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Abstract

Depression, which can be accompanied by many fatal diseases and a low life quality, has become the leading cause of ill health and disability worldwide. However, Chinese Pharmacopoeia, the most authoritative and evidence-based encyclopedia of Traditional Chinese Medicine (TCM), could contain leads and insights into the development of new antidepressant drugs. In this work, nine herbal medicines with ‘dispel melancholy functions’ specifically documented in Chinese Pharmacopoeia have been comprehensively reviewed with respect to clinical trials, and phytochemical and pharmacological aspects. The nine drugs are Rosae Chinensis Flos, Croci Stigma, Albiziae Cortex and Flos, Roase Rugosae Flos, Curcumae Radix, Hyperici Perforati Herba, Cyperi Rhizoma and Bupleuri Radix. The mechanisms of action of their functional antidepressant compounds, including gallic acid, hypericin, kaempferol, crocetin, crocin, quercetin, luteolin, isorhamnetin, curcumin, hyperforin, adhyperforin, catechin, rutin, puerarin, and saikosaponins A and D, have been collected and discussed. These traditional Chinese herbs and their active compounds provide a promising resource to develop effective new antidepressant drugs in future. Moreover, mechanistic investigations, safety verification and large-scale clinical trials are still expected to finally transform such TCM-based antidepressant resources to new drugs for patients suffering from depression.

Keywords

depression chinese pharmacopoeia herbal sources antidepressant mechanisms secondary metabolites

1. Introduction

Depression is characterized by anhedonia and the reduced ability to experience pleasure.¹ It is commonly accompanied by other additional symptoms including weight or appetite change, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feelings of worthlessness or guilt, lack of concentration, suicidal ideation, and low libido.² Moreover, the depression can be significantly related to certain medical illnesses, which further affect their treatment and prognosis.^3–5 Patients who have illnesses such as cancer, stroke, diabetes, autoimmune disease and myocardial infarction are likely to develop depression concomitantly, thus bringing challenges for integrative management or treatment of these medical conditions.^6–9

With a rapid increase of more than 18% over the last ten years, depression has already affected over 320 million people by 2017, making it the leading cause of ill health and disability worldwide.^10,11 This prevalence implies that the number of individuals under depressive conditions worldwide will remain and even rise to a very high level within a foreseeable period. Conventional pharmacotherapy of depressive disorders is through modulating neurotransmitters that play crucial roles in either central or peripheral nervous system function.¹² However, the low efficacy, tolerance (long term use) and substantial side effects, such as headaches, addiction, sexual dysfunction, seizures and suicide, of current drugs remains of great concern.^5,10,13 Moreover, the shortage of psychologists and the high costs involved limit the extensive application of anti-depressive psychotherapy in most areas of world. Therefore, searching for more effective, better-tolerated, and most easily accessible treatments, with fewer side effects, should be an important consideration.

The herbal medicines used popularly for thousands of years constitute the most obvious source for the application of therapeutically effective drugs. Previous pharmacological studies of medicinal plants in the traditional medicines of various cultures suggested that some were effective and led to the identification and isolation of compounds to develop new drugs. For example, artemisinin and its derivatives, extracted from Artemisia annua L., are successful anti-malarial drugs that have saved the lives of numerous patients.¹⁴ Perceived as an important and feasible remedy for depression, traditional herbal medicines are also valuable resources in the search for novel compounds and the development of antidepressant drugs. Herbal preparations of Hypericum perforatum (St John's wort) have gathered respectable clinical evidence worldwide over the past decade.¹⁵ Despite the lack of sufficient scientific evidence, the role of traditional plants, such as Crocus sativus (saffron), Curcuma longa (turmeric), Nepeta menthoides (catmint), Cuscuta spp. (dodder), Panax ginseng (Korean ginseng), Lavandula spp. (lavender) and Rhodiola rosea (roseroot), have also become more or less established for the treatment of depression.¹⁶ Meanwhile, Traditional Chinese medicine (TCM) is one of the most empirical systems of medicine, which has systematically used medicinal plants for disease treatment over centuries. A review of TCM plants therefore could enrich the current candidates for antidepressant drugs development, promote the relative phytochemical and pharmacological research, and eventually support their clinical applications. In this work, the scientific evidence will be collected, detailed and evaluated for phytochemistry and pharmacological insights, drug development, and medicinal uses of antidepressant herbs recorded in the official Chinese Pharmacopoeia.

2. Records in TCM Encyclopedia

The symptoms of depression are accordingly manifested in several diseases named in TCM as hysteria (脏躁), lily disease (百合病), dementia (癫狂), amnesia (健忘), and insomnia (不寐). The symptoms of hysteria mainly include sadness and being about to cry; this has a high incidence in women.¹⁷ Lily disease is the result of hyperpyrexia or emotional failure, leading to absent-mindedness, diet and behavior disorder, a bitter taste and red urine.¹⁷ The patients of dementia feel depressed firstly and then experience amnesia, irascibility and fear with less sleep and no hunger.¹⁸ Though depression is never defined as a disease in TCM, the above five diseases with related clinical symptoms are treated using a similar therapeutic strategy, defined as ‘dispel melancholy’ (解郁), which aims to release the depression syndrome (郁证). This syndrome of TCM is caused by emotional discomfort and Qi stagnation. Its main clinical manifestations include depression, mood restlessness, chest fullness, chest pain, irritability, crying, and a peculiar sense in the pharynx.¹⁹ According to this understanding, herbal medicines with ‘dispel melancholy’ attributes are broadly employed in TCM herbal formulae, empirically developed and claimed to treat depression-like symptoms in Chinese hospitals and TCM clinics.

The herbal formulae, usually decoctions comprising dozens of medicinal plants in respective amounts, are the typical dosage form of TCM. Medicinal plants within these formulae are, thus, considered as valuable resources in the search for novel compounds with potential pharmacological applications. Among the TCM Encyclopedias inherited for over a thousand years, the official Chinese Pharmacopoeia currently is one of the most highly authoritative collections of Chinese medicinal plants and used herein to search for herbs that ‘dispel melancholy’.

3. Herbs for Depression Treatment

Using the key words ‘dispel melancholy’ (解郁), 9 out of 2165 TCM herbs recorded in the Chinese Pharmacopoeia were identified and are reviewed in this work.²⁰ These herbs are Rosae Chinensis Flos, Croci Stigma, Albiziae Cortex and Flos, Roase Rugosae Flos, Curcumae Radix, Hyperici Perforati Herba, Cyperi Rhizoma and Bupleuri Radix. Among them, Albiziae Cortex and Flos are recorded as two individual herbs in the Chinese Pharmacopoeia and thus counted as two drugs hereafter in this work.

The authors searched a number of electronic databases, including Pubmed, Web of Science, and Elsevier up to October 20^th, 2021. The keywords for searching included Rosae Chinensis Flos (or Rosa chinensis), Croci Stigma (or Crocus sativus), Albiziae Cortex and Flos (or Albizia julibrissin), Roase Rugosae Flos (or Rosa rugosa), Curcumae Radix (Curcuma wenyujin, C. longa, C. kwangsiensis and C. phaeocaulis), Hyperici Perforati Herba (Hypericum perforatum), Cyperi Rhizoma (Cyperus rotundus) and Bupleuri Radix (Bupleurum chinense and B. scorzonerifolium). The titles and abstracts of each of the articles were assessed to delete duplication. Searching was limited to articles only in the English language. The articles with the contents unrelated to depression were excluded. Patents, abstracts, case reports, and abstracts in symposia and congress were excluded due to insufficient information for evaluation and comparison with other studies. Review articles were also excluded as the data were not original.

3.1 Rosae Chinensis Flos

Rosae Chinensis Flos is produced through shade or cold drying of the slightly blooming flowers of Rosa chinensis Jacq. (family Rosaceae). According to the TCM theoretical system, this drug can promote blood circulation to restore menstrual flow and recover from liver dysfunction to dispel melancholy.²⁰ The main compounds identified in Rosae Chinensis Flos are flavonoids, phenolic acid, ethereal oils, and tannin.^21–23 Among them, gallic acid, hypericin, kaempferol and quercetin, which have been reported to contribute to the antidepressant behaviors of other herbs, could be considered as active compounds of Rosae Chinensis Flos. However, the mechanisms underlying its antidepressant properties have not been reported and thus need exploration in future.

