperactivity by acting on the hippocampus to achieve its antidepressant effect (Fan et al., 2015).

Brain-derived neurotrophic factor (BDNF) is a crucial member of the neurotrophic factor family, initially discovered in pig brain in the 1980s (Leibrock et al., 1989). BDNF is primarily synthesized in neurons and is distributed throughout the central nervous system (CNS). It plays a role in synaptic plasticity recovery, 5-HT signal transduction, and regulating the levels of 5-HT in the brain (Bhattarai et al., 2020; Costa et al., 2022). Numerous studies have shown that BDNF is closely associated with the occurrence, development, and treatment of depression. In the field of neurobiology, BDNF is one of the most studied neurotrophic factors (Amagase et al., 2023; Wang et al., 2023a). Changes in BDNF activity and levels in the brain are closely related to the development of depression. Autopsy results have revealed that the expression levels of BDNF in the plasma of depressed patients are lower than in the control group (Gadad et al., 2021). Furthermore, research suggests that developing antidepressants targeting BDNF might be one of the most effective strategies for future antidepressant drug development (Deltheil et al., 2009; Furukawa et al., 2019).

In a study involving CUMS rats subjected to 28 days of CSS oral administration, it was observed that compared to the depression model group, the expression of BDNF in the prefrontal cortex of rats significantly increased. This indicates that CSS can exert effects similar to the antidepressant venlafaxine by regulating BDNF expression levels (Zhang and Liu, 2020). Tropomyosin receptor kinase B (TrkB) is a specific receptor for BDNF, and it has been confirmed that activating BDNF-TrkB signaling can have an antidepressant effect (Ma et al., 2020). Figure 4 After intervening with CSS in depression model rats, it was found that compared to the model group, rats in the CSS group exhibited significantly increased expression of BDNF and its receptor TrkB in the hippocampus, prefrontal cortex, and amygdala, suggesting that the mechanism through which CSS alleviates depressive states might be related to the increased expression of BDNF and its receptor TrkB in these brain regions (Ying et al., 2011).

Synapses are the fundamental structural units responsible for transmitting information in neurons. Changes in their morphology, quantity, density, and signal transmission efficiency are collectively referred to as synaptic plasticity (Suvrathan et al., 2016; Sweatt, 2016). Synaptic plasticity serves as the neurobiological foundation for the growth and development of the nervous system, repair after injury, and the processes of learning and memory (Sehgal et al., 2013). Figure 5 When examining synaptic structural changes under electron microscopy, it is observed that in comparison to the model group, synaptic improvements occur in the hippocampal region of CUMS-depressed rats following CSS intervention, with an increase in synaptic quantity. This suggests that CSS can effectively enhance synaptic plasticity in the hippocampal region of depressed rats (Fan et al., 2018).

Two specific protein markers, PSD95 and SYN, are used to measure synaptic plasticity. PSD95 is abundantly expressed in the postsynaptic density region and interacts with membrane receptors, ion channels, and cell adhesion molecules, thereby participating in the regulation of synaptic plasticity and learning and memory abilities. SYN is a crucial presynaptic vesicle membrane protein, and its expression accurately reflects synaptic distribution, quantity, and density, making it the most direct indicator of changes in synaptic plasticity. Research indicates that the continuous administration of CSS through oral gavage to depressed rats for 2 weeks results in a significant increase in the deposition of Syn-positive substances in the CSS group compared to the model group. This suggests that CSS can effectively inhibit hippocampal neuronal apoptosis, impact the expression of SYN and PSD95, promote the recovery of damaged synaptic structure and function, and consequently ameliorate depressive-like behaviors in rats (Lan et al., 2023).

NMDAR (N-methyl-D-aspartate receptor) is a glutamate-gated ion channel that regulates neuronal survival, dendritic and axonal development in neurons, excitatory synaptic plasticity, and the formation of neuronal circuits (Tashiro et al., 2006). NMDAR is considered a necessary condition for dendritic spine structural remodeling and is believed to be the cellular basis of learning and memory (Matsuzaki et al., 2004). Downregulation of hippocampal NR2A/NR2B has been associated with cognitive impairment (Luciano-Jaramillo et al., 2019). According to the NMDAR signaling pathway, TrkB is rapidly and persistently activated, serving as a crucial binding partner for BDNF in various forms of synaptic plasticity. Studies indicate that the increase in BDNF exerts neuroprotective effects by transducing the NR2A-CaMKIV-TORC1 pathway (Xu et al., 2015). CSS enhances the expression of BDNF, NR2A, and NR2B in the hippocampus, suggesting that the antidepressant effects of CSS may be mediated through the transduction of the NR2A-CaMKIV-TORC1 pathway, impacting hippocampal neuronal development and thus restoring the neural function of damaged synapses (Xu et al., 2021).

