Abstract
Depression is clinically defined as a mood disorder with persistent feeling of sadness, despair, fatigue, and loss of interest. The pathophysiology of depression is tightly regulated by the biosynthesis, transport and signaling of neurotransmitters [e.g., serotonin, norepinephrine, dopamine, or γ-aminobutyric acid (GABA)] in the central nervous system. The existing antidepressant drugs mainly target the dysfunctions of various neurotransmitters, while the efficacy of antidepressant therapeutics is undermined by different adverse side-effects. The present review aimed to dissect the molecular mechanisms underlying the antidepressant activities of herbal medicines toward the development of effective and safe antidepressant drugs. Our strategy involved comprehensive review and network pharmacology analysis for the active compounds and associated target proteins. As results, 45 different antidepressant herbal medicines were identified from various in vivo and in vitro studies. The antidepressant mechanisms might involve multiple signaling pathways that regulate neurotransmitters, neurogenesis, anti-inflammation, antioxidation, endocrine, and microbiota. Importantly, herbal medicines could modulate broader spectrum of the cellular pathways and processes to attenuate depression and avoid the side-effects of synthetic antidepressant drugs. The present review not only recognized the antidepressant potential of herbal medicines but also provided molecular insights for the development of novel antidepressant drugs.
1 Introduction
Depression is a common mental disease that seriously affects 5% of adults worldwide, especially postpartum women (1, 2). Diagnostic and statistical manual of mental disorders (DSM-5) divides depression disorder into eight categories: disruptive mood dysregulation disorder, major depressive disorder (including major depressive episode), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder (3). Patients with depression usually suffer from symptoms such as depressed mood, anxiety, loss of interest, lack of energy, pessimism, disappointment, self-denial and even suicidal thoughts, while 41% of depressed mothers may intend to harm their babies (4). Depression not only represents an ongoing medical challenge but also has emerged as a financial burden for global healthcare systems, for example, annual cost of nearly $210.5 billion in the United States (5). The existing treatments mainly alleviate depressive symptoms so that the remission rate is less than 60% (6). Most of antidepressant drugs cause different apparent adverse side-effects, resulting in the average withdrawal incidence rate of 56% (7, 8). Depression is well-known to be a multifactorial mental disease and exhibit various symptoms including sadness, anxiety, anger and irritability. Synthetic antidepressants are challenged by efficacy and severe side effects. Current first-line antidepressants like SSRIs and SNRIs are designed to specifically target the actions of serotonin and noradrenaline so that SSRIs and SNRIs may not be effective against depression as the result of multiple other causes (9). Thus, single-target therapies may fail in the treatment of multifactorial disease.
Nevertheless, 2.39–40% of patients in different countries and regions alternatively used herbal medicines (10–13). Encouragingly, traditional Chinese medicine (TCM) has achieved the effective use of herbal medicines to treat depression over thousands of years (14). Therefore, herbal medicines may serve as a rich source for the development of novel antidepressant therapies. These results stimulated us to examine the current understanding on the pathology of depression, the pharmacology of the existing antidepressant drugs and the antidepressant activity of herbal medicines toward the development of novel effective and safe antidepressant drugs.
2 Current understanding of depression
The causes of depression are complex, including genetic conditions, endocrine, mental state, living habits, and health status (15–17). Although the pathogenesis is complicated and remains elusive, several hypothesis/theories have been proposed to explain clinical manifestations from different perspectives. The pathology of depression was summarized in Figure 1 and elaborated as follows:
FIGURE 1
Pathology of depression. 5-HT, 5-hydroxytryptamine; DA, dopamine; NE, norepinephrine; GABA, gamma-aminobutyric acid; BDNF, brain derived neurotrophic factor; NGF, nerve growth factor; MDA, malondialdehyde; SOD, superoxide dismutase; CRH, corticotropin-releasing hormone; TRH, thyrotropin-releasing hormone; GnRH, gonadotropin-releasing hormone; ACTH, adrenocorticotropic hormone; TSH, thyroid stimulating hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; HPA, hypothalamus-pituitary-adrenal; HPT, hypothalamic-pituitary-thyroid; HPG, hypothalamic–pituitary–gonadal.
2.1 Monoamine hypothesis
Joseph J. Schildkraut proposed monoamine hypothesis as early as in 1965. The monoamine hypothesis describes that depression is resulted from the abnormal transmission of monoamine neurotransmitters, including synaptic deprivation of monoamine neurotransmitters, and dysfunctions of monoamine transporter and receptors (18, 19). Monoamine theory guided scientists to develop a number of antidepressant drugs including monoamine oxidase inhibitor isoniazid isopropylhydrazide although the drug was originally used to tuberculosis (6). Indeed, 80% of the antidepressant drugs that were approved by the United States Food and Drug Administration (FDA) target monoamine transmitter systems (20). The therapeutic effects of such drugs somehow approved monoamine hypothesis. The tricyclic drug tianeptine is known to promote serotonin reuptake and exhibit similar antidepressant effect as selective serotonin reuptake inhibitor (SSRI). However, some patients feel worse after taking tianeptine (21). Such clinical phenomena challenged monoamine hypothesis. The changes in monoamine levels appear to be the consequences other than the causes of depression.
2.2 Glutamatergic hypothesis and GABAergic deficit hypothesis
Glutamate is an excitatory amino acid that plays an essential role in cognitive functions such as learning and memory. Clinical studies observed a higher level of plasma glutamate in patients with depression (22). Indeed, N-methyl-D-aspartate receptor (NMDA-R) antagonists showed the potency of relieving depression symptoms (23). Thus, the glutamate hypothesis was proposed to highlight the elevation of glutamate between synapses as the causes of mental and emotional disorders. Accordingly, plasma glutamate level of patients is positively correlated with the severity of the disease (24). The inhibition of glutamate receptors became a therapeutic target for the development of novel antidepressant drugs. Interestingly, glutamate supplement exhibited antidepressant effects in some cases (25).
On the other hand, γ-aminobutyric acid (GABA) is synthesized from glutamate. Unlike glutamate, GABA is an inhibitory neurotransmitter. Under physiological conditions, the excitatory glutamate and the inhibitory GABA form a balance in the brains. GABA prevents the neurotoxicity of excess glutamate and termination of stress response (26). Depression patients and animal models suffered from the decreased levels of GABA and GABA-A receptor expression. Brexanolone alleviated postpartum depression by increasing GABA level and motivating the GABA-A receptor, suggesting the GABAergic deficit hypothesis (27, 28). Thus, depression may be caused by different pathological changes while the excitatory-inhibitory imbalance should be the common cause.