3.2 Croci Stigma

Croci Stigma is the dry stigma of Crocus sativus L. (family Iridaceae). This promotes blood circulation, gives blood stasis relief, dispels melancholy and has sedative effects. Traditionally, it is claimed that Croci Stigma can be used in the treatment of amenorrhea, postpartum stasis, depression and anxiety.²⁰ Recently, pilot double-blind, randomized, placebo-controlled trials dealing with the treatment of depression using Croci Stigma has increased. However, multicenter trials with larger sample size, longer treatment duration, and with different ethnic groups are required to verify the current results, but these studies indicate the efficacy of Croci Stigma in the treatment of mild to moderate, and even major depression, with few side effects.^24–29 This plant contains several characteristic secondary metabolites, including carotenoids, crocetin, crocin, picrocrocin, safranal, the aglycone of safranal, lycopene, kaempferol-3-O-sophoroside, kaempferol-3-O-glucoside, quercetin-3-O-sophoroside, zeaxanthin and vitamin B2.^30,31 Among them, crocetin, crocin and safranal have been reported to act as the main antidepressant components of Croci Stigma.^32,33 The antidepressant mechanisms of this herb have been correlated to maintain the level of serotonin (5-HT), dopamine (DA), and norepinephrine in the brain by inhibiting the reuptake of these substances in the synapse of animal models.^34–36 However, the exact pharmacological mechanism still cannot be determined without further phytochemical and clinical studies.

3.3 Albiziae Cortex and Flos

Albiziae Cortex is the dry bark of Albizia julibrissin Durazz. (family Leguminosae), and Albiziae Flos is its dry inflorescence or flower bud. In Chinese Pharmacopeia, the main characteristics of Albiziae Cortex and Flos are recorded as dispelling melancholy, sedative effects, improving blood circulation and detumescence. In TCM, these drugs are used empirically to treat patients distraught with worry, and suffering with depression and insomnia. Albiziae Cortex is also used for the treatment of pulmonary abscess, swelling and traumatic injury.²⁰ Albiziae Cortex and Flos contain triterpenoids, flavones, lignans, alkaloids, tannins, and polysaccharides.^37–46 Among them, quercetin, luteolin, isorhamnetin and kaempferol are reported to be the main compounds contributing to the antidepressant effects.⁴⁶ Using the learning and memory of the sleep-deprived Drosophila model, the boiled water extracts (drugs : water = 6 kg : 6 L) of Albiziae Flos (4.5 and 18 mg/mL) have been proved to effectively ameliorate memory loss induced by sleep deprivation.⁴⁷ However, the mechanisms underlying the antidepressant effects of Albizia julibrissin remain as an ongoing challenge.

3.4 Roase Rugosae Flos

Roase Rugosae Flos is the dry flower of Rosa rugosa Thunb. (family Rosaccae). It is collected in late spring and early summer when the flowers are just about to bloom, and should be dried at low temperature. According to TCM theory, the medicinal functions of Roase Rugosae Flos include promoting qi circulation, dispelling melancholy, regulation of qi and blood, and as an acesodyne. Traditionally, in TCM, Roase Rugosae Flos is used to treat stomachache and hepatodynia caused by emotional depression and qi stagnation, poor appetite, irregular menses and traumatic injury.²⁰ The constituents of Roase Rugosae Flos include polyphenols, flavonoids, essential oils, polysaccharides, pigments and vitamins.^48–52 Among them, quercetin and kaempferol have antidepressant activities and thus may be the main antidepressant constituents of the drug. The water extracts (drugs : water = 1 kg : 10 L) of Roase Rugosae Flos (1 g/kg b.w) were reported to prevent exercise-induced stress in experimental mice models. As the result of less lipid peroxidation, lower muscular antioxidant enzyme activities and lower cortisol level, the antidepressant effect was achieved through decreasing oxidative stress levels under the treatment of Roase Rugosae Flos.⁵³ The drug has also been identified as possessing antioxidant activity by significantly downregulating liver peroxide, protein oxidation, glutathione levels, and plasma ALT and AST activities in rats.⁵⁴

3.5 Curcumae Radix

Curcumae Radix is the dry block root of Curcuma wenyujin Y. H. Chen et C. Ling, C. longa L., C. kwangsiensis S. G. Lee et C. F. Liang and C. phaeocaulis Val. (family Zingiberaceae). It promotes blood and qi circulation, relieves pain, dispels melancholy, alleviates dysphoria, and eliminates jaundice. Traditionally, Curcumae Radix is an efficacious ingredient commonly used in a TCM formula for the treatment of chest pain, dysmenorrhea, epilepsy and jaundice.²⁰ The main compounds identified in Curcumae Radix are sesquiterpenes, alkaloids and polysaccharides.^55–62 Among them, curcumin is the only compound with reported antidepressant activity.⁶³ Moreover, though one study has reported that the petrol and ethyl acetate fraction of Curcumae Radix have an antidepressant effect, clinical trials and pharmacological investigations regarding the drug's antidepression activities remain an ongoing challenge.

3.6 Hyperici Perforati Herba

Hyperici Perforati Herba, commonly known as St John's wort, is the dried aerial portion of Hypericum perforatum L. (family Hypericaceae). According to TCM discipline, it is a medicine to disperse stagnated qi of liver, dispel melancholy, clear away heat, and promote diuresis, detumescence and lactogenesis. Hyperici Perforati Herba is traditionally used in TCM for the treatment of depression, painful swollen joints, acute mastitis and hypogalactia.²⁰ As one of the most widely used antidepressant herbs in many countries, H. perforatum has been extensively investigated for its constituents and its pharmacological and clinical properties.^64–66 In the last decade, the antidepressant properties of the plant have been evaluated and confirmed in various animal models in vivo.^67–70 Clinical trials have also provided consistent evidence that H. perforatum and its products present effective antidepressant activities that are superior to placebo, and at least comparable to widely prescribed synthetic medicines, such as fluoxetine, paroxetine, sertraline, and imipramine.⁷¹ Principally, H. perforatum acts in a similar way to the tricyclic antidepressants and selective 5-HT reuptake inhibitors class of antidepressants with fewer and milder side effects.⁶⁷ Moreover, treatment with H. perforatum is much cheaper for patients in comparison with these synthetic medicines.⁷² H. perforatum contains naphthodianthrones, phloroglucinols, flavonoids, procyanidins, tannins, essential oil, amino acids, phenylpropanes, xanthones and polysaccharides.^73–77 Among them, hypericin, hyperforin, adhyperforin, catechin, luteolin, quercetin, kaempferol, and rutin are the reported active antidepressant compounds.^65,78 H. perforatum extract has been identified as a potent but nonspecific inhibitor for the synaptosomal uptake of the five neurotransmitters, 5-HT, norepinephrine, DA, gamma-aminobutyric acid (GABA) and L-glutamate, thereby increasing their concentrations in the synaptic cleft of brain areas involved in the pathophysiology of depression.^66,79–81 Though these findings have indicated that pharmacological mechanisms of H. perforatum are partly shared with those of conventional antidepressant drugs, the exact mechanisms of its antidepressant action need further examination.¹⁵

3.7 Cyperi Rhizoma

Cyperi Rhizoma is the dry rhizome of Cyperus rotundus L. (family Cyperaceae). In TCM discipline, it is claimed to be able to disperse stagnated qi of liver, dispel melancholy, and relieve dysmenorrhea. Therefore, it is used to treat depression, chest and breast pain, abdominal distension, irregular menses, dysmenorrhea and amenorrhea.²⁰ Numerous constituents have been reported for Cyperi Rhizoma, including alkaloids, flavonoids, glycosides, phenols, tannins, steroids, starch and sesquiterpenoids.^82–95 Among them, cyprotuside A, cyprotuside B, rotunduside F-H, quercetin, kaempferol and luteolin have been reported to have antidepressant effects.^86,94,95 Though the ethanol extract (drugs : water = 10 kg : 150 L) and its fractions were claimed to display significant antidepressant effect in a mice model by Lin and colleagues, there has not been any other report about the antidepressant evaluation and mechanism of action of Cyperus rotundus.⁸⁶ Therefore, the exact mechanisms of the antidepressant activities of the drug need further exploration.

