Experimental Studies in Animals or Cells
Aconitum carmichaelii contains alkaloids and polysaccharides as active principles. While the polysaccharide
fraction had no effect on brain monoamine levels in the frontal cortex, it did increase
the expression of BDNF in the brains of mice, as well as the number of dentate gyrus
neurons [33]. In the case of the alkaloid fraction, it was shown to enhance the ratio of phosphorylated-CREB
and BDNF protein levels in the frontal cortex and hippocampus in ovariectomized mice.
Unfortunately, the 8-acetyl,14-benzoyl diester diterpene alkaloids are highly toxic;
however, during the preparation process (decoction), the toxic diester alkaloids can
be hydrolyzed into less toxic monoester aconitine alkaloids, which can then be converted
to even less toxic aconine alkaloids with no observable reduction in pharmacological
activity [34].
Both the essential oil and the water extract of Acorus calamus var. angustatus shows antidepressant-like effects in the FST and TST, but not in the OFT [35], [36], [37]. Using these same tests, Han et al. [35] demonstrated that the essential oil from the rhizomes of the plant, along with its
major compounds, principally β-asarone (47, Fig. 6S, Supplementary Information), exert antidepressant-like effects. Similar conclusions
were obtained by Dong et al. [36], who assayed β-asarone in a CUMS model and found that this compound significantly increased the
expression of BDNF at both the transcription and translation levels. With regard to
the mechanism of action, this compound acts in a stress-dependent manner to block
ERK1/2-CREB signaling but exhibited no effects in nonstressed rats. In a subsequent
study, Zang et al. [37] observed similar effects for the petroleum ether and water fractions, demonstrating
that even water fractions with only trace amounts of β-asarone exert antidepressant-like effects. The active extract contains different
phenolics with the activity due to the regulation of SERT activity [37].
Actaea cimicifuga reduced immobility duration in both the FST and TST without affecting locomotor activity,
enhanced the 5-hydroxytryptophan-induced head-twitch response, decreased the levels
of plasma ACTH, and lowered serum corticosterone and adrenal gland weight in CUMS-treated
female rats. Both serotonergic and noradrenergic activation are implicated in the
effects as well as the normalization of the HPA axis [38]. A related plant, Actaea racemosa is traditionally used for ameliorating premenstrual and dysmenorrheic disorders as
well as neurovegetative climacteric complaints. Winterhoff et al. [39] tested the standardized BNO 1055 extract using a TST and observed a significant
decrease in the period of immobility along with a reduction in the frequency of hot
flashes, a result that is in agreement with the therapeutic responses in climacteric
women [39]. Aegle
marmelos was analyzed for its potential antidepressant-like effect with a TST as well as with
the EPM as an anxiolytic test. While the extract showed demonstrable effects in the
TST, its activity was significantly decreased by the α
1 and D2 antagonists, as well as by the GABAB agonist, thus implying the involvement of the adrenergic and dopaminergic systems
[40]. The antidepressant-like mechanism of Agapanthus campanulatus was tested in vitro with a functional uptake inhibition assay against SERT, NAT, and DAT. The ethanolic
extract demonstrated dose-dependent antidepressant-like effects in the FST and TST
while inhibiting SERT, NAT, and DAT [41], [42]. Likewise, Akebia quinata was shown to decrease immobility in both the FST and TST in mice and reversed CUMS-induced
inhibition of sucrose consumption in rats. The effects
were associated with decreased levels of plasma ACTH and serum corticosterone
in CUMS-rats [43]. Jing et al. [44] established that hederagenin (1, Fig. 1S, Supplementary Information) was the principal active compound, finding that it inhibited
SERT, NAT, and DAT in rat brain membrane preparations and HEK293 cells transfected
with the corresponding human SERTs. Hederagenin increased both NA and 5-HT levels
as well as the expression of 5-HT1A receptor mRNA, while decreasing the expression of the mRNA for SERT and affecting
the expression of BDNF [45]. Alafia multiflora showed positive effects in both the anxiolytic (EPM, OFT) and antidepressant tests