2.3 Hormone dysregulation
Hypothalamic-pituitary-adrenal (HPA) axis mainly regulates stress response. Under negative emotions or stress, HPA axis remains active. The hypersecretion of cortisol (corticosterone in rodents) causes neuronal damage and structural disturbances in the hippocampus, resulting in depression symptoms (29). Down-regulation of receptor induces the weakening of negative feedback while aggravates HPA axis excitement, forming a vicious circle. Similarly, the depression process involves other hormone systems, such as hypothalamic-pituitary-gonadal (HPG) axis and hypothalamic–pituitary–thyroid (HPT) axis.
Two third of depression patients are female, largely due to the frequent fluctuation of sex hormones in addition to environmental and genetic factors (3, 30). Both aging men and women are prone to mood disorders with the change of corresponding sex hormone levels, but exhibit different clinical outcomes (31). Females respond to stress in more sensitive manner than males as the sex hormones decline (32). Possibly due to the more influential role of estrogen in mood regulation, women usually become emotionally fragile during the low-estrogen period (33). Estrogen not only modulates cognition and emotion in the brain, but also exhibits neuroprotective effect (33, 34). Surprisingly, males with higher estrogen level tend to suffer from depression (35). Thus, caution is needed to address hormone dysregulation in depression in both sexes.
Stress is known to increase cortisol level and subsequently decrease the release of thyroid stimulating hormone (TSH) (36). Patients with bipolar II depression and anxiety disorder exhibit a lower TSH level and less response to thyrotropin-releasing hormone (TRH), while emotion also influences thyroid hormones (37, 38). People with thyroid disease are commonly associated with mood disorders (39, 40). Hyperthyroidism induces anxiety and irritability, whereas hypothyroidism causes depression. Consequently, thyroid supplementation may be used in the clinical treatment of depression (41).
2.4 Neurogenesis and neuroplasticity hypothesis
Depression is an emotional disease and may show signs at the cell and organ levels. Neuroanatomy studies revealed that hippocampus volume appeared to be reduced in the brains of depression patients (42). Bipolar patients was found to have less gray matter volume (43). Such changes may be caused by the decline of neurotrophic factors, such as brain-derived neurotropic factor (BDNF), nerve growth factor (NGF), and glia-derived neurotropic factor (GDNF) (44).
2.5 Miscellaneous theories
Scientists proposed several other conjectures of depression including inflammation theory, gut microbiota theory, glial pathology theory, epigenetic theory, infection theory, and “dys-stress” theory (45, 46). These theories together provided a comprehensive perspectivity to explain the depression mechanisms.
2.6 Current antidepressants and limitations
FDA-approved antidepressant drugs for adults are divided into seven categories: selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants (TCAs and TeCAs), atypical antidepressants, monoamine oxidase inhibitors (MAOIs), N-methyl D-aspartate (NMDA) antagonist, neuroactive steroid, gamma-aminobutyric acid (GABA)-A receptor positive modulator (20). TCAs and MAOIs belong to the first generation of antidepressants with relatively strong short-term efficacy and low price (47). However, due to the severe side effects, these drugs are not considered the first choice for treating depression. SSRIs and SNRIs are considered as the first-line medications in clinical practice although side effects exist (9).
Most of synthetic antidepressant drugs are known to frequently cause severe side effects and exhibit symptoms including dizziness, nausea, weight change, sexual dysfunction, and apathy (48). The classification and common side effects of antidepressants are shown in the Table 1.
TABLE 1
| Class | Brand name | Generic name | Known targets | Side effects |
| SSRIs | Celexa | Citalopram | SLC6A4 inhibitor | Nausea, tremor, nervousness, problems sleeping, sexual problems, sweating, agitation, feeling tired |
| Lexapro | Escitalopram | SLC6A4 inhibitor | ||
| Luvox | Fluvoxamine* | SLC6A4 inhibitor | ||
| Paxil Paxil CR Pexeva | Paroxetine | SLC6A4 inhibitor | ||
| Prozac | Fluoxetine | SLC6A4 inhibitor | ||
| Trintellix | Vortioxetine | SLC6A4 inhibitor; HTR1A agonist; HTR3A, HTR7 antagonist; HTR1B partial agonist | ||
| Viibryd | Vilazodone | SLC6A4 inhibitor; HTR1A agonist | ||
| Zoloft | Sertraline | SLC6A4 inhibitor | ||
| SNRIs | Cymbalta | Duloxetine | SLC6A4, SLC6A2 inhibitor | Nausea, vomiting, dry mouth, constipation, fatigue, feeling drowsy, dizziness, sweating, sexual problems |
| Effexor Effexor XR | Venlafaxine | SLC6A4, SLC6A2 inhibitor | ||
| Fetzima | Levomilnacipran | SLC6A4, SLC6A2 inhibitor | ||
| Pristiq Khedezla | Desvenlafaxine | SLC6A4, SLC6A2 inhibitor | ||
| TCAs and TeCAs | Asendin | Amoxapine | SLC6A4, SLC6A2 inhibitor | Dry mouth, constipation, blurred vision, drowsiness, low blood pressure |
| Elavil | Amitriptyline | SLC6A4, SLC6A2 inhibitor; HTR2A antagonist | ||
| Ludiomil | Maprotiline* | SLC6A2 inhibitor | ||
| Norpramin | Desipramine | SLC6A4, SLC6A2 inhibitor; HTR2A antagonist | ||
| Pamelor | Nortriptyline | SLC6A4, SLC6A2 inhibitor; HTR2A antagonist | ||
| Sinequan | Doxepin | HRH1, HRH2 antagonist; SLC6A4, SLC6A2 inhibitor | ||
| Surmontil | Trimipramine | SLC6A4, SLC6A2 inhibitor | ||
| Tofranil | Imipramine | SLC6A4, SLC6A2 inhibitor | ||
| Vivactil | Protriptyline | SLC6A4, SLC6A2 inhibitor | ||
| Atypical antidepressants | Desyrel | Trazodone | SLC6A4 inhibitor; HTR1A antagonist and partial agonist; HTR2A antagonist; HTR2C agonist | Dry mouth, dizziness, blurred vision, feeling drowsy or sleepy, constipation feeling drowsy or sleepy, weight gain, dizziness, constipation, nausea, vomiting, blurred vision |
| Serzone | Nefazodone | SLC6A4, SLC6A2 inhibitor; HTR1A, HTR2A, HTR2C antagonist; ADRA1 | ||
| Remeron | Mirtazapine | HTR2A, 5HT3, ADRA2A antagonist | ||
| Wellbutrin Wellbutrin SR Wellbutrin XL | Bupropion | SLC6A3, SLC6A2 inhibitor | ||
| MAOIs | Amira Aurorix | Moclobemide* | MAOA antagonist and inhibitor | Nausea, dry mouth, constipation, diarrhea, insomnia, dizziness, anxiety, restlessness nausea, restlessness, problems sleeping, dizziness, drowsiness |
| Emsam (skin patch) | Selegiline | MAOB inhibitor | ||
| Marplan | Isocarboxazid | MAOA, MAOB inhibitor | ||
| Nardil | Phenelzine | MAOA, MAOB antagonist | ||
| Parnate | Tranylcypromine | MAOA, MAOB inhibitor | ||
| NMDA antagonist | Spravato (nasal spray) | Esketamine | NMDAR | Dissociation, dizziness, nausea, sleepiness, spinning sensation, decreased feeling or sensitivity, anxiety |
| GABA-A receptor positive modulator | Zulresso (intravenous infusion) | Brexanolone | GABR | Sedation (tiredness), dry mouth, loss of consciousness, flushing |
Molecular targets and side effects of synthetic antidepressant drugs.