3.8 Bupleuri Radix

Bupleuri Radix is the dried root of Bupleurum chinense DC. or B. scorzonerifolium Willd. (family Apiaceae). In TCM pharmacopeia, it is recorded as a medicine to disperse stagnated qi of liver, dispel melancholy, abate fever, and raise Yang qi. Traditionally, it is used to treat fervescence, chest pain, irregular menses, descensus uteri and archoptoma.²⁰ In a clinical trial, the root power of Bupleuri Radix (1 g daily) was reported to effectively ameliorate depression of patients within three months of treatment. The therapeutic effects were achieved through increasing serum levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), the low levels of which are known to be related to the likelihood of developing depression.⁹⁶ In animal models, the antidepressant-like effects of Bupleuri Radix were found in behavioral and molecular assays. Similarly, it exerted its effects through actions on the cAMP response element binding protein (CREB) and BDNF activation, leading to stimulation of the phosphoinositide 3-kinase (PI3K)/Akt/GSK-3 β signaling pathway.⁹⁷ Total saikosaponin extracts of Bupleurum chinense reduced the immobility time of mice in the tail suspension test (TST), thus exhibiting antidepressant activities in a dose-dependent manner.⁹⁸ Moreover, the polyacetylenes of Bupleuri Radix potently inhibited 5-HT, norepinephrine and DA reuptake in rat synaptosomes in vitro, thus demonstrating antidepressant activity.⁹⁹ The light petroleum fraction and ethanol extract of Bupleuri Radix also could produce an antidepressant effect through metabolic regulation of glycolysis, energy, amino acid, sphingolipid, inositol phosphate, lipid, glycerophospholipid, fatty acid and TCA cycle.^100,101

The plant contains many secondary metabolites such as essential oils, triterpenoid saponins, polyacetylenes, flavonoids, lignans, fatty acids and sterols.^99,102–104 Among them, saikosaponins a-d, quercetin, rutin, puerarin, (2Z,8Z/E,10E)-pentadecatriene-4,6-diyne-1-ol and (2Z,8Z/E,10E)-heptadecatriene-4,6-diyne-1-ol have been reported to be the active antidepressant constituents of Bupleuri Radix.^99,104–106 Taken together, the antidepressant activities of Bupleuri Radix have been elucidated in several experimental models, but the underlying mechanisms of its antidepressant effects and the active metabolites are largely unknown and need future investigation.

4 Antidepressant Compounds From Herbs in Chinese Pharmacopoeia

The active compounds contributing to the antidepressant activity of the nine herbs reviewed above include gallic acid, hypericin, kaempferol, crocetin, crocin, quercetin, luteolin, curcumin, hyperforin, adhyperforin, catechin, rutin, puerarin, safranal, isorhamnetin, cyprotusides a-b, rotundusides f-h, saikosaponins a-d, (2Z,8Z/E,10E)-pentadecatriene-4,6-diyne-1-ol, and (2Z,8Z/E,10E)-heptadecatriene-4,6-diyne-1-ol. To facilitate the future investigation and development of new antidepressant drugs, the pharmacological mechanisms underlying the antidepressant activities of these compounds are also reviewed as follows and summarized in Table 1.

Table 1.
The Mechanisms Underlying Antidepressant Activities of Compounds From Herbal Medicines That Dispel Melancholy in Chinese Pharmacopeia.

Significant constituents TCM names [Plant Latin name] Disease Models Mechanistic insights Refs

Gallic acid Rosae Chinensis Flos (Rosa chinensis Jacq.) TMT-induced depressant rats Antioxidant and amelioration of cell density loss in the hippocampus ¹⁰⁸

unpredictable chronic mild stressed mice Antioxidant and inhibition MAO-A activity and decrease in plasma nitrite and corticosterone levels ¹⁰⁹

balb/c mice with post-stroke depression Antioxidant ¹¹⁰

iAS-induced depressant male rats Antioxidant ¹¹¹

adult male BALB/c mice dual modulation of serotonergic and catecholaminergic systems ¹¹²

Hypericin Rosae Chinensis Flos (Rosa chinensis Jacq.); Hyperici Perforati Herba (Hypericum perforatum L.) neonatal rat hippocampal neurones increased neuronal action potential duration; transient I_A and delayed rectifier I_K potassium currents inhibition ¹¹⁷

male Sprague-Dawley rats elevation of plasma corticosterone; activation of 5-HT₂ receptors ¹¹⁶

male Sprague-Dawley rats inhibition of glutamate release; decrease in the voltage-dependent Ca²⁺ influx and mitogen-activated protein kinase activity ¹¹⁸

male CD rats increased 5-HT levels; decreased DOPAC and homovanillic acid levels ¹¹⁵

CUMS model rats excitatory amino acids and monoamine neurotransmitters regulation ¹¹⁹

Kaempferol Rosae Chinensis Flos (Rosa chinensis Jacq.); Albiziae Cortex and Flos (Albizia julibrissin Durazz.); Roase Rugosae Flos (Rosa rugosa Thunb.); Hyperici Perforati Herba (Hypericum perforatum L.); Cyperi Rhizoma (Cyperus rotundus L.) CSDS mouse Increased SOD, CAT, GPx and GST; decreased TNF-α and IL-1β; inhibition of CD11b; activated Akt/β-catenin cascade ¹²²

Crocetin Croci Stigma (Crocus sativus L.) chronic restraint stress Wistar albino rats Increased levels of MDA and GSH; reverted activities of antioxidant enzymes SOD, GPx, GR, and CAT ¹²⁵

Crocin Croci Stigma (Crocus sativus L.) MPTP-induced subacute PD male C57BL/6 mice improved the VTA-mPFC circuit through mTOR signaling to enhance the synaptic plasticity ¹²⁸

CORT-treated male C57BL/6J mice suppression of neuroinflammation (IL-1β); reduced oxidative damage by stimulating the SIRT3 pathway; improved mitochondrial function to produce increased ATP levels ¹²⁶

PNS Balb/cJ female and male mice activated the GHSR and the following PI3K signaling ¹³¹

COPD-induced depression male C57BL/6 mice reduced proinflammatory cytokines in BAL fluid, lung tissue and hippocampus; inhibited IκB phosphorylation and degradation, and NF-κBp65 nuclear translocation. ¹²⁹

BV2 microglia cells; LPS-induced Kunming mice inhibition of NLRP3 inflammasome and NF-KB; promoted M1 to M2 phenotypic conversion of microglia ¹³⁰

Adult male Wistar Albino rats increased CREB, BDNF, VGF and p-CREB ¹²⁷

Quercetin Rosae Chinensis Flos (Rosa chinensis Jacq.); Albiziae Cortex and Flos (Albizia julibrissin Durazz.); Roase Rugosae Flos (Rosa rugosa Thunb.); Hyperici Perforati Herba (Hypericum perforatum L.); Cyperi Rhizoma (Cyperus rotundus L.); Bupleuri Radix (Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd) UCMS adult male Wistar albino rats Antioxidant through inhibiting MDA levels, increasing CAT and SOD activity and restoring GSH levels; anti-inflammatory by decreasing TNF-α, NF-κB, IL-1β and IL-6 release and diminishing serum corticosterone ¹³⁸

FPS-induced male Sprague-Dawley rats increased expression of BDNF, Copine 6, p-TrkB and TREM 1 and decreased expression of TREM 2 ¹³⁶

OB female Swiss mice Decreased LOOH levels, inhibited NMDA and NO ¹⁴⁰

UCMS Swiss albino mice Increased SOD, GSH, CAT and 5-HT levels; decreased glutamate, TNF-α and IL-6 levels ¹³⁷

CUS Swiss albino mice reduced hippocampal TBARS and nitric oxide levels; restored total thiol and CAT levels; reduced hippocampal levels of TNF-α, IL-6, IL-1β and COX-2 ¹³⁹

Luteolin Albiziae Cortex and Flos (Albizia julibrissin Durazz.); Hyperici Perforati Herba (Hypericum perforatum L.); Cyperi Rhizoma (Cyperus rotundus L.) Corticosterone-treated male ICR mice Reduced expressions of GRP78 and GRP94 ¹⁴²