(FST) in rats and mice but had no effect on locomotor activity. The researchers suggested
the implication of monoamine systems but could not establish their involvement [46]. The
antidepressant and anxiolytic effects of Albizia julibrissin (water extract) were investigated with the EPM [47] while the methylene chloride fraction was assayed with the TST [48]. In the first case, an increase was noted in both time spent and arm entries, whereas
in the latter test, the fraction reduced the immobility time compared to the control
group [47]. This antidepressant-like effect was reversed by treatment with a 5-HT1A receptor antagonist but was not affected by treatment with 5-HT1B or 5-HT2A receptor antagonists; therefore, the plant extract seems to exert its antidepressant
effects through 5-HT1A receptors [48]. Several years later, Liu et al. [49] determined that one of the active principles of this plant extract was the compound
(−)-syringaresinol-4-O-β-D-apiofuranosyl-(1 → 2)-β-D-glucopyranoside (52, Fig. 6S, Supplementary Information), which increased the percentage of entries into and time
spent on the open arms of the EPM while lowering the concentration of ACTH and corticosterone
in plasma and decreasing the amount of neurotransmitters (DA, NA, 5-HT) and their
metabolites in the cerebral cortex and hippocampus of treated rat brains. These results
point to disease inhibition via the HPA axis [49]. Albizia lebbeck decreased the duration of immobility time in a dose-dependent manner in both the
FST and TST in mice but exerted no effect on the locomotor activity of the mice [50].
Daily administration of Allium cepa powder reduced the immobility time in the FST without changing the motor dysfunction.
The authors concluded that onionʼs antidepressant-like activity is independent of
the HPA axis because plasma corticosterone levels were not affected [51]. Ten years later, Samad et al. [52] tested onion powder in mice with various protocols, including the EPM, LDA, FST,
and MWM. They also examined the powderʼs effects on brain lipid peroxidation, antioxidant
enzymes, and AChE. They concluded that antioxidant enzymes have a relevant role in
the attenuation of stress-induced anxiety and depression and that they also enhance
cognitive function [52]. Allium macrostemon was likewise studied with the FST and TST protocols; in vitro tests with the born cells in the subgranular zone and the granule cell layer were
also carried out and the expression
levels of BDNF were examined by means of western blotting and immunohistochemistry.
The results demonstrated that the immobility duration in both tests was reduced, whereas
there were increases both in the number of cells and in the BDNF expression levels,
which are associated with neurogenesis [53]. Chen et al. [54] also studied the antidepressant-like effect of this species but with a rat model
of depression induced by exposure to chronic immobilization stress; the results were
obtained through chromatographic methods. Differences were noted between the plasma
lipid and acylcarnitine profiles of depressed rats and those in the control group,
with most of the dysregulated metabolites returning to their normal values in the
treated rats. These changes indicate that depression in rats is associated with several
inflammatory conditions along with an incomplete β-oxidation of fatty acids [54]. The third species of Amaryllidaceae to be studied was Allium sativum. In this case, researchers tested the effects of the essential oil after 28 consecutive
days, with a reduction of the immobility time (FST) and a reversal of the decrease
in the sucrose preference index induced by 5 wk of CUMS. The essential oil also decreased
the frontal cortex turnover ratio of 5-HT and DA by increasing their levels but had
no hippocampal effects. However, its chronic administration was shown to increase
hippocampal BDNF, CREB, and Akt expression, most likely due to the modulation of monoamine
neurotransmitters and the BDNF-related signaling pathway. The authors were unable
to unequivocally establish the main active principle; when they tested garlicʼs major
organosulfur component, diallyl disulfide, it showed less activity than the essential
oil, which points to the presence of other active principles in garlic [55].