Information comes from FDA, Drugbank, KEGG. *Fluvoxamine: Also used to treat COVID-19; maprotiline: TeCAs, others in this class are TCAs; moclobemide: Didn’t been approved by FDA yet.
Indeed, the existing antidepressants are limited by different other factors including efficacy, patient compliance, withdrawal reaction and recurrence. As for efficacy, antidepressants often need at least 2 weeks to take effect (49). Many patients may feel the improvement of symptoms after taking medication but are not satisfactory with the overall effect while some patients may be getting even worse (6, 50). As for patient compliance, compliance with antidepressants is extremely poor. Quite a portion of patients are unwilling to follow antidepressant treatment (51). The fear of side effects is a key reason for poor compliance. As for the withdrawal reaction, more than half of the patients experience withdrawal symptoms, including gastrointestinal symptoms, flu-like symptoms, sleep disorders, sensory disorders, movement disorders, and emotional disorders (8). Some patients may have severe symptoms. Finally, the recurrence is also an important problem. Patients may be considered as fully cured by antidepressant treatment but more likely have depression again than normal people (52). Indeed, a quarter of patients relapse depression (53). Therefore, there is a strong need for other complementary or alternative therapies. It is believed that herbal remedies possess better potential than different physiotherapies and psychotherapies.
3 Herbal medicines for the treatment of depression
Herbal ingredients are often used in combination. Presumably, different ingredients may act on several mechanisms in a coordinated manner. For example, hypericin, hyperforin, and eriodictyol may contribute to the antidepressant effects of Hypericum perforatum L. by targeting different mechanisms (54–57). On the other hand, some ingredients may act on more than one target. For example, puerarin not only acts on the 5-HT system and neurotransmitters but also regulates antioxidant and anti-inflammatory pathways, remodels gut microbiota, and modulates the HPA-axis (58–64). In this review, major ingredients and the related antidepressant mechanisms were searched from the recent literatures via PubMed and Google Scholar and summarized in Table 2 and Figure 2. In fact, different active compounds might act on one or several target proteins involved in the regulation of neurotransmitter function, HPA axis, BDNF signaling pathway, anti-inflammatory response, oxidative stress, intestinal microbiota and ferroptosis.
TABLE 2
| Herbal source | Active constituents | Model | Depression model | Administration | Mechanism of action | References |
| Acori tatarinowii Rhizoma | α-asarone; β-asarone | Primary astrocytes from rat | N/A | 15, 30, 50 μM | Increase synthesis and release of neurotrophic factors (NGF, BDNF, and GDNF) | (121) |
| α-asarone | Adult male, Institute of Cancer Research (ICR) mice of age 8–10 weeks | AMPT (100 mg/kg, i.p., a catecholamine synthesis inhibitor) | 20 mg/kg, i.p. (4 h after AMPT administration) | modulate α1 and α2 adrenoceptors, 5-HT1A receptors | (122) | |
| Albizia julibrissin flower | SAG; SBG lignan glycosides | HeLa cells | N/A | 10 μM SAG or 16 μM SBG | Non-competitively inhibit serotonin transporter | (123) |
| SAG | 8-week-old male Sprague-Dawley (SD) rats | Acute restraint-stressed | 3.6 mg/kg, 7 days, p.o. | Modulate HPA axis and monoaminergic systems | (124) | |
| Alpinia officinarum Hance | Hydroalcoholic extract | Male BALB/c mice | Daily chronic unpredictable stress (CUS), 3 weeks | 50 and 100 mg/kg/day, 21 days, i.p. | Antioxidation | (125) |
| Galangin | In vitro enzyme inhibition and binding test | Inhibit MAO-A and MAO-B | (126) | |||
| Angelica sinensis (Oliv.) Diels | 75% ethanol extract | Male SD rats (weighing 180 ± 20 g) | Chronic unpredictable mild stress (CUMS), 3 weeks | 3.6 and 7.2 g/kg. | Modulating the hematological anomalies | (127) |
| 75% ethanol extract | Male SD rats weighing 140–160 g | Chronic unpredictable mild stress (CUMS), 5 weeks | 1 g/kg | Activating the BDNF signaling pathway (BDNF-ERK 1/2-CREB) and upregulating the hippocampal BDNF, p-ERK 1/2 and CREB expression. | (128) | |
| Z-ligustilide | Male SD rats (weight, 160–200 g; age, 7 weeks) | CUMS 35 days | 20 and 40 mg/kg, 12 days, i.p. | Upregulate progesterone and allopregnanolone | (129) | |
| Apocynum venetum L. | Apocynum venetum leaf extract | Adult male Wistar rats (42 days old) weighing 180–220 g | CUMS, 8 weeks | 30, 60, and 125 mg/kg, 4 weeks, i.g. | Antioxidation, reduced hippocampal neuronal apoptosis, and enhanced hippocampal BDNF levels | (130) |
| Astragalus | Astragaloside IV | Male ICR mice, weighing 23–26 g | Repeated restraint stress (RRS)-induced mice, 9 days | 16, 32, and 64 mg/kg/d, 12 days, i.g. | Anti-inflammation (via PPARγ/NF-κB/NLRP3 inflammasome axis) | (131) |
| Lipopolysaccharide (LPS)-induced mice, 1 mg⋅kg-1⋅d-1, i.p., 2 days | 20, 40 mg/kg/d, 14 days, i.p. | |||||