C6 cells; primary hippocampal neurons; ovariectomized depressed SD rats downgraded PMAT; upgraded BDNF expression; inhibited 5-HT reuptake; increased monoamine neurotransmitters in the synaptic cleft ¹⁴³

male ICR mice; HEK-293 cells promoted Cl⁻ ion influx; modulated GABAA receptor ¹⁴¹

Curcumin Curcumae Radix (Curcuma wenyujin Y. H. Chen et C. Ling, Curcuma longa L., Curcuma kwangsiensis S. G. Lee et C. F. Liang or Curcuma phaeocaulis Val.) UCMS model improved antioxidant enzymes activities; inhibited effect on AchE activity ¹⁴⁷

UCMS Male Wistar rats Reduced CUMS-induced glial activation and IL-1β overexpression; attenuated neuronal apoptosis ¹⁴⁸

Adult male WKY rats increased hippocampal BDNF ¹⁴⁹

OB male albino rats normalized levels of DA, DOPAC, NA, 5-HT and 5-HIAA ¹⁵³

Male C57BL/6J mice increased BDNF protein and ERK phosphoryation ¹⁵¹

Male SD rats increased levels of DA, 5-HT, NA, 5-HIAA and DOPAC ¹⁵⁵

OB-induced adult male Wistar rats increased serum corticosterone levels, reduced MDA and nitrite levels, restored GSH and CAT levels, increased TNF-α and caspase-3; enhanced BDNF ¹⁵⁷

CUMS-treated male Wistar rats Increased expression of BDNF, PSD-95 and synaptophysin ¹⁵²

CUD-treated male SD rats induced deactivation of the left primary auditory cortex and activation of amygdalohippocampal cortex ¹⁶¹

Rotenone-induced depressive Albino-Wistar rats Increased DA, DOPAC, 5-HT and 5-HIAA in striatum and hippocampus ¹⁵⁴

CUMS-treated male SD rats decreased IL-1 β, IL-6 and TNF-α; suppressed the activation of NF-γ B, P2X7R/NLRP3 inflammasome axis and IDO; decreased kynurenine/tryptophan ratio ¹⁶⁰

CUS-induced male Wistar rats Increased hippocampal BDNF and ERK levels ¹⁵⁰

CUMS-treated male SD rats Increased BDNF and decreased COX-2 ¹⁵⁶

LPS-treated adult male Kun-Ming mice Inhibited microglial activation; decreased IL-1, TNF-α, nitric oxide synthase, cyclooxygenase2, ameliorated NF-γ B activation ¹⁵⁹

CMS-treated Male Wistar rats inhibited NF-γ B ¹⁵⁸

Adult male SD rats blocked the Ca_v2.2 and Ca_v2.1 channels; inhibited glutamate release ¹⁶²

Hyperforin Hyperici Perforati Herba (Hypericum perforatum L.) CUMS-treated rodent model increased zinc concentration and BDNF level ¹⁶³

CUS Adult male Wistar rats TRPC6 activation ¹⁶⁶

primary cultures of cortical neurons enhanced Ca²⁺ influx ¹⁶⁷

cells expressing a dominant negative mutant of TRPC6 inhibited 5-HT and norepinephrine; induced sodium, calcium entry and currents; TRPC6 activation ¹⁶⁴

Primary cultures of cortical neurons from embryonic E13 C57BL6/J mice upregulated TrkB; expression of TRPC6; activated PKA; Ca²⁺ entry; phosphorylation of CREB ¹⁶⁸

Adhyperforin Hyperici Perforati Herba (Hypericum perforatum L.) CUMS-treated Swiss mice Inhibited uptake of 5-HT, NE and DA ⁷⁷

male Wistar rats Inhibited uptake of 5-HT, NE and DA; inhibited DA translocation ¹⁶⁹

Catechin Hyperici Perforati Herba (Hypericum perforatum L.) CUMS-treated SD mice recovered CAT, glutathione and SOD levels ¹⁷²

Rutin Hyperici Perforati Herba (Hypericum perforatum L.); Bupleuri Radix (Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd) CUS-induced Adult Swiss albino mice Recovered hippocampal neuronal loss. ¹⁷³

Pregnant NMRI mice Decreased expression of NR2B and NR2A subunits of NMDA receptors, increased CA3 diameter and decreased percentage of dark neurons in the hippocampus ¹⁷⁴

PCPA and AMPT-treated male Swiss mice increased 5-HT and NA in the synaptic cleft. ¹⁰⁶

Puerarin Bupleuri Radix (Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd) CUS-treated SD mice Decreased progesterone, allopregnanolone, 5-HT, 5-HIAA; blocked CRH, Cort and ACTH ¹⁷⁸

Male C57BL/6J mice activation of AMPAR-induced mTOR signaling pathway; increased GluR1 phosphorylation and BDNF ¹⁰⁵

SNI-induced mice Increased BDNF and activation of CREB pathway ¹⁷⁵

CUS-treated male C57BL/6 mice Increased FGF-2 ¹⁷⁷

OVX ICR mice increased transcription of BDNF and ER mRNA ¹⁷⁶

Saikosaponin A Bupleuri Radix (Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd) SD rats Reduced IL-1 β, IL-6 and TNF-α; activation of P38MAPK pathway ¹⁷⁹

CUMS-treated female Wistar rats promoted BDNF-TrkB signaling; reduced IL-1 β, IL-6 and TNF-α; restored the HPA axis ¹⁸⁰

CUMS-treated male SD rats increased PRRT2 and DA ¹⁸¹

Saikosaponin D Bupleuri Radix (Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd) CUMS-treated male SD rats Increased p-CREB and BDNF; restored the HPA axis ¹⁸³

CUMS-treated male SD rats Reduced NF-γ B and miR-155; enhanced FGF2 ¹⁸⁴

LPS-treated Male ICR mice; Primary microglia culture Decreased IL-1 β, IL-6 and TNF-α; inhibited HMGB1 translocation; decreased TLR4, p-I γ B-α, NF-γ Bp6 ¹⁸²

