Depression is classified as a mental disorder characterized primarily by persistent low mood, diminished interest or pleasure in activities, reduced initiative, and lack of energy (Marwaha et al., 2023). The research indicates that as a consequence of the global COVID-19 pandemic in 2020, there was a 27.6% increase in the number of patients with severe depressive disorder worldwide (Myles et al., 2023). According to a report by the World Health Organization (WHO), as of March 2023, 280 million people worldwide suffer from depression, and more than 700,000 people die each year due to impulsive behaviors related to depression (Jing and Ding, 2024). Currently, depression stands as one of the leading causes of disability and contributes significantly to the overall global disease burden (Zheng S. et al., 2024). It imposes substantial psychological and financial burden on patients and their families, making it an urgent public health issue that requires immediate attention (Haghish et al., 2024).

To date, the etiological mechanisms of depression remain incompletely understood, potentially involving factors such as inflammation, neurotransmitters, neuroplasticity and neuroregeneration, the hypothalamic-pituitary-adrenal (HPA) axis, as well as genetic and environmental influences (Peters et al., 2024). Recent studies have shown that chronic psychosocial stress leads to persistent activation of the HPA axis, subsequently triggering the release of glucocorticoids, which is closely associated with the onset of depression (Liu et al., 2024). Patients with depression often exhibit dysfunction of the HPA axis, accompanied by elevated levels of circulating glucocorticoids (Qin et al., 2024). However, elevated glucocorticoid levels further impair central nervous system function, leading to reduced hippocampal neurogenesis and inducing neuronal apoptosis (Qin et al., 2024). The onset of depression is also associated with reduced expression of neurotrophic factors (Zhou et al., 2024). Inhibition of the expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the peripheral nervous system is related to abnormal neural function in the brains of patients with depression (Luo et al., 2023). Abnormal oxidative stress and inflammation in patients with depression impair neuroplasticity by inhibiting the expression of BDNF and NGF (Luo et al., 2023).

Currently, the primary treatments for depression include cognitive behavioral therapy, transcranial direct current stimulation, and pharmacotherapy (Kong et al., 2024). Most antidepressants are developed based on the principle of increasing the concentration and utilization of monoamine neurotransmitters in the synaptic clefts of central neurons (Colla et al., 2024). For instance, the first generation of antidepressants primarily consists of tricyclic antidepressants, which work by increasing the transmission of monoamine neurotransmitters, and monoamine oxidase inhibitors (MAOIs), which primarily act by inhibiting the degradation of these neurotransmitters (Kim and Amsterdam, 2023). Modern antidepressants commonly used today primarily function by inhibiting the reuptake of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) (Veraart et al., 2022). Examples include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and norepinephrine-dopamine reuptake inhibitors (NDRIs) (Hovorka et al., 2022). These antidepressants often come with side effects, and their overall efficacy ranges from 50% to 75% (Laux, 2022). Therefore, finding safe and effective medications for the treatment of depression has become a major focus of research.

Baicalin is a flavonoid compound isolated from the roots of Scutellaria baicalensis, which possesses various biological activities including antibacterial, diuretic, anti-inflammatory, and antioxidant effects (Cho et al., 2024). Research has shown that it possesses strong neuroactive and neuroprotective properties (Zheng et al., 2024b). It can effectively alleviate nerve damage caused by glucose-oxygen deprivation, inhibit the overactivation of NMDAR glutamate receptors, counteract central inflammatory responses and oxidative stress, and promote neuronal cell differentiation (Zhong et al., 2019). In addition, it improves nerve damage induced by scopolamine and seizure-like symptoms in rats (Cintra et al., 2024). Recent studies have found that baicalin can effectively alleviate depressive symptoms caused by chronic stress in rats, demonstrating strong antidepressant activity (Fan et al., 2020; Chalermwongkul et al., 2023; Hu et al., 2023).

At present, accumulating pharmacological evidence suggests that baicalin may hold significant potential in the treatment of depression (X. Jin et al., 2023; Ma et al., 2023). However, research on the use of baicalin for treating depression has not been comprehensively evaluated or summarized. This study provides a rigorous and comprehensive systematic review and meta-analysis of the literature concerning the use of baicalin in treating depression in animal models. It explores various behavioral changes and potential mechanisms, aiming to provide evidence for clinical practice.