| Atractylodes macrocephala Koidz. | Atractylenolide III | Male SD rats (weighing 260–280 g on arrival) | CUMS, 28 days | 3, 10, and 30 mg/kg, 14 days, p.o. | Anti-inflammation | (132) |
| Camellia sinensis | L-Theanine | Patients with MDD (four males; mean age: 41.0 ± 14.1 years, 16 females; 42.9 ± 12.0 years) | 250 mg/day, 8 weeks | Blocking glutamate receptor | (80) | |
| Capsicum annuum L. (Chili pepper) | Capsaicin | Four-week-old male C57BL/6J mice (bodyweight: 16–18 g) | 0.052/0.104/0.208/0.415/ 0.83 mg/kg LPS, 5 days, i.p. | 0.005% capsaicin in standard laboratory chow plus, 4 months | Regulation of 5-HT and TNF-α; remodeling gut microbiota | (133) |
| Centella asiatica (L.) Urban | Triterpenes | Male albino Wistar rats, aged 8–10 weeks and weighing 180–220 g | CUMS 8 weeks | Extraction 400 and 800 mg/kg, 8 weeks, p.o. | Upregulation of 5-HT, NE, and DA; regulation of HPA-axis | (134) |
| Acori tatarinowii Rhizoma | α-asarone; β-asarone | Primary astrocytes from rat | N/A | 15, 30, 50 μM | Increase synthesis and release of neurotrophic factors (NGF, BDNF, and GDNF) | (121) |
| Chelidonii herba | Chelidonic acid | Male ICR mice (3 weeks old, 10–12 g) | N/A | 0.02, 0.2, and 2 mg/kg, 14 days, p.o. | Upregulation of hippocampal 5-HT, dopamine, NE, and BDNF; anti-inflammation | (135) |
| Citrus unshiu | Peel extract | Male ICR mice (9-week-old, weighing 20–25 g) | Dexamethasone 40 mg/kg, 7 days, i.p. | 30, 100, and 300 mg/kg, 14 days, p.o. | Modulate BDNF/TrkB/CREB signaling | (135) |
| SH-SY5Y cells | dexamethasone 200 μM | 10, 50, or 100 μg/mL | ||||
| Cornus officinalis (Cornus) | Loganin | Adult male Wistar rats, weighing 200–250 g | Depression and anxiety-like diabetic rats | 40 mg/kg, 10 days, p.o. | Anti-inflammation | (136) |
| Cornusfural B | PC12 cells | 500 μM corticosterone, 24 h | 10 μM, 24 h | Neuroprotective effects | (137) | |
| Morroniside | SD rats (220 ± 10 g, 7 weeks old) | immobilization stress, 14 days | Extract 100 mg/kg, 14 days, i.g. | Antioxidation (Blocked the MAPK/COX-2 Signaling Pathways in Rat Hippocampus) | (138) | |
| SH-SY5Y cells | 300 μM H2O2, 24 h | Extract 20, 50, and 100 μg/mL, pretreat 2 h | Alleviated H2O2-Induced Apoptosis; enhance SOD, CAT, BDNF expression | |||
| Crocus sativus L. (Saffron) | Crocin | Male Balb/cJ mice (18–24 g, 8–10 weeks of age) | CUMS, 7 weeks | 30 mg/kg, 4 weeks, i.g. | Modulate HPA-axis, | (139) |
| PC12 cells | CORT (200 μM), 24 h | 12.5, 25, and 50 μM, pretreat 1 h | Upregulation of pituitary adenylate cyclase-activating polypeptide (PACAP) expression and phosphorylation of CREB and ERK | |||
| Six-week-old male C57BL/6 J mice | Chronic restraint stress (CRS)-induced | 40 mg/kg, 6 weeks, p.o. | Modulate gut microbiota composition; reduced low-grade inflammation in the colon; reverse the decrease of fecal short-chain fatty acids (SCFAs) | (140) | ||
| Six-week-old male C57BL/6 J mice | Corticosterone 20 mg/kg, 4 weeks, s.c. | 20 and 40 mg/kg, 2 weeks, i.g. | Antioxidation (stimulate SIRT3 pathway); anti-inflammation | (141) | ||
| Curcuma longa L. | Curcumin | Male SD rats (180–220 g) | CUMS 28 days | 100 mg/kg/d, 28 days, i.g. | Antioxidation (via Nrf2-ARE signaling pathway) | (103) |
| SD rats (male, weight: 180–220 g, age: 40–45 day) | CUMS 6 weeks | 100 mg/kg/d, 6 weeks, i.g. | Modulate PGC-1α/FNDC5/BDNF signaling pathway | (142) | ||
| Cyperus rotundus L. | α-cyperone | Male adult C57BL/6 mice | CUMS 5 weeks | 5 and 10 mg/kg, 5 weeks, i.g. | Enhance neuroplasticity (via SIRT3/ROS/NF-κB pathway); suppressing NLRP3 inflammasome | (143) |
| Epimedii Herba | Icariin; icaritin | Male, 7-week-old C57 BL/6J mice | Social defeat (SD) stress 10 days | 20 mg/kg, 4 weeks, p.o. | Anti-inflammation; regulation of BDNF: suppressing HMGB1-RAGE signaling, activating TLR4-NF-κB signaling | (144) |
| Fraxinus rhynchophylla | Esculin; esculetin; fraxin | Seven-week-old male c57BL/6 mice | Reserpine 0.5 mg/kg, 10 days, i.p. | 50 mg/kg, 10 days, p.o. | Anti-inflammation; upregulate pCREB/BDNF expression | (145) |
| Fructus arctii | Arctigenin | Adult male C57BL/6 (WT B6) mice (8–10 weeks old, 18–22 g) | CUMS 6 weeks | 25, 50, or 100 mg⋅kg | Anti-inflammation (via HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signaling pathways); decrease neuronal apoptosis; increase serum levels of 5-HT and dopamine | (146) |
| Arctiin | Male C57BL/6 mice (18–22 g weight, 9 weeks old) | CUMS 8 weeks | 25, 50 mg/kg, 4 weeks, i.g. | (147) | ||
| Morus macroura Miq. (Mulberry) | Ethanol extracts | Male rats | Post-myocardial infarction (MI) depression | 200 mg/kg, 21 days, p.o. | Antioxidation; increase serotonin, dopamine, GABA, and ATP brain levels | (148) |
| Ganoderma | Polysaccharides | Male C57BL/6 mice 7–8 weeks old | Chronic social defeat stress (CSDS), 10 days | 1 mg/kg, 5 mg/kg, and 12.5 mg/kg, 6 days | Mediate Dectin-1 receptors; enhanced AMPA receptor synaptic plasticity; anti-inflammation | (149) |
| Ganoderic acid A | The SD rats (male; 240–260 g) | post-Stroke depression (CUMS 3 weeks) | 10, 20, and 30 mg/mL, i.v. | Anti-inflammation (via the ERK/CREB pathway) | (150) | |