Significant constituents	TCM names [Plant Latin name]	Disease Models	Mechanistic insights	Refs
Gallic acid	Rosae Chinensis Flos (Rosa chinensis Jacq.)	TMT-induced depressant rats	Antioxidant and amelioration of cell density loss in the hippocampus	¹⁰⁸
	unpredictable chronic mild stressed mice	Antioxidant and inhibition MAO-A activity and decrease in plasma nitrite and corticosterone levels	¹⁰⁹
	balb/c mice with post-stroke depression	Antioxidant	¹¹⁰
	iAS-induced depressant male rats	Antioxidant	¹¹¹
	adult male BALB/c mice	dual modulation of serotonergic and catecholaminergic systems	¹¹²
Hypericin	Rosae Chinensis Flos (Rosa chinensis Jacq.); Hyperici Perforati Herba (Hypericum perforatum L.)	neonatal rat hippocampal neurones	increased neuronal action potential duration; transient I_A and delayed rectifier I_K potassium currents inhibition	¹¹⁷
	male Sprague-Dawley rats	elevation of plasma corticosterone; activation of 5-HT₂ receptors	¹¹⁶
	male Sprague-Dawley rats	inhibition of glutamate release; decrease in the voltage-dependent Ca²⁺ influx and mitogen-activated protein kinase activity	¹¹⁸
	male CD rats	increased 5-HT levels; decreased DOPAC and homovanillic acid levels	¹¹⁵
	CUMS model rats	excitatory amino acids and monoamine neurotransmitters regulation	¹¹⁹
Kaempferol	Rosae Chinensis Flos (Rosa chinensis Jacq.); Albiziae Cortex and Flos (Albizia julibrissin Durazz.); Roase Rugosae Flos (Rosa rugosa Thunb.); Hyperici Perforati Herba (Hypericum perforatum L.); Cyperi Rhizoma (Cyperus rotundus L.)	CSDS mouse	Increased SOD, CAT, GPx and GST; decreased TNF-α and IL-1β; inhibition of CD11b; activated Akt/β-catenin cascade	¹²²
Crocetin	Croci Stigma (Crocus sativus L.)	chronic restraint stress Wistar albino rats	Increased levels of MDA and GSH; reverted activities of antioxidant enzymes SOD, GPx, GR, and CAT	¹²⁵
Crocin	Croci Stigma (Crocus sativus L.)	MPTP-induced subacute PD male C57BL/6 mice	improved the VTA-mPFC circuit through mTOR signaling to enhance the synaptic plasticity	¹²⁸
	CORT-treated male C57BL/6J mice	suppression of neuroinflammation (IL-1β); reduced oxidative damage by stimulating the SIRT3 pathway; improved mitochondrial function to produce increased ATP levels	¹²⁶
	PNS Balb/cJ female and male mice	activated the GHSR and the following PI3K signaling	¹³¹
	COPD-induced depression male C57BL/6 mice	reduced proinflammatory cytokines in BAL fluid, lung tissue and hippocampus; inhibited IκB phosphorylation and degradation, and NF-κBp65 nuclear translocation.	¹²⁹
	BV2 microglia cells; LPS-induced Kunming mice	inhibition of NLRP3 inflammasome and NF-KB; promoted M1 to M2 phenotypic conversion of microglia	¹³⁰
	Adult male Wistar Albino rats	increased CREB, BDNF, VGF and p-CREB	¹²⁷
Quercetin	Rosae Chinensis Flos (Rosa chinensis Jacq.); Albiziae Cortex and Flos (Albizia julibrissin Durazz.); Roase Rugosae Flos (Rosa rugosa Thunb.); Hyperici Perforati Herba (Hypericum perforatum L.); Cyperi Rhizoma (Cyperus rotundus L.); Bupleuri Radix (Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd)	UCMS adult male Wistar albino rats	Antioxidant through inhibiting MDA levels, increasing CAT and SOD activity and restoring GSH levels; anti-inflammatory by decreasing TNF-α, NF-κB, IL-1β and IL-6 release and diminishing serum corticosterone	¹³⁸
	FPS-induced male Sprague-Dawley rats	increased expression of BDNF, Copine 6, p-TrkB and TREM 1 and decreased expression of TREM 2	¹³⁶
	OB female Swiss mice	Decreased LOOH levels, inhibited NMDA and NO	¹⁴⁰
	UCMS Swiss albino mice	Increased SOD, GSH, CAT and 5-HT levels; decreased glutamate, TNF-α and IL-6 levels	¹³⁷
		CUS Swiss albino mice	reduced hippocampal TBARS and nitric oxide levels; restored total thiol and CAT levels; reduced hippocampal levels of TNF-α, IL-6, IL-1β and COX-2	¹³⁹
Luteolin	Albiziae Cortex and Flos (Albizia julibrissin Durazz.); Hyperici Perforati Herba (Hypericum perforatum L.); Cyperi Rhizoma (Cyperus rotundus L.)	Corticosterone-treated male ICR mice	Reduced expressions of GRP78 and GRP94	¹⁴²
	C6 cells; primary hippocampal neurons; ovariectomized depressed SD rats	downgraded PMAT; upgraded BDNF expression; inhibited 5-HT reuptake; increased monoamine neurotransmitters in the synaptic cleft	¹⁴³
	male ICR mice; HEK-293 cells	promoted Cl⁻ ion influx; modulated GABAA receptor	¹⁴¹
Curcumin	Curcumae Radix (Curcuma wenyujin Y. H. Chen et C. Ling, Curcuma longa L., Curcuma kwangsiensis S. G. Lee et C. F. Liang or Curcuma phaeocaulis Val.)	UCMS model	improved antioxidant enzymes activities; inhibited effect on AchE activity	¹⁴⁷
	UCMS Male Wistar rats	Reduced CUMS-induced glial activation and IL-1β overexpression; attenuated neuronal apoptosis	¹⁴⁸
	Adult male WKY rats	increased hippocampal BDNF	¹⁴⁹
	OB male albino rats	normalized levels of DA, DOPAC, NA, 5-HT and 5-HIAA	¹⁵³
	Male C57BL/6J mice	increased BDNF protein and ERK phosphoryation	¹⁵¹
	Male SD rats	increased levels of DA, 5-HT, NA, 5-HIAA and DOPAC	¹⁵⁵
	OB-induced adult male Wistar rats	increased serum corticosterone levels, reduced MDA and nitrite levels, restored GSH and CAT levels, increased TNF-α and caspase-3; enhanced BDNF	¹⁵⁷
	CUMS-treated male Wistar rats	Increased expression of BDNF, PSD-95 and synaptophysin	¹⁵²
	CUD-treated male SD rats	induced deactivation of the left primary auditory cortex and activation of amygdalohippocampal cortex	¹⁶¹
	Rotenone-induced depressive Albino-Wistar rats	Increased DA, DOPAC, 5-HT and 5-HIAA in striatum and hippocampus	¹⁵⁴
	CUMS-treated male SD rats	decreased IL-1 β, IL-6 and TNF-α; suppressed the activation of NF-γ B, P2X7R/NLRP3 inflammasome axis and IDO; decreased kynurenine/tryptophan ratio	¹⁶⁰
	CUS-induced male Wistar rats	Increased hippocampal BDNF and ERK levels	¹⁵⁰
	CUMS-treated male SD rats	Increased BDNF and decreased COX-2	¹⁵⁶
	LPS-treated adult male Kun-Ming mice	Inhibited microglial activation; decreased IL-1, TNF-α, nitric oxide synthase, cyclooxygenase2, ameliorated NF-γ B activation	¹⁵⁹
	CMS-treated Male Wistar rats	inhibited NF-γ B	¹⁵⁸
	Adult male SD rats	blocked the Ca_v2.2 and Ca_v2.1 channels; inhibited glutamate release	¹⁶²
Hyperforin	Hyperici Perforati Herba (Hypericum perforatum L.)	CUMS-treated rodent model	increased zinc concentration and BDNF level	¹⁶³
	CUS Adult male Wistar rats	TRPC6 activation	¹⁶⁶
	primary cultures of cortical neurons	enhanced Ca²⁺ influx	¹⁶⁷
	cells expressing a dominant negative mutant of TRPC6	inhibited 5-HT and norepinephrine; induced sodium, calcium entry and currents; TRPC6 activation	¹⁶⁴
	Primary cultures of cortical neurons from embryonic E13 C57BL6/J mice	upregulated TrkB; expression of TRPC6; activated PKA; Ca²⁺ entry; phosphorylation of CREB	¹⁶⁸
Adhyperforin	Hyperici Perforati Herba (Hypericum perforatum L.)	CUMS-treated Swiss mice	Inhibited uptake of 5-HT, NE and DA	⁷⁷
	male Wistar rats	Inhibited uptake of 5-HT, NE and DA; inhibited DA translocation	¹⁶⁹
Catechin	Hyperici Perforati Herba (Hypericum perforatum L.)	CUMS-treated SD mice	recovered CAT, glutathione and SOD levels	¹⁷²
Rutin	Hyperici Perforati Herba (Hypericum perforatum L.); Bupleuri Radix (Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd)	CUS-induced Adult Swiss albino mice	Recovered hippocampal neuronal loss.	¹⁷³
	Pregnant NMRI mice	Decreased expression of NR2B and NR2A subunits of NMDA receptors, increased CA3 diameter and decreased percentage of dark neurons in the hippocampus	¹⁷⁴
	PCPA and AMPT-treated male Swiss mice	increased 5-HT and NA in the synaptic cleft.	¹⁰⁶
Puerarin	Bupleuri Radix (Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd)	CUS-treated SD mice	Decreased progesterone, allopregnanolone, 5-HT, 5-HIAA; blocked CRH, Cort and ACTH	¹⁷⁸
	Male C57BL/6J mice	activation of AMPAR-induced mTOR signaling pathway; increased GluR1 phosphorylation and BDNF	¹⁰⁵
	SNI-induced mice	Increased BDNF and activation of CREB pathway	¹⁷⁵
	CUS-treated male C57BL/6 mice	Increased FGF-2	¹⁷⁷
	OVX ICR mice	increased transcription of BDNF and ER mRNA	¹⁷⁶
Saikosaponin A	Bupleuri Radix (Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd)	SD rats	Reduced IL-1 β, IL-6 and TNF-α; activation of P38MAPK pathway	¹⁷⁹
	CUMS-treated female Wistar rats	promoted BDNF-TrkB signaling; reduced IL-1 β, IL-6 and TNF-α; restored the HPA axis	¹⁸⁰
	CUMS-treated male SD rats	increased PRRT2 and DA	¹⁸¹
Saikosaponin D	Bupleuri Radix (Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd)	CUMS-treated male SD rats	Increased p-CREB and BDNF; restored the HPA axis	¹⁸³
	CUMS-treated male SD rats	Reduced NF-γ B and miR-155; enhanced FGF2	¹⁸⁴
	LPS-treated Male ICR mice; Primary microglia culture	Decreased IL-1 β, IL-6 and TNF-α; inhibited HMGB1 translocation; decreased TLR4, p-I γ B-α, NF-γ Bp6	¹⁸²