According to the preset retrieval strategy, a total of 568 articles were retrieved. After the exclusion of unrelated articles, 432 articles remained. Further exclusions included reviews (n = 118), meeting reports (n = 72), scientific and technological achievements (n = 59), abstracts (n = 6), and network pharmacology studies (n = 9). Thus, 168 studies were included in the full manuscript screening. Non-pharmacodynamic experimental studies (n = 33) and in vitro studies (n = 38) were excluded by reading titles and abstracts. Finally, 22 articles were included for comprehensive analysis after excluding articles that did not meet the outcome criteria (n = 26) and articles that could not provide data (n = 49). The detailed literature search and screening process is illustrated in Figure 1.

Figure 1. Literature retrieval flow chart.

The basic characteristics of the 22 studies are shown in Table 1. This meta-analysis included a total of 1,050 animals, with 700 in the model group and 350 in the baicalin group. The model group consisted of four different animal models of depression: chronic unpredictable mild stress (CUMS), corticosterone (CORT), olfactory bulbectomy (OBX), and lipopolysaccharide (LPS). The model group received oral treatments with fluoxetine, fasudil, or amitriptyline. The baicalin group was treated only with baicalin at doses ranging from 3.35 to 160 mg/kg for a duration of 1–5 weeks.

Table 1. Characteristics of included studies.

The animal species involved are C57BL/6 (130/1,050) accounting for 12.38%, C57BL/6J (86/1,050) accounting for 8.19%, Institute of Cancer Research (ICR) (451/1,050) accounting for 42.95%, and Sprague Dawley (SD) (275/1,050) accounting for 26.19% (Figure 3A). The proportion of male and female animals was 89.52% (940/1,050) and 4.76% (50/1,050), respectively (Figure 3B). Furthermore, 31.90% (335/1,050) of animals were rats, and 68.10% (715/1,050) of animals were mice (Figure 3C). The body weight of rats and mice ranged from 18g to 320 g. The distribution is as follows: 63.64% (14/22) CUMS, 27.27% (6/22) CORT, 4.55% (1/22) LPS, and 4.55% (1/22) OBX (Figure 3D). In terms of quality assessment scores, 18% (4/22) of the studies had seven points, 27% (6/22) of the studies had eight points, and 55% (12/22) of the studies had nine points (Figure 3E).

The quality assessment of the 22 studies was conducted using the 10-item CAMARADES checklist, with scores ranging from 8/10 to 10/10. Specifically, all studies utilized appropriate animal models of depression and calculated sample sizes. Additionally, all 22 studies mentioned random allocation and concealed distribution. Twenty-one studies avoided the use of neurotoxic or protective anesthetics. Furthermore, all studies demonstrated compliance with animal welfare principles and declared no conflicts of interest. The specific risk of bias items is presented in Figures 2, 3E.

Figure 2. Risk of bias and quality assessment scores in each study.

Figure 3. Characteristics of eligible studies. (A) Animal species (B) gender proportion (C) Type classification (D) Experimental model classification (E) Quality assessment scores.

The SPT is widely recognized as a prevalent method for assessing anhedonia. A total of 17 studies compared the differences in SPT before and after baicalin treatment. Due to significant heterogeneity between studies (P < 0.00001, I2 = 69.3%), the random-effects model was adopted. Compared with model group, baicalin could significantly increase the preference for sucrose [SMD = 21.31, 95%CI (16.32, 26.31), P < 0.00001] (Figure 4A). The sensitivity analysis indicated that the findings were robust and consistent (Figure 4B).

Figure 4. (A) Forest map and (B) sensitivity analysis of SPT.

The TST is the most commonly used behavioral despair model experiment and serves as a classic method for evaluating antidepressant drugs. A total of 10 studies compared the differences in TST before and after baicalin treatment. The fixed effects model was employed (P < 0.00001, I2 = 0.42%). Compared with model group, the immobility time was significantly decreased in the baicalin treatment group [SMD = −39.3, 95%CI (−49.71, −28.89), P < 0.0001] (Figure 5A). The sensitivity analysis indicated that the findings were robust and consistent (Figure 5B).