| Hedyotis corymbosa | Ethanol extracts | SD rats (male; body weight—250–275 g) | Olfactory bulbectomy induced depression | 50, 100, and 200 mg/kg, 14 days, p.o. | Upregulation of BDNF; regulation of HPA-axis; upregulation of 5-HT | (151) |
| Hericium erinaceus | Erinacine A | Male ICR mice weighing 20–25 g | Restraint stress 4 weeks | Extract 100, 200, and 400 mg/kg, 4 weeks, p.o. | Increase BDNF expression (via PI3K/Akt/GSK-3β pathway) | (152) |
| Ethanol extract | PC-12 cells | 400 μM corticosterone 24 h | 0.125, 0.25, 0.5, and 1 mg/ml | Antioxidation | (153) | |
| Hypericum perforatum L. | Hypericin | Female SD rats, 180–220 g | Postpartum depression | 6.12 mg/kg, 42 days, i.g. | Anti-inflammation; up-regulate the estrogen receptor (ER) expression; reduce the level of CORT (via reversing the activity of 11β-HSD2 enzyme) | (154) |
| Hyperforin | Male C57BL/6 J mice (7 weeks old) | CUMS 8 weeks | 2.5 and 5 mg/kg, 45 days, i.p. | Regulate BDNF pathway and zinc homeostasis | (56) | |
| Eriodictyol | Male SD rats weighting 240–260 g | LPS 1 mg/kg, 2 days, i.p. | 10, 30, and 100 mg/kg, 28 days, i.g. | Anti-inflammation; anti-oxidation (via Nrf2/HO-1 axis) | (102) | |
| CUMS 28 days | ||||||
| Lavandula angustifolia Mill (Lavender) | Essential oil | Male SD rats weighing 240–260 g (6–7 weeks of age) | 40 mg/kg corticosterone, 14 days, s.c. | Exposed to a cotton saturated with 2.5% LEO, 14 days | Upregulation of BDNF and oxytocin | (155) |
| Leonurus japonicus Houtt | Leonurine | Male C57BL/6 (8–10 weeks) mice with a body weight of 18–22 g | Chronic mild stress (CMS) 10 weeks | 30 and 60 mg/kg, 4 weeks, i.g. | Improvement of monoamine neurotransmitters (5-HT, NE, and DA); anti-inflammation | (156) |
| PC12 cells | 300 μM CORT 24 h | 10, 20, 40, 60, 80, and 100 μM, pretreat 2 h | Neuroprotective effects (via GR/SGK1 signaling pathway) | (157) | ||
| Magnolia officinalis | Honokiol | Male SD rats, weighing 200–220 g | CUMS 28 days | 10 mg/kg Honokiol, 21 days, i.g. | Regulate HIF-1α-VEGF signaling pathway, VEGFR-2-mediated PI3K/AKT/mTOR signaling pathway | (158) |
| PC 12 | N/A | 2, 5, 8, 10, and 16 μM, 24 h/48 h | Regulate HIF-1α-VEGF signaling pathway | |||
| Magnolol | Female C57BL/6J mice (18–22 g) | CUMS 7 weeks | 50 and 100 mg/kg, 3 weeks, i.g. | Inhibit M1 microglia polarization and promoted M2 microglia polarization via Nrf2/HO-1/NLRP3 signaling | (159) | |
| BV2 cells | LPS (1 μg/ml) + ATP (20 μM) 24 h | (5, 10, and 20 μM) 2 h prior | ||||
| Morinda officinalis | Fructooligosaccharides | Male SD rats (160 ± 20 g, 6-week-old) | CUMS 7 weeks | 50 mg/kg, 3 weeks, i.g. | Remodel gut microbiota; decrease urine and plasma corticosterone | (160) |
| Monodora myristica (Gaertn.) | Essential oils | Male Wistar rats (150–180 g) | CUMS 5 weeks | 150 and 300 mg/kg, 5 weeks, p.o. | Decrease serum CORT and brain MAO-A levels | (161) |
| Nelumbinis semen | Neferine | C57BL/6J mice (6-week-old, male) | CUMS 8 weeks | 20 mg/kg, 4 weeks, i.p. | Remodeling gut microbiota | (162) |
| Paeonia lactiflora Pall. | Albiflorin | Male SD rats (180–200 g) | CUMS 8 weeks | 7 and 14 mg/kg, 14 days, p.o. | Remodel gut microbiota; inhibit D-amino acid oxidase | (163) |
| Male ICR mice (18–22 g) | 4 mg/kg reserpine, i.p. | 7 and 14 mg/kg, 7 days, p.o. | ||||
| Paeoniflorin | Male C57BL/6 J mice weighted at 19–23 g at 6–9 weeks | CRS 5 weeks | 10, 30, and 60 mg/kg, 5 weeks, i.p. | Affect the ERK1/2 pathway | (164) | |
| Panax ginseng C. A. Mey. | Ginsenoside Rg1 | Male SD rats (weight: 200–250 g) | CRS 28 days | 20 mg/kg, 28 days, i.g. | Regulate GAS5/EZH2/SOCS3/NRF2 Axis | (165) |
| Ginsenoside Rb1 | CD1 (12 months old, male) and C57BL/6J (7–8 weeks old, male) mice | CSDS 28 days | 35 and 70 mg/kg, 28 days, i.g. | Regulate BDNF–TrkB signaling pathway | (166) | |
| Perilla frutescens | Volatile oil | Female SD rats (180–200 g) | Menopausal depression (ovariectomy + CUMS 14 days) | 10.8, 32.4, and 97.2 mg/kg, 14 days, i.g. | Regulate metabolites | (167) |
| Platycodins folium | Extract | Adult male ICR mice, weighing 20 ± 2 g | LPS (0.83 mg/kg), 24 h, i.p. | 100, 200, and 400 mg/kg, 7 days, i.g. | Regulation of several metabolic pathways | (168) |
| Rhizoma polygonati | Polysaccharide | Male C57BL/6 mice (3 months old, 20–25 g) | LPS (2 mg/kg), 24 h, i.p. | 100, 200, and 400 mg/kg, 10 days, i.g. | Anti-inflammation; reduce ROS/HPA axis hyperfunction | (169) |
| CUMS 35 days | 400 mg/kg, 35 days, i.g. | |||||
| Pueraria Lobelia | Puerarin | SD rats (male, 200 ± 20 g) | CUS 28 days | 30, 60, and 120 mg/kg, 10 days | Regulate monoamine neurotransmitter; regulate HPA-axis; regulate HPG-axis | (60) |
| male C57BL/6N mice (7–8 weeks, 18–25 g) | LPS (0.083 mg/kg) 24 h | 30, 60, and 120 mg/kg, 25 h, i.g. | Anti-inflammation; inhibited the RagA/mTOR/p70S6K pathway | (63) | ||
| Highly Differentiated PC12 Cell | LPS (200 ng/ml) 24 h | 10, 25, and 50 μM, 24 h | ||||