4.1 Gallic Acid

Gallic acid, a trihydroxybenzoic acid, has been widely reported to be used in depression treatment.¹⁰⁷ It demonstrated antidepressant-like activities in a range of animal models. Gallic acid treatment (50-150 mg/kg) alleviated the trimethyltin chloride (TMT)-induced hippocampal cellular loss and ameliorated the depression state in rats.¹⁰⁸ In mice subjected to unpredictable mild stress, gallic acid (10-20 mg/kg) demonstrated antidepressant-like activities through inhibiting monoamine oxidase-A (MAO-A) activity and decreasing plasma nitrite and corticosterone levels.¹⁰⁹ Gallic acid (25-50 mg/kg) was also found to be active in modulating depressive symptoms and reducing oxidative stress in balb/c mice with post-stroke depression.¹¹⁰ Recently, Samad and his colleagues reported that gallic acid (50-100 mg/kg) had protective effects on sodium arsenite (iAS)-induced depression and memory alteration in male rats via its antioxidant potential.¹¹¹ Overall, the antidepressant activities of gallic acid are mainly attributed to the amelioration of antioxidative enzymes in the development of depression, enhanced 5-HT and catecholamine levels in synaptic clefts of the central nervous system, and the modulation of alpha adrenergic, serotonergic and dopaminergic receptors.^112,113

4.2 Hypericin

Hypericin, a naphthodianthrone, is the characteristic constituent of the genus Hypericum (Hypericaceae).⁷⁵ Moreover, commercial products of St. John's wort are frequently adjusted to contain a standard concentration of hypericin.¹¹⁴ Administration of hypericin was found to modify levels of depression-related neurotransmitters in brain regions. It could elevate plasma corticosterone, increase 5-HT levels, and decrease 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid levels in the hypothalamus of rat models.^115,116 The indirect activation of 5-HT₂ receptors may partly lead to the regulation of some of them.¹¹⁶ Extracellularly applied hypericin could increase neuronal action potential duration, which might be ascribed to its inhibitory effect on transient I_A and delayed rectifier I_K potassium currents. As the result of increased neuronal action potential duration, the synaptic efficiency was significantly enhanced under hypericin treatment, thus exerting an antidepressant effect.¹¹⁷ Excessive glutamate release is known in the pathophysiology of depression, and hypericin has been reported to inhibit this release from rat cerebrocortical nerve terminals through a decrease in the voltage-dependent Ca²⁺ influx and mitogen-activated protein kinase activity, thus exerting an antidepressant activity.¹¹⁸ The excitatory amino acids and monoamine neurotransmitter metabolites, such as tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) (tyrosine and 5-HT metabolites), in the urine were affected by hypericin treatment of chronic unpredictable mild stress (CUMS) model rats. Especially, urinary valine was remarkably increased, which may indicate the potential hypericin targets.¹¹⁹

4.3 Kaempferol

Kaempferol is a flavonoid exerting a wide range of pharmacological actions, including antidepressant.^120,121 In the chronic social defeat stress (CSDS) mouse model, kaempferol significantly increased the bodyweights, sucrose consumption, social interaction time and the mobility time of TST, thus contributing antidepressive effects. These effects may be achieved through increasing the activities of oxidative stress enzymes, such as SOD, CAT, GPx, and GST, decreasing levels of inflammatory mediators and microglial activation, such as IL-1β and TNF-α, and activating and enhancing Akt/β-catenin cascade activity in the prefrontal cortex.¹²² Moreover, using computer-based analysis of Network Construction and Clustering, Lin et al recently proposed that kaempferol alleviated depression symptoms through regulating MAO-A, MAO-B and ESR1, which are crucial target genes of various mental diseases, and particularly important for depression.¹²³

4.4 Crocetin

Crocetin, a carotenoid, has a polyunsaturated conjugated oleic acid structure. Treatment with crocetin (12.5, 25 and 50 mg/kg) was able to decrease the immobility time in the forced swim test (FST) and TST without affecting the baseline locomotor activity and coordination of mice.¹²⁴ It has also been reported to effectively ameliorate the immobility time and the number of crossings in chronic restraint stress rats through reverting the levels of MDA and GSH, as well as the activities of antioxidant enzymes.¹²⁵

4.5 Crocin

Crocin is a water soluble carotenoid dominated by crocin I, formed by galacturonic acid and either gentian disaccharide or glucose. Oral administration of crocin significantly ameliorated the immobility time in FST without affecting the baseline locomotion of mice at a concentration of 100 mg/kg.¹²⁴ Its antidepressant activities were also evidenced in the animal model of chronic corticosterone (CORT)-induced depression by the open field test (OFT), FST and TST.¹²⁶ The mechanisms underlying these activities are partially related to enhanced CREB, BDNF, vascular growth factor (VGF) and p-CREB protein expressions in rat hippocampus.¹²⁷ In the study using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced subacute mouse Parkinson's disease (PD) mice, crocin exerted an anti-depression-like behavior through protecting the dopaminergic projection neurons in the ventral tegmental area (VTA) by mammalian target of rapamycin (mTOR) activation and subsequently enhancing neural synaptic plasticity of the medial prefrontal cortex (mPFC).¹²⁸ Crocin was also reported to reduce the levels of proinflammatory cytokines (IL-1β) and the expression of the SOD family, thus suppressing neuroinflammation and oxidative stress in the hippocampi to attenuate depression-like behaviors. It reduced accumulation of nicotinamide, improved the synthesis of NAD ( + ), stimulated the activity of SIRT3 deacetylase, and elevated the activity of antioxidants such as SOD2 and glutathione reductase. Moreover, crocin inhibited the levels of oxidative damage markers including reactive oxygen species and malonaldehyde, rescued impaired mitochondrial function and restored the level of ATP production.¹²⁶ In the chronic obstructive pulmonary disease (COPD) model, crocin administration was also reported to reverse depression and reduce proinflammatory cytokines in the hippocampus. Meanwhile, it inhibited inflammatory cell numbers, suppressed the infiltration of peribronchial inflammatory cells and reduced the concentration of proinflammatory cytokines in bronchoalveolar lavage (BAL) fluid and lung tissue through the regulation of PI3K/Akt-mediated inflammatory pathways.¹²⁹

Similarly, crocin exhibited effects against LPS-induced depressive-like behaviors through anti-inflammatory and anti-oxidant activities. In BV-2 cell lines, it inhibited the production of NO and the release of cytokines TNF-α, IL-1 β and ROS, decreased the expression of iNOS, NF-γ B p65 and CD16/32, as well as elevating the expression of CD206. In the hippocampus of LPS-induced mice, expression of NLRP3, ASC and caspase-1 were neutralized with a reduction in the level of IL-1 β, IL-18 and TNF-β.¹³⁰ In a prenatal stress (PNS) mice model, crocin restored the expression of impaired hippocampal synaptic plasticity-associated proteins by modulation of the growth hormone secretagogue receptor (GHSR)- PI3K pathway, which led to a fast-onset and prolonged antidepressant effect.¹³¹