Neuroinflammation is an innate immune response of the nervous system (Meseguer et al., 2014), and it plays a role in the pathological processes of various neurological and psychiatric disorders. Patients with severe depression and animal models of depression often exhibit elevated levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α (Yang et al., 2023). Cytokines are secreted proteins with growth, differentiation, and activation functions. They regulate and determine the nature of immune responses, control immune cell trafficking, and organize the cellular arrangement of immune organs (Borish and Steinke, 2003). In the context of neurodevelopment, the role of cytokines is reflected in pro-inflammatory cytokines impairing neurogenesis, while anti-inflammatory cytokines protect or promote neurogenesis (Soares et al., 2023).

Neuroglial cells play a significant role in the normal physiological processes of the central nervous system, including synaptic transmission, neural plasticity, regulation of neurons, and the local microenvironment (Fang et al., 2023). Microglial cells are the resident immune cells of the CNS, constituting approximately 5%–10% of CNS cells in mice and 0.5%–16.6% in human CNS cells. They participate in pathogen clearance, phagocytosis of dead or apoptotic cells, and the promotion or inhibition of inflammation to maintain brain health. Under normal physiological conditions, microglial cell bodies have elongated processes and continually monitor changes in the brain environment. However, in response to pathological stimuli, microglia are rapidly activated, their numbers increase, and their cell bodies enlarge while their processes become shorter (Zhu et al., 2023). Under pathological conditions, microglia transition from a resting state to an activated state, adopting two polarization phenotypes, M1 and M2. M1 microglial cells secrete many inflammatory mediators to engulf pathogens, while M2 microglial cells secrete protective cell regulators and participate in repairing local tissues and the microenvironment, thus protecting neural tissue (Smith et al., 2012; Pozzo et al., 2019). In an in vitro post-stroke depression model, microglial cell polarization shifts toward the M1 phenotype. However, treatment with GSK3β overexpression virus, CSS, or JAK-STAT3 inhibitors can reverse this polarization. Analysis of inflammation-related protein levels and expression of the JAK/STAT3-GSK3β/PTEN/Akt pathway reveals that the antidepressant effects of CSS may be achieved through the activation of the JAK/STAT3-GSK3β/PTEN/Akt pathway, regulating microglial cell polarization and suggesting that CSS exerts its antidepressant effects by inhibiting neuroinflammation (Fan et al., 2023). CSS can inhibit neuroinflammation in the brain by activating the important SIRT1/NF-κB inflammation signaling pathway in the prefrontal cortex of rats, thus exhibiting its antidepressant effects (Di and Liu, 2021). CSS can reduce the levels of serum TNF-α and IL-6 in depressed rats. It can also effectively inhibit the activation of hippocampal p38 mitogen-activated protein kinase (p38MAPK) and activate the extracellular signal-regulated kinase 5 (ERK5) signaling pathway to achieve its antidepressant effects (Qiu, 2014).

Research has shown that the composition of the gut microbiota is altered in individuals with depression compared to healthy individuals, particularly in terms of microbial diversity and the relative abundance of specific bacterial taxa. This suggests a connection between gut dysbiosis and depression. In depression, the phyla Firmicutes, Actinobacteria, and Bacteroidetes are the most affected (Nikolova et al., 2021). After 28 days of gastric gavage treatment with CSS in CUMS, fresh fecal samples were collected and analyzed. It was observed that in the CSS group, the abundance of Firmicutes significantly increased, and the abundance of Actinobacteria decreased markedly compared to the model group. This indicates that CSS can regulate gut microbiota at the phylum level, mitigating the dysbiosis caused by chronic stress (Meng et al., 2020). In CRS mice, CSS intervention led to an increase in the relative abundance of Actinobacteria. While the results differ, a study that performed 16s rRNA sequencing of gut microbiota in patients with depression found a significant disruption in gut microbiota composition (Han et al., 2021). Differences in bacterial strain abundance led to a reduced ability of MDD patients to produce short-chain fatty acids (SCFA). The lack of SCFAs may weaken gut barrier function (Zheng et al., 2016). Metabolites from the gut, microbial cell components, and even the gut microbiota itself translocate systemically through a compromised gut barrier, often referred to as “leaky gut.” This exacerbates systemic inflammation, such as Th17/Treg imbalance, IL-6, IL-1β, and TNF-α, all of which are closely related to the pathogenesis of depression. Further induced immune responses may be related to the onset and development of depression (Młynarska et al., 2022). Therefore, the antidepressant effect of CSS may be achieved through the regulation of gut microbiota, reshaping the structure and composition of the gut microbiota, and exerting its effects through the microbiota-gut-brain axis (Ma et al., 2022).