Aloysia gratissima was tested by Zeni et al. [56] in mice. The anti-immobility effect caused by the TST was prevented by specific
antagonists of the monoaminergic receptors, leading to the conclusion that the activity
of the compound depends on the serotonergic (5-HT1A and 5-HT2A/2C), noradrenergic (α
1 and α
2), and dopaminergic (D1 and D2) systems [56]. Aloysia polystachya was tested in both the EPM and FST on female rats. The authors established that the
monoterpenes thujone and carvone, among others, may be potential active compounds,
with a possible mechanism in which GABA could be implicated [57]. However, in a second study they cited flavonoids as the most likely active compounds
[58]. Recently, the main chemical compound of the extracts was established as being
acteoside (53, Fig. 6S, Supplementary Information), which might also be the active principle. This experiment
involved examining the effect of caffeine on zebrafish, which produces an anxiogenic
effect that can be reversed by the hydroalcoholic extract in the same way that fluoxetine
does. The researchers thus concluded that A. polystachya has anxiolytic and antidepressant-like activity, probably due to the presence of
acteoside [59]. In the case of Aloysia citriodora, the authors proposed the implication of the GABAergic and serotoninergic systems,
which could mean that this plant may also function as an antidepressant-like drug
in addition to its anxiolytic properties [60]. There are other studies on the plantʼs CNS activity; however, the use of different
extracts (polar and non-polar) hinders an accurate evaluation of the results in order
to elucidate the activity of lemon verbena as an
antidepressant-like plant [61].
When Anacyclus pyrethrum was tested for antidepressant-like activity, it reduced the immobility caused by
both the FST and TST, prompting the authors to hypothesize that the antidepressant-like
effect could be due to its interaction with adrenergic and dopaminergic receptors,
and through an increase in DA and NA levels in the brains of mice [62]. The main bioactive principle of Andrographis paniculata, andrographolide (23, Fig. 3S, Supplementary Information), which had previously been tested for multiple pharmacological
properties, was recently evaluated as a potential antidepressant agent in mice. Andrographolide
showed activity in both the FST and TST without influencing the locomotor activity
of the test mice; it also exhibited significant antidepressant-like effects in the
CUMS model and prevented decreases in hippocampal BDNF signaling and neurogenesis
in mice, an effect that could be considered the antidepressant-like
mechanism [63]. Using the FST, Ren et al. tested the effects of sarsasapogenin (6, Fig. 1S, Supplementary Information) isolated from Anemarrhena asphodeloides in mice. The compound affected the immobile response but did not modify the locomotor
activity. It also increased NA and 5-HT levels in both the hypothalamus and the hippocampus.
Moreover, sarsasapogenin inhibited MAO in the mouse brain. The authors therefore hypothesized
that the antidepressant-like activity of sarsasapogenin involves the central monoaminergic
neurotransmitter systems [64], [65].
Riparin III (80, Fig. 8S, Supplementary Information) from Aniba riparia was studied as an antidepressant-like compound in different protocols. The compound
decreased the immobility time in both the TST and FST, with no effects on the spontaneous
motor activity in mice [66]. In a complementary study, these same authors established that the antidepressant-like
effect is dependent on the compoundʼs interaction with the serotonergic, noradrenergic
(α
1 and α
2), and dopaminergic (D2) receptors [67]. In addition, mice exposed to the corticosterone-induced chronic depression model
and treated with riparin III showed increased BDNF protein levels in the hippocampus
[68]. The compound likewise exhibited anxiolytic-like properties [69]. Riparin II (79) [70] and riparin I
(78, Fig. 8S, Supplementary Information) [71] were also tested as potential antidepressant-like agents. The former was tested
in rodents, with the results showing a significant decrease of immobility time in
both the FST and TST. Pretreatment of test mice with receptor antagonists (α
1, D1, D2, and 5-HT1A), an inhibitor of 5-HT synthesis, and a serotonin receptor antagonist completely
blocked the anti-immobility effects elicited by riparin II in the FST. These results
indicate that the antidepressant-like activity of riparin II is dependent on its interaction
with the noradrenergic, dopaminergic, and serotonergic systems [70]. When riparin I was tested using the FST and TST, it also decreased the immobility
time. Pretreatment with monoamine antagonists likewise demonstrated the implication
of these systems in the compoundʼs effects [71].
Martínez-Vázquez et al. [72] studied an alkaloid-enriched extract from Annona cherimolia in mice, using the FST for evaluating the compoundʼs activity as well as different
agonist and antagonist effects of monoamines. The results gave a positive result,
with the mechanism being attributed to an increase in monoamine turnover. The alkaloids
in the extracts were identified as anonaine (63), liriodenine (64), nornuciferine (65), and 1,2-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinoline-3,8,9,10-tetraol (66) (see Fig. 7S, Supplementary Information) [72]. Annona coriacea was also evaluated, as well as caffeic acid (48, Fig. 6S, Supplementary Information), the major phenolic present in the extract. The results
indicated that both samples have antidepressant-like effects as well as anxiolytic
properties, both involving the GABAergic and monoaminergic systems
[73]. Annona vepretorum’s essential oil was tested in a protocol similar to that used for A. coriacea with similar results, but in this case, the antidepressant-like effect was related
to its action on serotonergic receptors whereas it anxiolytic properties were associated
with the GABAergic system. [74].