| Male SD rats (160–180 g) | High-fat diet (HFD)/CUMS 11 weeks | 30, 60, and 120 mg/kg, 7 days | Inhibit TLR4-associated inflammatory responses | (64) | ||
| Radix Bupleuri | Saikosaponin A | Female Wistar rats (36-week old and 350–370 g weight) | CUMS 8 weeks | 25, 50, or 100 mg/kg, 4 weeks, p.o. | Up-regulation of the BDNF-TrkB signaling pathway; anti-inflammation; regulation of HPA-axis | (170) |
| Saikosaponin-d | Male ICR mice, 5 weeks old, weighing 20–22 g | LPS with increasing dose (0.052/0.104/0.208/0.415/ 0.83 mg/kg), 4 days, i.p. | 0.5 and 1 mg/kg, 2 weeks, i.g. | Mitigate LPA1-mediated neuronal apoptosis; attenuate LPS-induced activation of RhoA/MAPK/NFκB signaling pathway | (171) | |
| SH-SY5Y | LPA (4 μM)/LPS (1 μg/ml) | 0.5, 1, and 2 μM) | ||||
| Rehmannia glutinosa | Catalpol | Adult male Kunming mice (weighing 18–22 g, 3–4 weeks old) | Depressive-like behavior of STZ (streptozocin)-induced hyperglycemia models | 5, 10, and 20 mg/kg, 21 days, i.g. | Antioxidation (via PI3K/AKT/Nrf2/HO-1 signaling pathway) | (172) |
| Rhubarb | Emodin | 8-week-old male SD rats | CUMS 7 weeks | 80 mg/kg, i.g. | Anti-inflammation (targeting miR-139-5p/5-LO) | (173) |
| Salvia miltiorrhiza | Cryptotanshinone | Male C57BL/6 mice (8 weeks, 20–25 g) | CUS 14 days | 20 mg/kg, 14 days, i.g. | Anti-inflammation (via NF-κB signaling pathway); restore hippocampal neurogenesis (via BDNF/TrkB pathway) | (174) |
| Santalum album seeds | Extract | Ten weeks old Male Swiss mice weighing 20 to 25 g | Cecal ligation and puncture (CLP) model | 100 and 200 mg/kg, 24 h | Antioxidation | (175) |
| Schisandra chinensis Fructus | Schisantherin A | Male ICR mice, weighing 20 ± 2 g | N/A | 1.75, 3.5, and 7 mg/kg, 7 days, i.g. | Regulate GABA/Glu system | (176) |
| Schisantherin B | Male KM mice, 10-week old (20–25 g) and 11-month old (50–60 g) | Acute stress (FST) | 15 mg/kg, 10 days, i.p. | Promote PI3K/AKT/mTOR pathway | (177) | |
| Gomisin A | N9 microglial cells | LPS (1 μg/ml) 24 h | 1, 3, 10, 30, and 100 μM, pretreat 2 h | Inhibit TAK1-IKKα/β-IκB-NF-κB and MAPKs inflammatory signaling pathways; anti-oxidation | (178) | |
| Gomisin N | Seven-week-old male ddY mice | LPS 500 μg/kg, 24 h, i.p. | 100 mg/kg, 25 h, p.o. | Anti-inflammation | (179) | |
| BV2 cells | LPS 0.1 μg/mL, 6 h | 1.6–50 μM, 7 h | ||||
| Scutellaria baicalensis Georgi | Decoction (contain baicalin, baicalein, wogonoside, and wogonin) | Male SD rats (190–220 g) | CUMS 6 weeks | 500 and 1,000 mg/kg, 3 weeks, i.g. | Regulate CREB and BDNF (via activating cAMP/PKA pathway) | (180) |
| Wogonin; baicalein | N/A | N/A | enzyme assays | Inhibit MAO | (181) | |
| Baicalin | Adult male ICR mice (7–8 weeks, weighing 20–25 g) | CUMS 21 days | 50 and 100 mg/kg, 21 days | Regulating neurogenesis (via Wnt/β-catenin pathway) | (182) | |
| Scutellarin | Male C57BL/6 mice (6–8-week-old) | LPS 0.83 mg/kg, 7th day, i.p | 50 mg/kg, 9 days, i.p. | Anti-inflammation (via TLR4/NF-κB pathway) | (183) | |
| Silybum marianum | Silibinin | Male SD rats (8 weeks old with a body weight of 220–350 g) | Single prolonged stress (SPS) | 25, 50, and 100 mg/kg, 14 days, i.p. | Increase 5-HT synthesis; modulate monoamine levels (DA and NE) | (184) |
| Silymarin | Swiss albino mice weighing 30–35 g (70–80 days old) | CUMS 28 days | 100 and 200 mg/kg, 21 days, p.o. | Modulate HPA axis; antioxidation; anti-inflammation; increasing BDNF expression; modulate monoamines | (184) | |
| Ziziphus jujuba Mill. seeds | Ethanol extract | Male ICR mice (6 weeks old, 30 ± 1 g) | CUMS 31 days | 100 and 300 mg/kg, 28 days, p.o. | Upregulate 5-HT and NE (inhibit MAO-B and AChE); upregulate BDNF | (185) |
Active constituents and molecular targets of herbal medicines.
FIGURE 2
Potential antidepressant mechanism of botanical drugs.
3.1 Regulation of neurotransmitter function
3.1.1 Targeting monoamine neurotransmitters system
Monoamine neurotransmitters include serotonin (5-HT), noradrenaline (NE), and dopamine (DA). 5-HT is an indole neurotransmitter and induces a happy mood in the brain (65). As two types of catecholamines. NE is an excitatory neurotransmitter and alerts people by producing excitement and anger, whereas DA is called the happiness hormone (66). The deficiency of these neurotransmitters results in apathy and the lack of energy. Unlike chemically synthesized antidepressants, herbal medicines may exhibit a broad spectrum of effects on the activity of multiple neurotransmitters. As a key herbal medicine antidepressant, hyperforin derived from St. John’s wort simultaneously inhibits the reabsorption of 5-HT, NE, and DA with similar effectiveness (54). Protopine reduces the reuptake of 5-HT and NE via inhibiting the transporter (67). Apigenin, luteolin, and quercetin from Cayratia japonica inhibit the activities of MAO-A and MAO-B (68). Highly like the current antidepressants, herbal medicines target 5-HT receptors as the main antidepressant mechanism. Puerarin derived from Radix puerariae acts not only as the antagonist for 5-HT2C and 5-HT2A receptors but also as the agonist for 5-HT1A receptor (58, 59).