Traditional Chinese botanical drug formulations are characterized by complex compositions, making it challenging to characterize functional biomarker ingredients and understand the intricate compatibility rules of multiple ingredients. Research indicates that employing multi-omics approaches is more advantageous for identifying critical ingredients in traditional Chinese medicine (TCM), which is approach helps identify systemic targets for diseases and facilitate a deeper exploration of the mechanisms behind TCM formulations (Wang et al., 2021c). Commonly used methods in this context include network pharmacology, proteomics, and metabolomics.

Network pharmacology analysis has revealed 24 potential targets for the treatment of depression by CSS. Functional enrichment analysis indicates that the PI3K/AKT signaling pathway may be significantly influenced by CSS in MDD treatment. In vivo experiments demonstrate that CSS can ameliorate depressive-like behaviors in CUMS mice and promote neurogenesis. Additionally, CSS can increase the phosphorylation of PI3K/PI3K and AKT/AKT levels while reducing GSK3β/GSK3β levels in the hippocampus of CUMS mice (Zhang et al., 2021b). Research utilizing combined network pharmacology and bioinformatics analysis has identified that the mechanism of CSS primarily focuses on two main cascading signal modules. The first module involves a cascade reaction through ADCYAP1-ADCYAP2R3-GNAS-ADCY3-cAMP-PRKACA, controlling downstream genes like GRIA2, GRIN8A, GSK1A, CREB1, BDNF, FOS, ATF1, MAPK1, and JUND, which play a role in treating depression. The second module targets FOS for depression treatment through the DRD1/5-GNAQ-PLC B1-DAG-PRKCA cascade signal (Wang et al., 2021b).

Using quantitative proteomics and bioinformatics analysis methods to identify and analyze CSS, it appears that CSS may exert its antidepressant effects by influencing the synthesis, release, reuptake, and degradation pathways of GABA. Proteins such as Gad2, Vamp2, and Pde2a may be associated with the alleviation of depression by CSS. Therefore, these proteins may serve as potential antidepressant targets for CSS. Previous studies have demonstrated that CSS exerts its antidepressant effects by modulating the HPA axis and inhibiting neurotransmitter reuptake, such as norepinephrine, serotonin, and dopamine (Zhang et al., 2011b). Hence, it is hypothesized that CSS affects the glutamate and GABA signaling pathways via the HPA axis for depression treatment (Zhu et al., 2021) Table 1.

Serum metabolomics results indicate that 16 proteins and 63 genes are regulated by CSS. Sphingolipid metabolism and arachidonic acid metabolism appear to be the most significantly affected metabolic pathways related to depression induced by CUMS. Multiple studies have demonstrated that depression often accompanies sphingolipid metabolism disturbances (Li et al., 2022), and clinically, low levels of arachidonic acid in blood are associated with adult depression (Tsuchimine et al., 2015). Metabolomic studies of the hippocampus and serum in chronic variable stress (CVS)-induced rats reveal 10 metabolites from the hippocampus and 11 from serum that are considered potential biomarkers involved in the development of depression. CSS collaboratively regulates metabolic network abnormalities, including energy metabolism, neurotransmitter synthesis, tryptophan, phospholipids, fatty acids, bile acid metabolism, bone loss, and liver detoxification. CSS reverses the decrease in BDNF, ERK2/1, and pERK2 in CVS rats, suggesting that the ERK signaling system may be one of the targets for antidepressant effects of CSS (Su et al., 2014).