Apocynum venetum, used in traditional Chinese medicine [75], was studied by Butterweck et al. [76] as a potential antidepressant-like agent in rats. The researchers speculated that
the effect might be related to the major flavonoids present in the extract, hyperoside
(37) and isoquercitrin (38, Fig. 1S, Supplementary Information) [76]. They also compared the short-term (2 wk) and long-term (8 wk) effects of this extract
with those of imipramine, detecting marked changes in DA and NA levels in the rat
hypothalamus, striatum, and hippocampus after 8 wk; 5-HT levels were not affected.
They also established the relationship between decreased NA levels and presynaptic
α
2-receptors, whereas there was no effect on the β-adrenergic receptors [77]. These results were corroborated by Zheng et al. [78], who studied the antidepressant-like effect and monoaminergic mechanism of a flavonoid-enriched
extract of this plant. The results were attributed to increased levels of NA and DA,
together with their respective metabolites, in the mouse hippocampus, which were dependent
on the interaction of the extract with D1 and D2 receptors [78]. Previously, these same authors had suggested that the flavonoid hyperoside could
be the principal antidepressant agent and proposed a possible mechanism of action
involving a heightened expression of BDNF and CREB through the signal pathway AC-cAMP-CREB
[79]. Additional studies with the same extract in rats using the CUMS model showed reduced
serum corticosterone and ACTH levels. The extract also increased the activities and
gene expression of antioxidant enzymes such as SOD, catalase, and glutathione peroxidase,
while decreasing ROS generation levels
and lipid peroxidation in the rat hippocampus. Moreover, the extract suppressed
the apoptosis of hippocampus cells by modulating the Bcl-2/Bax pathways and improved
hippocampal BDNF expression. The researchers concluded that the extract exerted antidepressant-like
effects through prevention of oxidative stress, the inhibition of hippocampal neuronal
apoptosis, and the upregulation of hippocampal BDNF levels [80]. In a similar study, Wu et al. [81] demonstrated that the extract improved depressive behavior in CUMS rats because
it reversed the increased apoptosis of hippocampus and cortical neurons and increased
Bcl-2, BDNF, and CREB protein expression while simultaneously decreasing Bax, cytochrome
c, and caspase family protein expression. These findings indicate that A. venetum exerts its antidepressant-like activity mainly through the suppression of neuronal
apoptosis.
Areca catechu is the fourth most widely used psychoactive substance in the world after caffeine,
nicotine, and alcohol [82]. Previous reports have shown that this nut exerts antidepressant-like effects in
mice and rats in both the FST and TST while also decreasing the levels of MAO in rat
brain homogenates. Areca nut has also been shown to have antidepressant-like effects
in mice and rats; in this case, the activity was associated with the regulation of
DA and 5-HT levels through MAO inhibition [83]. It has also been tested using behavioral and biochemical tests in rats and showed
activity in both the acute and sub-chronic FST, with the saponins being the most likely
active compounds due to the significant elevation of 5-HT and NA levels compared to
the controls [82]. Artemisia absinthium reduced the immobility period in both the FST and TST in a dose-dependent manner.
In
this case, the activity was associated with the compoundʼs antioxidant properties,
which come from its high content in flavonoids and other phenolics [82]. Asparagus racemosus decreased immobility in the FST and increased the avoidance response in the LHT,
which is indicative of antidepressant-like activity. The authors concluded that this
activity could be mediated through the serotonergic and the noradrenergic systems,
as well as an increase in antioxidant defenses [84], [85]. Moreover, A. racemosus is a nonselective competitive inhibitor for both AChE and MAO enzymes and thus may
produce some interactions with other drugs and food [86].