4.6 Quercetin

Quercetin is a bioflavonoid reported to produce antidepressant activities in a range of animal models.^132–135 In TST, FST and sucrose consumption test (SCT), quercetin enhanced the anti-depressive-like behavior in the unpredictable chronic mild stress (UCMS) and LPS-induced rat model of depression.^136–138 Quercetin treated the depression by its antioxidant and anti-inflammatory effects, including inhibited MDA levels, reduced hippocampal TBARS and nitric oxide levels, increased 5-HT, total thiol, CAT and SOD activity, restored GSH levels, decreased glutamate, COX-2, TNF-α, NF-κB, IL-1β and IL-6 release, and diminished serum corticosterone.^137–139 More recently, Fang et al reported that quercetin was able to ameliorate the decreased expression of BDNF, Copine 6, p-TrkB, and the triggering receptors expressed on myeloid cells (TREM) 1, and increase levels of TREM 2 in the hippocampus and the prefrontal cortex (PFC), thus alleviating LPS-induced depression-like behaviors and impairment of learning and memory in rat models.¹³⁶ In the olfactory bulbectomy (OB) animal model of depression, quercetin treatment could reverse the increased lipid hydroperoxide (LOOH) levels and exert antidepressant effects by inhibition of the N-methyl-_D-aspartate (NMDA) receptors, nitric oxide synthase and nitric oxide production.¹⁴⁰

4.7 Luteolin

Luteolin is a phytoestrogen with antidepressant effects reported in several experimental models. Luteolin treatment increased the intracellular Cl⁻ flux in cultured human neuroblastoma cells, while this influx could be attenuated by the GABA_A receptor antagonist, bicuculline. To an extent, its antidepressant effects could be related to the modulation of the GABA_A receptor.¹⁴¹ Using TST and FST, luteolin demonstrated antidepressant capacity with reduced despair state by regulating the expression of endoplasmic reticulum stress-related proteins (GRP78 and GRP94) in corticosterone-treated depression mice.¹⁴² Luteolin also could downregulate plasma membrane monoamine transporter (PMAT) through estrogen β receptor (ERβ) and mRNA expression, and subsequently decrease the protein expression and transporter activity in C6 cells and primary hippocampal neurons. Moreover, it directly inhibited 5-HT reuptake of transporters located in the presynaptic membrane and enhanced the monoamine neurotransmitter in the synaptic cleft, thereby exhibiting antidepressive activities.¹⁴³

4.8 Isorhamnetin

Isorhamnetin was reported to induce neurofilaments expression through potentiating NGF-induced neurite outgrowth, thus being a potential candidate for treating depression.¹⁴⁴

4.9 Curcumin

Though the clinical efficacy remains mainly controversial, the antidepressant activity of curcumin and its diverse mechanisms of action have been demonstrated in various animal and human studies.^145,146 Curcumin was found to attenuate UCMS-induced depression symptoms and increased load of oxidative stress by improving antioxidant enzyme activities. The memory function could also be improved by modulation of cholinergic activity by curcumin treatment.¹⁴⁷ Also in UCMS-induced rat models, chronic administration of curcumin (5 weeks) significantly alleviated depression-like behaviors through inhibition of IL-1β-induced neuronal apoptosis within neurons of the ventromedial prefrontal cortex (vmPFC).¹⁴⁸ Chronic curcumin treatment also could lead to increased BDNF protein in the hippocampi and amygdala, at least in part, by increased levels of ERK phosphorylation, thus providing antidepressant effects in animal models of depression.^149–151 Similarly, Zhang et al found that prevention of the decreased BDNF and synaptophysin protein expression, and amelioration of PSD-95 expression by curcumin may also be involved in its antidepressant-like effects to CUMS exposure.¹⁵² Moreover, curcumin reversed levels of central monoaminergic neurotransmitters, including DOPAC, noradrenaline (NA), 5-HT and 5-HIAA in the hippocampus region, while restoring the levels of DA, NA, and 5-HIAA in the frontal cortex of the OB and FST rat models.^153–155 Choi et al found that curcumin could enhance postsynaptic electrical reactivity and cell viability in intact neural circuits through modulation of the expression of BDNF and inflammatory factors.¹⁵⁶ In OB-induced depression models, curcumin treatment could increase serum corticosterone levels, reduce MDA and nitrite levels, restore reduced GSH and CAT levels, increase inflammatory cytokines (TNF-α) and apoptotic factor (caspase-3) levels, and enhance BDNF expression.¹⁵⁷ Additionally, curcumin demonstrated antidepressant activities through inhibition of the NLRP3 inflammasome and kynurenine pathway. It decreased the expression of proinflammatory cytokines, such as IL-1β, IL-6 and TNFα, restored the levels of inducible nitric oxide synthase and cyclooxygenase2, suppressed microglial and NFγ B activation, the stress-induced P2X7R/NLRP3 inflammasome axis, and indolamine-2, 3-dioxygenase (IDO).^158–160 Meanwhile, an increased kynurenine/tryptophan ratio was ameliorated.¹⁶⁰ Curcumin treatment could also reverse depression behaviors and abnormal brain glucose metabolism through inducing strong deactivation of the left primary auditory cortex and activation of the amygdalohippocampal cortex in chronic unpredictable stress (CUS)-induced models.¹⁶¹ Another reported possible mechanism underlying curcumin's antidepressant activity was to inhibit glutamate release from rat prefrontal cortex nerve terminals by the suppression of presynaptic Ca_v2.2 (N-type) and Ca_v2.1 (P/Q-type) channels, but not by blocking intracellular Ca²⁺ release or Na⁺/Ca²⁺ exchange.¹⁶²

4.10 Hyperforin

Hyperforin is a bicyclic polyprenylated acylphloroglucinol derivative that underlies the antidepressant activities of many herbal medicines. In CUMS rat models, hyperforin treatment could reverse the decreased zinc concentration in the frontal cortex and hippocampus, and increase the levels of BDNF in the hippocampus.¹⁶³ The canonical transient receptor potential 6 (TRPC6) has been found to be one of the key molecular targets of hyperforin. Hyperforin could inhibit the uptake of neurotransmitters, such as neuronal 5-HT and norepinephrine, and induce sodium and calcium entry, as well as currents, by specific activation of TRPC6.^164,165 Liu et al found that the cognitive defect of depression could be ameliorated by hyperforin treatment through activation of TRPC6 protein in CUS rat models.¹⁶⁶ Intracellular Ca²⁺ levels of cortical neurons were also modulated by hyperforin by activating Ca²⁺-conducting non-selective TRPC6 channels.¹⁶⁷ Furthermore, the activation of TRPC6 channels and the expression of BDNF receptor TrkB were medicated by hyperforin through SKF-96365-sensitive channels, which control a downstream signaling cascade involving Ca²⁺, protein kinase A, CREB and p-CREB in primary cultures of cortical neurons.¹⁶⁸

4.11 Adhyperforin

Tian et al reported that adhyperforin could increase the number of crossings and rearings of OFT and the sucrose intake in CUMS rat models, while reducing the immobility time of FST and TST in reserpine-induced models. Moreover, adhyperforin also inhibited uptake of neurotransmitters, including 5-HT, NE and DA in rat synaptosomes, enhanced robust binding affinities for the 5-HT and NE transporters, and inhibited DA translocation.^77,169

4.12 Catechin

The antidepressant activities of catechin have been demonstrated in several animal models.^170,171 Especially in CUMS-induced depression models, catechin was found to improve sucrose intake and reduce immobility time of FST. Meanwhile, it also ameliorated oxidative stress through modulation of antioxidant parameters, including CAT, glutathione and SOD.¹⁷²

4.13 Rutin

Rutin, quercetin-3- rutinoside, also known as sophorin, is a flavanol glycoside comprised of the flavanol quercetin and the disaccharide rutinose. In CUS-induced depressant rat models, rutin treatment could produce an intact hippocampus with cell number and morphology similar to that of normal animals, thus protecting the hippocampal neuronal loss.¹⁷³ Similarly, in mouse models of maternal separation (MS) stress, rutin also exerted an antidepressant effect via a neuroprotective effect on the hippocampus, including expression inhibition of NR2B and NR2A subunits of NMDA receptors, modulation of CA3 diameter and percentage of dark neurons in the hippocampus.¹⁷⁴ Machado et al also demonstrated that the regulation of serotonergic and noradrenergic and/or dopaminergic systems was also involved in the antidepressant action of rutin using p-chlorophenylalanine methyl ester (PCPA) and α-methyl-p-tyrosine (AMPT)-treated animal models.¹⁰⁶