In summary, antidepressant effects of CSS are believed to be primarily related to monoamine neurotransmitters, the HPA axis, BDNF, synaptic plasticity, gut microbiota, and inflammatory responses (Figure 6; Table 2). It is thought to directly regulate these factors or indirectly act on various related proteins, receptors, or signaling pathways, which are primarily concentrated in the brain, the main targeted organ in current depression research.

Saikosaponin possess a wide range of anti-inflammatory and immune-regulatory properties, making them effective ingredients in the treatment of depression with botanical drug medicine (Liu et al., 2020a; Wang et al., 2023b). The antidepressant effect of saikosaponin A may be associated with the modulation of DA levels and the transmembrane protein 2 rich in proline (PRRT2) in the hippocampus of depressive rats induced by CUMS (Guo et al., 2020). Saikosaponin A have been demonstrated to increase the expression of BDNF. In the MCAO + CUMS model, the administration of Chaihu Saponins significantly upregulated the protein levels of p-CREB, BDNF, Bax, and Caspase-3, promoting BDNF and Bcl-2 expression, consequently preventing hippocampal neuronal apoptosis and improving depressive-like behavior in post-stroke depression rats (Wang et al., 2021a).

As a critical regulator of the pro-inflammatory cytokine signaling pathway, NF-κB plays a pivotal role in immune responses, including stress, and has been associated with cognitive and memory impairments as well as depressive symptoms (Singh and Singh, 2020). Saikosaponin D can negatively regulate NF-κB, which, in turn, downregulates FGF2 expression through miR-155 downregulation. FGF2, as a key growth factor in synaptic plasticity and neuron growth, enhances synaptic plasticity and protects neurons, contributing to the antidepressant effect (Chao et al., 2020).

Saikosaponin A exhibits an antidepressant-like effect on peri-menopausal depressive rats induced by CUMS, and Saikosaponin A restores the hyperactivity of the HPA axis and pro-inflammatory cytokines while promoting BDNF-TrkB signaling in the hippocampus. SSA plays an antidepressant-like role in peri-menopausal rats by restoring hippocampal neuroendocrine, neuroinflammatory, and neurotrophic systems (Chen et al., 2018). Microglial cells serve as the first line of immune defense in the central nervous system, responding rapidly to external threats and secreting a substantial amount of oxidative stress substances and inflammatory cytokines, such as nitric oxide, reactive oxygen species, and IL-1β (Arioz et al., 2019). Activated microglial cells aim to remove antigens and restore brain homeostasis, but excessive activation can lead to neuronal damage. Saikosaponin D pretreatment effectively inhibits the release of inflammation-related cytokines (IL-1β, IL-6, and TNFα) mediated by activated microglial cells in vitro and in vivo. Saikosaponin D exerts its anti-inflammatory action by inhibiting the translocation and extracellular release of HMGB1, and inhibiting downstream TLR4/NF-κB signaling (Su et al., 2020). The elevated levels of glutamate induced by CUMS can lead to synaptic damage, which can be reversed through treatment with SSD. The amelioration of glutamate-induced synaptic injury appears to be mediated through the regulation of the Homer1-mGluR5 pathway and downstream mTOR signaling. It was observed that SSD treatment attenuated the increase in glutamate levels in the hippocampal CA1 region induced by chronic stress, which is known to contribute to synaptic damage and enhance the expression of synaptic proteins. Therefore, SSD may alleviate depressive-like behavior in CUMS-exposed rats by modulating the Homer1-mGluR5 and mTOR signaling pathways. These findings suggest that SSD can serve as a natural neuroprotective agent for the prevention of depression (Liu et al., 2022b). Therefore, saikosaponin A and saikosaponin D are promising ingredients in inhibiting the inflammatory response, which might be a potential mechanism underlying their antidepressant effects.

Paeoniflorin is a monoterpenoid glycoside obtained from the roots of peony or moutan, typically extracted from Bai Shao, a traditional low-toxicity Chinese botanical drug medicine widely used in the treatment of depression. Regardless of the type of stress animals are exposed to, reduced BDNF levels can potentially impact various brain functions, such as neurogenesis, neuron survival, and plasticity, promoting depressive-like behavior in stressed animals. Paeoniflorin exerts neuroprotective effects through the ERK-CREB signaling pathway, ameliorating depressive-like behavior in CUMS rats (Zhong et al., 2018). In an acute depression animal model induced by forced swimming, paeoniflorin significantly increases the serum and hippocampal BDNF levels in rats, offering protection against hippocampal pathological changes (Mu et al., 2020).