Figure 5. (A) Forest map and (B) sensitivity analysis of TST.

The FST is used to evaluate despair behavior in mice or rats and serves as a key indicator for assessing depressive-like behavior. A total of 15 studies compared the differences in FST before and after baicalin treatment. The fixed effects model was employed (P < 0.00001, I2 = 18.8%). Compared with the control group, baicalin treatment also reduced the inactivity time [SMD = −39.86, 95%CI (−48.9, −30.82), P < 0.0001], suggesting that it has an antidepressant like behavioral effect (Figure 6A). The sensitivity analysis revealed that the results were robust and consistent (Figure 6B).

Figure 6. (A) Forest map and (B) sensitivity analysis of FST.

The OFT is a widely used experimental paradigm based on observing the behavioral characteristics, exploratory behavior, and anxiety levels of animals in unfamiliar environments. A total of five studies (Li et al., 2013; Jiduo et al., 2016; Yue et al., 2016; Lu et al., 2019; Yongyong et al., 2019) compared the differences in OFT before and after baicalin treatment. Due to significant heterogeneity between studies (P < 0.00001, I2 = 79.6%), the random-effects model was adopted. Baicalin treatment significantly improved the frequency of crossing compared to the model group [SMD = 32.44, 95%CI (17.74–47.13), P < 0.00001] as illustrated in Figure 7A. The sensitivity analysis revealed that the results were robust and consistent (Figure 7B).

Figure 7. (A) Forest map and (B) sensitivity analysis of OFT.

Publication bias regarding the changes in SPT, FST, OFT, and TST was evaluated using a funnel plot. The included studies were evenly and symmetrically distributed on both sides of the axis, under the cover of the triangle in the funnel plots, suggesting a minimal risk of publication bias. This was additionally validated by the outcomes of Egger’s test (P > 0.05) (Figure 8).

Figure 8. Publication bias of baicalin. (A) SPT (B) TST (C) FST (D) OFT.

To investigate the impact of different factors on outcome measures, we conducted a subgroup analysis of the baicalin group based on baicalin dosage, animal species, and depression animal models (Table 2). When conducting a subgroup analysis, it is essential to include at least two articles; a single article will not be subjected to subgroup analysis.

Table 2. Subgroup analysis outcomes after baicalin intervention.