4.14 Puerarin

Puerarin is a glycosyl isoflavone with multiple biological activities, including antidepressant. In spared nerve injury (SNI)-induced depression models, puerarin induced BDNF expression and markedly promoted the activation of the CREB pathway via the ERK pathway.¹⁷⁵ Similarly, in ovariectomized (OVX) mice, the downregulated transcription of BDNF and ER mRNA was also reversed by puerarin in a dose-dependent manner.¹⁷⁶ Puerarin was also reported to increase the expression of hippocampal fibroblast growth factor-2 (FGF-2), a neurotrophic or anti-inflammatory regulator in the central nervous system, thus attenuating anhedonia and despair behaviors in chronic stress induced depressive-like mice.¹⁷⁷ In controlling the CUS-induced behavioral deficits, chronic treatment with puerarin attenuated the biosynthesis of progesterone and allopregnanolone, blocked the increase in the hypothalamic-pituitary-adrenal (HPA) stress hormone, corticotropin releasing hormone (CRH), corticosterone (Cort) and adrenocorticotropic hormone (ACTH), and decreased the levels of monoamine neurotransmitters 5-HT and 5-HIAA in the prefrontal cortex and hippocampus of rat models.¹⁷⁸ Moreover, Huang et al found an activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionaic acid receptor (AMPAR)-induced mTOR signaling pathway under puerarin treatment. As the consequence of this activation, a significant increase in GluR1 phosphorylation at its PKA site and BDNF released were promoted to exert antidepressant effects on experimental animals.¹⁰⁵

4.15 Saikosaponin A

Tang et al recently attributed the antidepressive behaviors of saikosaponin A to its anti-inflammation activities. It could attenuate neuroinflammation through the P38MAPK pathway and reduction of pro-inflammatory cytokines, such as IL-1 β, IL-6 and TNF-α released in the serum.¹⁷⁹ In CUMS-treated perimenopausal animal models, saikosaponin A ameliorated the depression through restoration of neuroendocrine, neuroinflammation and neurotrophic systems in the hippocampus. It enhanced the expression of BDNF through promoting BDNF-TrkB signaling, reduced the release of IL-1 β, IL-6 and TNF-α, and restored the HPA axis.¹⁸⁰ Moreover, fifteen hippocampal proteins with different physiological functions were identified to be involved in the antidepressant behaviors of saikosaponin A treatment using proteomic screening. Among them, proline-rich transmembrane protein 2 (PRRT2), known to play a key role in the process of neurotransmitter release, was proved to affect DA content in hippocampal tissue. Thus, the antidepressant activities of saikosaponin A were also related to the upregulation of PRRT2 expression and increased DA content in the hippocampus.¹⁸¹

4.16 Saikosaponin D

Su et al reported that saikosaponin D could prevent lipopolysaccharide (LPS)-induced microglia activation and neuroinflammation, thus improving depressive-like behaviors in both in vitro and in vivo models. Especially, the overexpression of inflammatory factors, including IL-1 β, IL-6 and TNF-α, nuclear-extracellular translocation of high mobility group box 1 (HMGB1) and protein levels of TLR4, p-I γ B-α, and NF-γ Bp65 were all inhibited by saikosaponin D treatment in the hippocampus of mice and primary microglia cells.¹⁸² In UCMS-treated rats, saikosaponin D exerted its antidepressant activities through ameliorating the dysfunction of the HPA axis and consolidating hippocampal neurogenesis. p-CREB and BDNF were significantly increased as a result of saikosaponin D treatment.¹⁸³ Moreover, saikosaponin D also ameliorated depression-like behaviors in the UCMS-treated rats by downregulating NF-γ B and its target miR-155, and upregulating fibroblast growth factor 2 (FGF2).¹⁸⁴

4.17 Others

Besides the compounds reviewed above, the antidepressant effects of safranal, cyprotusides a-b, rotundusides f-h, saikosaponins b-c, (2Z,8Z/E,10E)-pentadecatriene-4,6-diyne-1-ol and (2Z,8Z/E,10E)-heptadecatriene-4,6-diyne-1-ol have also been reported in the literature. However, the pharmacological mechanisms underlying their activities have not been elucidated and thus need further exploration.

5 Concluding Remarks and Future Prospect

With specific functions of ‘dispel melancholy’ recorded in Chinese Pharmacopoeia, Rosae Chinensis Flos, Croci Stigma, Albiziae Cortex and Flos, Roase Rugosae Flos, Curcumae Radix, Hyperici Perforati Herba, Cyperi Rhizoma and Bupleuri Radix have been comprehensively reviewed in this paper with regard to clinical trials, and phytochemical, and pharmacological aspects. The mechanistic insights into their functional antidepressant compounds, including gallic acid, hypericin, kaempferol, crocetin, crocin, quercetin, luteolin, isorhamnetin, curcumin, hyperforin, adhyperforin, catechin, rutin, puerarin, and saikosaponins A and D, have been collected and summarized (Table 1).

The numerous studies reviewed help to validate the antidepressant potential of nine traditional Chinese herbs and their active compounds, and strongly support ongoing and any further proposed clinical trials. The phytochemical investigations have been widely reported and produced numerous secondary metabolites with various bioactivities for further elucidation. According to the current bioactive and pharmacological research using experimental models either in vitro or in vivo, these herbs do present the antidepressant activities claimed in the Chinese pharmacopeia and the relative TCM documents. Most important, clinical trials have been conducted and reported of the effective therapeutic effects for patients with depression in some of those herbs including Croci Stigma (Crocus sativus L.), Hyperici Perforati Herba (Hypericum perforatum L.) and Bupleuri Radix (Bupleurum chinense DC. or B. scorzonerifolium Willd.). Taken together, the nine antidepressant herbs reviewed herein certainly have the potential to be developed as versatile adjuvants or even pharmaceutical agents with promising therapeutic and industrial applications. However, the major shortfalls of this development are: 1) the pharmacological mechanisms underlying the antidepressant activities of these herbs need clarification for future investigation and drug development; 2) few studies have been performed to assess the treatment effects of these herbs against depression and phytochemical metabolism in human subjects to confirm the therapeutic outcomes. Even for the three herbs which had been evaluated in clinical trials, properly designed multicenter trials with larger sample size, longer treatment duration and with different ethnic groups are still needed to verify the current results. Regarding the active compounds of the herbs reviewed in this paper, their antidepressant behaviors could mainly be attributed to five mechanistic aspects: 1) inhibition of the expression of MAO and reversal of the depletion of monoamine and certain neurotransmitters, such as NE, 5-HT, DA, 5-HIAA and 3,4-DOPAC, in the hippocampus and frontal cortex; 2) regulation of the expression of the neurotrophic factor hippocampal BDNF by activating its intracellular targets; 3) prevention of neuroinflammation through reduction in the level of pro-inflammatory cytokines, commonly including IL-1, IL-6 and TNF-α; 4) reduction in the production of oxidative markers and improvement in the activities of antioxidant enzymes; 5) alleviation of HPA axis disturbances. The identified mechanisms, especially pharmacological targets, could contribute to the design and establish the experimental models for screening of potential active metabolites from natural products and the development of antidepressant drugs in future.

Based on the review of current research, there is a need in this area for further properly designed clinical trials to provide meaningful data in determining the efficacy and safety of a given antidepressant treatment by the herbal medicines reviewed in this paper. Moreover, efforts should also be made to determine the pharmacokinetics, bioavailability, and detailed pharmacological mechanisms of the functional antidepressant constituents of these herbs. Safety verification and clinical trials are expected to progress TCM-based antidepressant drug development and finally succeed in transforming such herbal medicines or their secondary metabolites to new drugs for patients suffering from depression.

Supplemental Material

sj-docx-1-npx-10.1177_1934578X211059312 - Supplemental material for Chinese Pharmacopoeia Revisited: A Review of Anti-Depression Herbal Sources

Supplemental material, sj-docx-1-npx-10.1177_1934578X211059312 for Chinese Pharmacopoeia Revisited: A Review of Anti-Depression Herbal Sources by Dongyi Hu, Jiayu Gao, Xiao Yang and Ying Liang in Natural Product Communications

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

Ethical Approval

Not applicable, because this article does not contain any studies with human or animal subjects.

Informed Consent

Not applicable, because this article does not contain any studies with human or animal subjects.

ORCID iD

Jiayu Gao

Trial Registration

Not applicable, because this article does not contain any clinical trials.

Supplemental material

Supplemental material for this article is available online.

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