3.1.2 Targeting GABAergic system
GABA receptors have long been therapeutic targets for anxiety disorders. The current antidepressants improve depression in mice via regulating the GABA system and enhancing the activity of GABAnergic neurons (69). Anxiety and depression often co-exist and influence each other in clinical practice (70). GABA-A receptor positive modulator Zulresso was approved by FDA in 2019 as a treatment for postpartum depression (71). The bark of Magnolia officinalis is well-documented for treating depression in traditional Chinese medicine formulations, while honokiol and magnolol are considered as the active ingredients. Indeed, magnolol treatment reversed the depressive symptoms in rats after chronic unpredictable mild stress (CUMS). Following the treatment, CUMS rats performed equally well in the tests for sucrose preference, locomotor activity, and forced swimming test compared with the rats in the control group, indicating that magnolol may be equally effective as Fluoxetine hydrochloride (72). Honokiol and magnolol positively regulate GABA-A receptors, especially δ-containing receptors (73). It was recently found that GABA-B receptor inhibitors might be potential antidepressant drugs (74). Interestingly, GABA-B1 receptor knockout mice appeared to more anxious than wild breeds. Presumably, GABA-B receptor positive allosteric agents are anxiolytic whereas the antagonists could be antidepressants (75). Nevertheless, both inhibitors and agonists were found to exhibit an antidepressant effect (76).
3.1.3 Targeting L-glutamate signaling pathway
Glutamate receptors include ionotropic and metabotropic forms for rapidly transmitting excitation and widely affecting neural function by coupling with G protein, receptively (77). Depressive symptoms could be relieved by N-methyl-d-aspartate (NMDA) receptor antagonists, group I metabotropic glutamate receptor (mGluR1 and mGluR5) antagonists, and positive modulators of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (78). L-Theanine from Camellia sinensis share similar structure with glutamate and binds to several glutamate receptors, thereby blocking the action of glutamate and reducing glutamate excitotoxicity (79). After treatment for 8 weeks, L-theanine improved depressive symptoms including anxiety, sleep disturbance, and cognitive impairment in MDD patients (80).
3.2 Regulation of HPA-axis
The HPA-axis involves three hormones [i.e., corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol] and mainly mediates stress in the human body (81). As a stress hormone, cortisol affects the levels of neurotransmitters such as 5-HT. Anti-glucocorticoid therapy benefits the brain’s reward mechanisms and alleviates depression (82). Many herbs, such as Scutellaria baicalensis, Phellodendron phellodendri, and Chuanxiong, are known to induce significant reduction of plasma corticosterone levels in depressed mice (83). Based on radiometric ligand-binding assays, icariin could restore the down-regulation of glucocorticoid receptor in social defeat mouse model of depression (84). Several flavonoids (e.g., hypericin, hyperoside, isoquercitrin, and miquelianin) from St. John’s wort significantly reduced the levels of ACTH and corticosterone in rats, and could achieve better effects than imipramine positive control (85).
3.3 Regulation of BDNF signaling pathway
Brain-derived neurotropic factor is known to regulate the growth and function of neuron cells and thereby plays an important role in the regulation of learning and memory (86). Stress reduces the level of BDNF in the brain, leading to atrophy and cell loss in hippocampus and prefrontal cortex, suggesting the link of BDNF with depression (87). Indeed, most of antidepressant drugs could booster the expression of BDNF (88). Peony glycosides from Radix Paeoniae Alba increased the BDNF mRNA level in the brain and improved depressive-behaviors in CUMS-induced mouse model of depression (89). Traditional Chinese medicine formulation PAPZ of four ingredients (i.e., Radix Ginseng, Radix Angelicae Sinensis, Radix Polygalae, and Semen Ziziphi Spinosae) increased the protein expression of BDNF and alleviated the depressive behavior in corticosterone-challenged mice (90). Esculetin from Cichorium intybus L. activated BDNF/TrkB pathway in LPS-depressed mice by increasing BDNF expression (91). BDNF was also found to enhance the function of 5-HT transporter and reduce the level of 5-HT in the synaptic cleft, indicating a need to investigate the cross-talks between different systems (92).
3.4 Regulation of anti-inflammatory response
Depression patients generally show marked increase in pro-inflammatory cytokines (e.g., CRP, IL-3, IL-6, and IL-12) (93). Indeed, anti-inflammatory drugs like celecoxib could effectively relieve the symptoms of depression (94). Many herbal medicines are well-documented for anti-inflammatory properties and potential in the treatment of depression in the inflammatory model of depression (95). Crocus sativus L. (Saffron) is an important medicinal ingredient and also a common spice in North African, Mediterranean, and Middle Eastern countries. As one of the main components, crocin improved depressive symptoms and reduced the expression of inflammatory cytokines (e.g., IL-1β, IL-18, and TNF-α) in the hippocampus of LPS-depressed mice (96). The cellular experiments found that crocin skewed the polarization of glial BV-2 cells from the inflammatory M1 phenotype to the M2 phenotype by inhibiting the NF-kB and NLRP3 signaling pathway (96). Esculetin as a coumarin compound in various plants exhibited strong anti-inflammatory effect, reduced the levels of IL-1β, IL-6, and TNF-α in serum and hippocampus, and down-regulated the hippocampal expression of iNOS and COX-2 in LPS-depressed mice (91). Moreover, BDNF exhibits anti-inflammatory effect, suggesting that the increase in BDNF level also represents an anti-inflammatory mechanism (97).
3.5 Regulation of oxidative stress
Oxidative stress is implicated in various neurodegenerative diseases including AD and PD (98). Depression patients often suffer from cognitive impairment, likely as the result of oxidative stress (99). The antioxidant system is likely disturbed in people with depression (100). Interestingly, 5-HT deficiency appeared to be associated with altered expression of antioxidant enzymes (101). Many herbal medicines are well-known for antioxidative effects and may relieve depression symptoms through antioxidant activity. Eriodictyol is a bitter-masking flavanone, a flavonoid derived from Eriodictyon californicum. Eriodictyol reduced oxidative damage, prevented cell apoptosis, induced glutathione synthesis, and reduced ROS production in H2O2-treated PC12 cells (57). On the other hand, eriodictyol profoundly ameliorated sucrose preference, reduced immobility time in forced swimming test and feeding latency in novelty-suppressed feeding test in LPS- and CUMS-induced rat model of depression (102). Turmeric is one of the raw materials of curry as a spice, and curcumin in it can restore the effects of oxidative stress and prevent depression caused by CUMS (103, 104). Polyphenols are found in many fruits and vegetables, and it has been suggested that diet therapy may be used to relieve depression (105).