Oxidative stress is defined as an imbalance between the generation of reactive oxygen species (ROS) and the antioxidant capacity of cells, which is a major contributor to depression (Liu et al., 2023). Paeoniflorin can exhibit antidepressant effects through a multitarget pharmacological approach. For example, rats subjected to the forced swim test (FST) exhibit decreased plasma and hippocampal levels of serotonin, norepinephrine, and dopamine, as well as reduced plasma BDNF and superoxide dismutase (SOD) levels (Mu et al., 2020).

The HPA axis is associated with the pathophysiology of depression. Experimental evidence indicates that paeoniflorin can reverse depressive-like behavior. Neurogranin (Ng), a recently discovered postsynaptic protein widely distributed in the hippocampus, is found to be significantly lower in the hippocampus of depressive rats (Xiang et al., 2020). Paeoniflorin significantly increases the expression of Ng protein in the hippocampus. Furthermore, paeoniflorin decreases hippocampal glutamate (Glu) levels by inhibiting the expression of SNAP25, VAMP2, Syntaxin1a, and related proteins, as well as EAAT2/3, NR1, and NR2A proteins. These findings suggest that paeoniflorin can improve depressive-like behavior through modulation of the HPA axis, GR function, and Glu transporters (Li et al., 2020c).

Growing evidence suggests a close relationship between neuroinflammation and depression, making the inhibition of neuroinflammation a crucial treatment strategy for depression (Wei et al., 2023). Paeoniflorin can inhibit the TLR4/NF-κB/NLRP3 signaling pathway in the mouse hippocampus induced by LPS, reducing the levels of pro-inflammatory cytokines and microglial activation. Fibroblast growth factor-2 (FGF-2) plays a role in regulating neuron proliferation and differentiation (Koizumi, 2021). Paeoniflorin can increase FGF-2 levels and dendritic spine density. Therefore, paeoniflorin may exert its neuroprotective and antidepressant effects by inhibiting hippocampal microglial activation and activating the FGF-2/FGFR1 signaling pathway in neurons (Cheng et al., 2021).

Ferulic acid (FA) is an aromatic acid originating from Chuanxiong (Szechuan lovage rhizome) and has shown antidepressant effects in clinical or animal studies (Zhang et al., 2018b). Among the various pharmacological actions of FA, its potential antidepressant effects have gained increasing attention. FA is a potent antioxidant that can scavenge hydrogen peroxide, hydroxyl radicals, superoxide radicals, and peroxynitrite (Xie et al., 2020a). Additionally, FA possesses characteristics of anti-apoptosis, anti-tumor, and anti-thrombotic properties. It can also inhibit neuroinflammatory responses and promote neurogenesis in the hippocampus (Kaur et al., 2022).

Hippocampal SIRT6 is involved in the in vivo lentivirus-mediated knockdown of depression induced by chronic unpredictable stress (CUS). Knockdown of hippocampal SIRT6 can prevent CUS-induced depressive-like phenotypes (Li et al., 2018). The PI3K/AKT signaling pathway is implicated in mediating antidepressant effects. The hippocampal SIRT6/AKT/CRMP2 signaling pathway is involved in the mechanism of antidepressant action of FA. CRMP2 is well-characterized as a target for neuronal plasticity and behavior regulation, regulating various aspects of neuron development, including axon guidance, dendritic morphology, and synaptic plasticity. Overexpression of CRMP2 effectively prevents acute axonal degeneration (Zhang et al., 2018a). CRMP2 activity is regulated by the SIRT6/AKT signaling pathway. Therefore, FA effectively activates the AKT/CRMP2 signaling pathway, improving CUS-induced depressive-like behavior and exerting neuroprotective effects through the SIRT6/AKT/CRMP2 pathway (Li et al., 2020b).

Ferulic acid can ameliorate depression in mice through antioxidative pathways. Studies have shown that ferulic acid increases the activities of SOD, catalase (CAT), and glutathione peroxidase (GSH-Px) in the blood, hippocampus, and cerebral cortex, while reducing levels of thiobarbituric acid reactive substances (TBA-RS). When the antioxidant defense system is modulated, ferulic acid can exert its antidepressant effects (Lenzi et al., 2015). In CUMS mice, FA improves depressive-like behavior in the tail suspension test (TST) and sucrose preference test (SPT). FA inhibits the activation of the NLRP3 inflammasome, the NF-κB signaling pathway, and the expression of IL-1β, IL-6, and TNF-α, suggesting that anti-inflammatory mechanisms are involved in antidepressant effects of ferulic acid in stressed mice (Liu et al., 2017).