This study indicates that baicalin significantly improves the outcome measures of SPT, TST, FST, and OFT in animal models of depression. Our research findings are consistent with the systematic reviews by Ma and Wang et al. on the treatment of depression using Scutellaria baicalensis and its active components, although their studies did not explicitly demonstrate the efficacy of baicalin when used alone (Ma et al., 2024; Wang and Gao, 2024). Additionally, our results align with the effects of antidepressants fluoxetine and imipramine in reversing depressive behaviors in CUMS rats, further supporting the potential role of baicalin in depression treatment (Ossowska et al., 2004). The four outcome indicators of SPT, TST, FST, and OFT respectively reflect the different depressive states of patients. Specifically, the SPT indicates anhedonia, demonstrating a diminished capacity to anticipate or enjoy pleasurable activities. The TST and FST measure feelings of helplessness and despair, respectively. The OFT assesses increased anxiety. These indicators of anhedonia, despair, helplessness, and anxiety are critical for assessing depression progression and treatment response. Existing evidence has shown that baicalin improves symptoms in depression primarily through anti-inflammatory effects, inhibition of oxidative stress, regulation of the HPA axis, and restoration of neuroplasticity (Shiyuan et al., 2023). (Figure 9). It has been found that neuroinflammation and oxidative stress are closely related to anhedonia and anxiety in patients with depression (da Silva et al., 2024). Neuroinflammation can lead to the overactivation of microglia, which inhibits synaptic transmission in hippocampal neurons, causing neuronal dysfunction and resulting in depressive symptoms (Zou et al., 2022). Numerous studies have shown that inflammatory mediators and cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) are frequently present in the peripheral blood of patients with depression (Tian et al., 2024). In patients with depression, pathogen-associated molecular patterns (PAMPs) such as inducible nitric oxide synthase (iNOS) and nitric oxide (NO), and danger-associated molecular patterns (DAMPs) such as IL-1β and interleukin-18 (IL-18) enter the cytoplasm of hippocampal microglia (Tian et al., 2024). These are recognized by the pattern recognition receptor NOD, LRR, and pyrin domain-containing protein 3 (NLRP3), stimulating an immune response (Mokhtari and Uludag, 2024). This leads to the recruitment of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and Pro-caspase-1 (Cysteine-aspartic protease-1) (Huang et al., 2023). Activated caspase-1 cleaves Pro-IL-1β and Pro-IL-18 into their active forms, IL-1β and IL-18, thereby stimulating hippocampal inflammatory cells, exacerbating inflammation, promoting the formation of neurotoxic A1 astrocytes, and inducing depressive-like behaviors such as anxiety and despair (Huang et al., 2023). Liu et al. found that baicalin significantly inhibited the levels of inflammatory factors in serum, hippocampal homogenate and PC12 cell medium in CUMS rat models (Liu and Liu, 2017). Furthermore, research has proved that baicalin significantly downregulates the expression of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), and phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 in the hippocampus of CUMS mice, and inhibits the levels of IL-1β, IL-6, and TNF-α in serum and hippocampal homogenate (Liu et al., 2019). These findings suggest that baicalin may regulate the HMGB1/TLR4/NF-κB pathway to exert anti-neuroinflammatory effects and improve depressive symptoms (Liu et al., 2019). There is evidence that HMGB1 is a key trigger in the crosstalk between normal and inflammatory cells. HMGB1 binds to TLR4, leading to the recruitment and promotion of NF-κB, thereby activating the transcription of inflammatory cytokines, chemokines, and adhesion molecules, and promoting the development of depression (Jia et al., 2024). Glycogen synthase kinase three beta (GSK3β) is a serine/threonine kinase widely present in the central nervous system, primarily localized in neurons (Olianas et al., 2011). When the activity of GSK3β increases, it can promote neuronal apoptosis, whereas decreased activity can regulate neuronal plasticity (Jin et al., 2019). The primary mechanism by which neurons regulate GSK3β activity is through phosphorylation at its Ser9 site (Ahmed et al., 2023). Studies have shown that the regulation of GSK3β activity is directly or indirectly related to the mechanisms of action of many mood stabilizers and antidepressants, primarily mediated through cAMP response element-binding protein (CREB), which regulates the transcription of BDNF to achieve an antidepressant effect (Lee et al., 2019). Zhang et al. found that baicalin might exert neuroprotective effects by inhibiting the activation of the GSK3β/NF-κB/NLRP3 signaling pathway, promoting neuronal maturation, and preventing neuronal apoptosis (Zhang C. Y. et al., 2018). Katrenčíková et al. discovered that antidepressant treatment significantly increased superoxide dismutase (SOD) activity in patients with depression. In recent years, studies have found that baicalin inhibits hippocampal neuronal apoptosis in CUMS rats by reducing malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD) levels (Katrenčíková et al., 2021). Similarly, Fu et al. found that baicalin enhanced SOD activity, inhibited MDA production, downregulated NF-κB levels, and significantly increased nuclear nuclear factor erythroid 2-related factor 2 (Nrf2) content (Fu et al., 2021). Evidence suggests that the anxiety and despair symptoms in depression patients might originate from hyperactivity of the HPA axis, leading to the excessive release of stress hormones such as corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and CORT, resulting in impaired and dysregulated negative feedback mechanisms in the body (de Kloet et al., 2005). High levels of stress hormones further damage the structure and function of the hippocampus, causing atrophy and dysfunction of pyramidal neurons, ultimately manifesting as depressive symptoms (Myers et al., 2014). Zhang et al. found that baicalin treatment restored glucocorticoid receptor (GR) protein levels in the cytoplasm and nucleus of CORT-treated mice, reduced corticosterone and ACTH levels, restored HPA axis negative feedback function, and alleviated depressive symptoms Zhang et al. (2016). Neuroplasticity refers to the reversible structural and functional changes in the brain under stress and other conditions (Minbay et al., 2024). Clinical studies have shown that patients with depression often exhibit reduced hippocampal volume, which is associated with decreased neurogenesis and impaired neuroplasticity (Medeiros et al., 2024). Gao et al. demonstrated that neuronal apoptosis in the damaged hippocampal region is associated with anxiety- and depression-like behaviors, and identified amyloid beta precursor protein-like 2 (APPL2) as a potential therapeutic target for depression and olfactory deficits (Gao et al., 2018). Baicalin inhibited the APPL2/GR signaling pathway in APPL2 transgenic mice and corticosterone-induced depressed mice, promoting neuronal apoptosis in the subventricular zone (SVZ), olfactory bulb (OB), and hippocampus of APPL2 transgenic mice (Gao et al., 2018). This suggests that the antidepressant mechanism of baicalin might be related to the regulation of the APPL2/GR signaling pathway. Zhang et al. demonstrated that baicalin activates protein kinase B (Akt) and upregulates forkhead box G1 (FOXG1) in the hippocampus, thereby helping prevent neuronal apoptosis (Zhang et al., 2019a). Recent studies have found that baicalin increases the protein expression of Wnt3a, dishevelled segment polarity protein 2 (DVL2), and β-catenin in the hippocampus, inhibits the phosphorylation level of GSK3β, thereby stabilizing β-catenin, which is critical for neurogenesis (Xiao et al., 2021). Meanwhile, Lu et al. discovered that baicalin activates Ras-related C3 botulinum toxin substrate 1 (Rac1) and enhances LIM domain kinase (LIMK) phosphorylation in the hippocampal CA3 region, which is crucial for dendritic spine formation and synaptic plasticity (Lu et al., 2019). The activation of cAMP promotes neurogenesis and synaptic plasticity, improving anhedonia (Chen et al., 2018). Zhang et al. pointed out that baicalin increases cAMP levels in the dentate gyrus of the hippocampus, activates protein kinase A (PKA), subsequently phosphorylates CREB, enhancing its transcriptional activity, thereby regulating mood and cognitive functions (Zhang et al., 2018b). In summary, baicalin on inflammatory responses, oxidative stress, regulation of the HPA axis and modulation of neuroplasticity via HMGB1/TLR4/NF-κB, PI3K/Akt/FoxO1, GSK3β/NF-κB/NLRP3, TLR4/NF-κB/NLRP3, Akt/FOXG1, Wnt/β-catenin, Rac1/LIMK/Cofilin, and cAMP/PKA pathways.