3.6 Modulation of intestinal microbiota
The enteric nervous system (ENS) is known to control gastrointestinal behavior via the actions of neurons and neurotransmitters in a manner independent of central nervous system (CNS) input, thereby also known as the “second brain” (106). Indeed, intestinal flora directly produces neurotransmitters (e.g., serotonin and GABA), and regulates brain functions and emotion through the microbiota–gut–brain (MGB or BGM) axis (107, 108). Gut microbiota in the large intestine synthesize various short-chain fatty acids (SCFAs) as the major metabolites for modulating the levels of neurotransmitters and neurotrophic factors and directly affecting brain functions (109, 110). Probiotics Allobaculum and Bifidobacterium were considerably reduced in the gut of depressed patients (111). Interestingly, traditional Chinese medicine formulation Kaixinsan could increase the relative abundance of Allobaculum and Bifidobacterium in the gut of CUMS mice (112). The concurrent use of antibiotics decreased the antidepressant effect of Kaixinsan, suggesting the link of Allobaculum and Bifidobacterium with depression (112). Moreover, puerarin reversed stress-induced disruption of gut microflora via increasing the level of beneficial bacteria and decreasing the inflammatory bacteria in CUMS mouse (113). Collectively, herbal medicines might exhibit antidepressant activity by affecting gut microbiota.
3.7 Regulation of ferroptosis
Ferroptosis describes iron-mediated oxidative cell death, largely due to the toxicity from dramatical increase in the level of intracellular iron ions (114, 115). Ferroptosis has emerged as a hot target for cancer therapy in the past decade. Lipid peroxidation is hyperactive in the depressed population than in the normal population and tightly associated with ferroptosis, suggesting a new therapeutic target (116). A recent analysis of hippocampal proteomes identified the hyperactivation of ferroptosis pathway in CUMS mice (117). Interestingly, traditional Chinese medicine formulation Xiaoyaosan was shown to substantially reduce the total iron and ferrous content in the hippocampus from CUMS mouse model, possibly by regulating PEBP1-GPX4-mediated ferroptosis (118). Galangin, a polyphenolic compound from Alpinia officinarum, also inhibited ferroptosis in the hippocampus by activating the SLC7A11/GPX4 axis (119). Iron chelators and lipophilic antioxidants were suggested for preventing ferroptosis (120). Considering the number, chemical diversity and potency, herbal products represent a rich source for the discovery of new ferroptosis-targeting antidepressants.
3.8 Pathway enrichment analysis
The potent active compounds were further examined through network pharmacology analysis while the target proteins were accordingly predicted (Figures 3, 4). Specifically, the prediction and screening of potential depression-related targets were performed using Similarity Ensemble Approach (SEA) at https://sea.bkslab.org, the Search Tool for Interactions of Chemicals (STITCH) at http://stitch.embl.de, SwissTargetPrediction at http://www.swisstargetprediction.ch, Therapeutic Target Database (TTD) at http://db.idrblab.net/ttd, Comparative Toxicogenomics Database (CTD) at http://ctdbase.org, PharmGKB at https://www.pharmgkb.org, DisGeNET at https://www.disgenet.org, and GeneCards at https://www.genecards.org. Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Enrichment of selected targets were performed using the online bioinformatics tool DAVID at http://david.ncifcrf.gov. Interestingly, the pathway enrichment analysis suggests that active herbal compounds mainly target serotonergic synapse pathway (KEGG: map04726) and dopaminergic synapse pathway (KEGG: map04728) in relation to depression. As shown in Figure 3, eight targets (i.e., APP, CASP3, PRKCA, MAOA, ALOX12, ALOX15, ALOX5, and CYP2C19) were enriched for regulating serotonergic synapse pathway, whereas the most related compounds were curcumin from Curcuma longa L. and baicalein from Scutellaria baicalensis Georgi. As shown in Figure 4, eight targets (i.e., SLC6A3, AKT1, PRKCA, FOS, MAOA, DRD1, DRD2, and DRD5) were enriched for regulating the dopaminergic synapse pathway whereas neferine from Nelumbinis semen was mostly studied.
FIGURE 3
Network pharmacology analysis of herbs and the active compounds for targeting serotonergic synapse pathway.
FIGURE 4
Network pharmacology analysis of herbs and the active compounds for targeting dopaminergic synapse pathway.
4 Conclusion
In this review, we initially discussed the current understanding on the pathology of depression and the molecular targets for different classes of synthetic drugs. Subsequently, we performed comprehensive review and network pharmacology analysis to understand the antidepressant activities of herbal medicines and reveal the underlying mechanisms. Herbal medicines appear to be effective for the treatment of depression without causing undesirable side-effects. As such, the present review may pave a new avenue for the development of novel antidepressant strategies.
Statements
Author contributions
YS prepared the original draft. JR and JZ designed, reviewed, and revised the manuscript. JR supervised the work. All authors contributed to the article and approved the submitted version.
Funding
This research and open access publication fees were funded by the Research and Cultivation Plan of High-Level Hospital Construction (HKUSZH201902040), Health and Medical Research Fund (16171751 and 17181231), General Research Fund (17119619), and Science, Technology and Innovation Commission of Shenzhen Municipality (JCYJ20180306173835901).
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.
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Summary
Keywords
depression, molecular mechanisms, herbal medicines, active constituents, antidepressant
Citation
Sun Y, Zhao J and Rong J (2022) Dissecting the molecular mechanisms underlying the antidepressant activities of herbal medicines through the comprehensive review of the recent literatures. Front. Psychiatry 13:1054726. doi: 10.3389/fpsyt.2022.1054726
Received
27 September 2022
Accepted
07 December 2022
Published
22 December 2022
Volume
13 - 2022
Edited by
Xinjing Yang, South China Hospital of Shenzhen University, China
Reviewed by
Magdalena Sowa-Kucma, University of Rzeszów, Poland; Yue Li, Tianjin University of Traditional Chinese Medicine, China
Updates
Copyright
© 2022 Sun, Zhao and Rong.
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.
*Correspondence: Jia Zhao, zhaojia7@hku.hkJianhui Rong, jrong@hku.hk
This article was submitted to Anxiety and Stress Disorders, a section of the journal Frontiers in Psychiatry
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