Mitochondrial energy homeostasis mediated by ferulic acid is another potential mechanism of its antidepressant action. Dysfunction of mitochondria can lead to abnormal energy metabolism, triggering depressive episodes. Ferulic acid can promote glycogen metabolism in the brain, increase ATP levels, and activate neural function. FA also upregulates the gene expression of Ddc and Ppp1r1b, which are involved in dopamine signaling. FA treatment increases brain dopamine and norepinephrine levels, and thus, FA exerts its antidepressant effect by promoting dopamine synthesis (Sasaki et al., 2019).

Dysbiosis of the gut microbiota is closely associated with the onset of depression. FA effectively reduces the levels of pro-inflammatory cytokines, such as IL-6, IL-1β, TNF-α, while increasing the anti-inflammatory cytokine IL-10 in serum. This suggests that FA reduces systemic inflammation. 16S rRNA sequencing reveals that FA intervention reduces the abundance of the Proteobacteria phylum and significantly increases the abundance of Lactobacillus spp., Allobaculum spp., and Unspecified_S24_7. FA may exert its antidepressant effects by upregulating short-chain fatty acids. Furthermore, UHPLC-QTOF-MS/MS detection reveals that FA affects 459 microbial metabolites, primarily involved in tryptophan or thiamine metabolism. Tryptophan is an amino acid clinically used to alleviate depression, and a causal relationship exists between disrupted thiamine metabolism and depression (Wilson et al., 2023). Therefore, FA may exert its antidepressant effects by inhibiting pro-inflammatory cytokines, remodeling the gut microbiota, and modulating microbial metabolism (Hao et al., 2021).

Naringin is an active ingredient derived from the pericarp of citrus fruits, exhibiting a wide range of biological activities, such as anti-inflammatory and antioxidative properties (Kim and Kim, 2017), and has been employed in alleviating various neurological disorders (Emran et al., 2022). Adult hippocampal neurogenesis is crucial in the establishment of circuitry networks involving emotion-regulating regions like the amygdala and hypothalamus. Naringin promotes neuronal differentiation in normal mice, induces neural stem/progenitor cell (NSPC) migration to the subventricular zone-olfactory bulb (SVZ-OB) system, accelerates neuronal maturation in CORT-induced depressed mice, and enhances dendritic arborization, thereby exerting its antidepressant and anxiolytic effects via the promotion of neuronal differentiation target CREB (Gao et al., 2022). Moreover, naringin enhances BDNF through the cAMP-CREB-BDNF signaling pathway while suppressing neuroinflammation and neuronal apoptosis, ameliorating depressive behaviors in CORT-induced depressed mice (Zhang et al., 2023). Neurobehavioral characteristics of naringin are also accompanied by increased neuro-antioxidative and cholinergic activities. Furthermore, it significantly reduces the levels of malondialdehyde and nitrites, indicating involvement in the oxidative/nitrosative pathways, suggesting that naringin treatment may contribute to functional behavioral effects through mechanisms associated with enhanced cholinergic transmission, antioxidant defense systems, and the inhibition of lipid peroxidation and nitrosative processes (Ben-Azu et al., 2019). Rutin increases the levels of GAD67 in the striatum, prefrontal cortex, and hippocampus while reducing AChE activity. Additionally, Rutin region-dependently decreases TNF-α, IL-6, malondialdehyde, and nitrite concentrations while increasing glutathione levels. Our study suggests that Naringin attenuates SDS-induced depressive-like behaviors by increasing GAD67 synthesis, inhibiting AChE activity, oxidative and nitrosative stress, and neuroinflammation processes in stress-sensitive brain regions (Oladapo et al., 2021).