Figure 9. Mechanism of action of baicalin.

The management of depression has become a significant global public health issue (Mohamed Ibrahim et al., 2020). Currently, the single-drug efficacy of commonly used antidepressants like SSRIs and SNRIs is often inadequate, leading to patient disappointment in treatment outcomes (Fagiolini et al., 2021). Clinicians may attempt dose escalation or combination therapies to improve efficacy, which can lead to unnecessary side effects, particularly affecting cardiovascular, nervous, or mental health (e.g., increased suicide risk, serotonin syndrome, arrhythmias, and liver damage) (Liu et al., 2017; Papakostas et al., 2018). Therefore, there is an urgent need to develop new antidepressant drugs that can achieve significant therapeutic effects in the short term with fewer side effects. Baicalein, a traditional herbal medicine, offers multitarget properties, accessibility, and high safety compared to conventional Western medications (Munjal et al., 2024). However, no Chinese herbal extracts have been marketed for formal promotion as antidepressant drugs. The research on baicalin in treating depression remains at the stage of animal experiments. To advance baicalin as a novel drug for clinical depression treatment, it is crucial to validate its efficacy in animal models. Thus, this article aims to comprehensively assess and meta-analyze the efficacy of baicalin in depression animal models to clarify its potential value in depression treatment and promote its further application in clinical practice.

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