Hesperidin, an active ingredient derived from tangerine peel, possesses antioxidative, anti-inflammatory, and antiviral properties, while also promoting neurogenesis and enhancing memory function (Li et al., 2023). Studies have indicated that hesperidin exhibits antidepressant effects (Li et al., 2016). Hesperidin has been found to decrease the expression of the NLRP3 inflammasome (NLRP3, caspase-1, and ASC) in the prefrontal cortex (PFC) of rats induced with CUMS. It reduces the number of activated microglia in the PFC and levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). Elevated levels of pro-inflammatory cytokines released by activated microglia contribute to neuroinflammatory responses, and hesperidin can inhibit the activation of pro-inflammatory cytokines in microglia induced by LPS and the NLRP3 signaling pathway (Xie et al., 2020b). In a comorbid diabetic depression rat model, hesperidin also exerts antidepressant effects. Hesperidin reduces depressive behaviors in diabetic rats by enhancing the function of Glo-1 in the amygdala and hippocampus, thereby reducing the formation of advanced glycation end products (AGEs) and oxidative stress-induced damage. Furthermore, the upregulation of Glo-1 by hesperidin is associated with the activation of the Nrf2/ARE signaling pathway, further elucidating the molecular mechanisms through which hesperidin inhibits the formation of brain AGEs and oxidative stress in diabetic rats. In vitro studies suggest that hesperidin treatment can reverse the reduced expression of Nrf2 induced by high glucose (HG). Therefore, the antidepressant-like effects of hesperidin are primarily mediated through the activation of the Nrf2/ARE/Glo-1 pathway (Zhu et al., 2020a). In a rat model of depression induced by PTSD, hesperidin can ameliorate depressive-like behavior in rats by inhibiting the activity of MAO-A and the expression of tryptophan hydroxylase-1 in the hippocampus. This leads to an increase in the release of serotonin (5-HT) (Lee et al., 2021).

Nootkatone is the primary monomeric ingredient found in lotus plumule and exhibits various pharmacological properties, including antimicrobial, antioxidant, and anti-allergic activities. Nootkatone functions as a neuroprotective agent and improves cognitive impairments by inhibiting neuroinflammation through the TLR4/NF-κB/NLRP3 pathway in the hippocampus (Wang et al., 2018). Recent studies have shown that nootkatone also possesses antidepressant and anxiolytic effects by activating the Keap1/Nrf2/HO-1 antioxidant pathway in response to liver injury-induced depression (Yan et al., 2021). Nootkatone significantly increases the reduced expression of PKA and p-CREB caused by CUS, suggesting that the PKA/CREB pathway may be involved in regulating BDNF expression in response to nootkatone treatment. Additionally, Nootkatone improves neurogenesis in the hippocampal dentate gyrus, indicating that it may exert antidepressant effects by enhancing neurogenesis. Therefore, nootkatone likely exhibits antidepressant activity through increasing neurogenesis in the hippocampal dentate gyrus and activating the PKA/CREB pathway to enhance BDNF expression (Wang et al., 2022). In a CUMS-induced depression model, Nootkatone improves depressive symptoms by inhibiting neuroinflammation mediated by the NF-κB/NLRP3 pathway (Zhao et al., 2023a).

Glycyrrhizin, the principal active ingredient in licorice, possesses pharmacological properties such as anti-inflammatory and antioxidant effects. A metabolomics analysis of the effects of Glycyrrhizin on depression in rats was conducted using UHPLC-Q-TOF MS and UHPLC-TQ MS, revealing the screening of 47 different metabolites in the urine of depressed rats. This suggests that Glycyrrhizin may exert its antidepressant effects through metabolic pathways (Yang et al., 2020). Glycyrrhizin can lower the levels of FGF-2 in the hippocampus of LPS-induced depressive model mice, increase dendritic spine density, and significantly reduce the number of Iba-1 positive cells. This indicates that Glycyrrhizin may exert its antidepressant effects by inhibiting the activation of microglial cells, suppressing the release of pro-inflammatory cytokines, and protecting dendritic spine morphology in the hippocampal region (Chen et al., 2020). Research also suggests that Glycyrrhizin exerts its antidepressant effects in part by inhibiting the levels of cytokines triggered by the NLRP3 inflammasome, highlighting the role of antioxidative stress and the inhibition of NLRP3 inflammasome activation in antidepressant properties of Glycyrrhizin (Liu et al., 2022a). Glycyrrhizin is applicable in various depression models, as it can reduce the levels of FSH and estradiol E2 in the serum, improve the decreased 5-HT and NE levels in the hypothalamus, and increase the levels of monoamine neurotransmitters, thereby ameliorating depressive-like behavior in perimenopausal rats (Lan et al., 2020).