Bacopa monnieri is used as a dietary antioxidant and has been described as a protector of the brain
against oxidative damage and age-related cognitive decline [87], [88], [89]. Sairam et al. [90] described the effect of a standardized extract (38% of bacoside A, 7, Fig. 2S, Supplementary Information) as antidepressant-like in FST and LHT models of depression
in rats, but no mechanisms were proposed [90]. Bhattacharya et al. [91] demonstrated its antioxidant properties while also finding evidence of reduced oxidative
stress in the aging brain, which could be hypothesized as a mechanism for improving
cognition [89]. Basella alba showed similar activity in both the FST and TST, most likely due to the main compounds
present in the extract, which include
alkaloids, tannins, and flavonoids, but no mechanism was proposed [92]. In the case of Benincasa hispida, the activity (assayed with the FST) is due to the inhibition of MAO-A; an interaction
with the dopaminergic, α
1-adrenergic, serotoninergic, and GABAergic systems was implicated in the mechanism
[93]. Boophone disticha was also tested with the FST and TST and showed functional inhibition of SERT, NAT,
and DAT. Various studies with Amaryllidaceae alkaloids, including those present in
this plant, showed activity with regard to SERT, while the alkaloids buphanidrine
(76) and buphanamine (77, Fig. 7S, Supplementary Information) were shown to exhibit selective 5-HT reuptake inhibition,
leading the authors to establish alkaloids as the active compounds in this plant [41], [94]. Bupleurum falcatum reduced the
total duration of immobility in mice in the TST with no modification observed
in the OFT. The activity was dose-dependent and involved the serotonergic and noradrenergic
systems [95]. In addition, it significantly reduced depression-like symptoms following repeated
restraint stress through hypothalamic CRF modulation and noradrenergic system regulation
in the locus coeruleus of treated rats [96].
Camellia sinensis leaves are commercially available in different forms, differing mostly in the degree
of fermentation, which has an effect on their antioxidant properties [97]. Several studies have established the relationship between a higher consumption
of green tea and a lower prevalence of depression [98]. To confirm these properties, Zhu et al. [99] used different mouse models of depression (FST and TST) for testing green tea polyphenols
and their mechanisms of action as potential antidepressant agents. Green tea polyphenols
were found to reduce immobility in both tests. They also reduced serum corticosterone
and ACTH levels, but did not modify the locomotor activity in the OFT. This led the
researchers to conclude that the polyphenols in green tea exert their antidepressant-like
effects in mice through the inhibition of the HPA axis [99]. In a
complementary study, Liu et al. [100] investigated the antidepressant-like effects of tea polyphenols using the mouse
model of CUMS-induced depression and found that the activity was exerted through both
monoaminergic pathways (5-HT and NA) and antioxidant defenses [100]. Similar results were obtained by Di Lorenzo et al. [101], who used both green tea and GABA green tea (special green tea with a high GABA
content) in a mouse model of post-stroke depression. Both teas showed a significant
effect on the modulation of depressive symptoms, restoring normal behavior and improving
the antioxidant endogenous defenses through the reduction of oxidative stress [101]. GABA green tea was also studied by Teng et al. [102], who observed that the GABA present in green tea has a healthy effect on the prevention
and alleviation of depression
by modulating GABAergic neurotransmission in the mouse cerebral cortex by up-regulating
the expression of the GABAA receptor α
1 subunit [102].
Concanavalin Br is a lectin with mannose/glucose affinity isolated from Canavalia brasiliensis seeds. When this compound was tested in a mouse FST model, it elicited an anti-immobility
effect that could be prevented by pretreating the test mice with different receptor
antagonists (5-HT1A/1B/β, 5-HT1A, 5-HT2A/2C, D2, and α
2) but not with the D1 or α
1 receptor antagonists. This indicates that the antidepressant-like effect of this
lectin elicited in this protocol is due to its interaction with the serotoninergic,
noradrenergic, and dopaminergic systems. Considering the presence of lectins in the
brain and based on these results, the elucidation of a possible role of endogenous
lectins in the modulation of CNS system function is of great interest [103]. The same research group [104], [105] thus went on to study the role of concanavalin Br in the brain along with the role
of endogenous lectins in the modulation of CNS function. Because many receptors, ion
channels, and transporters making up the CNS are glycoproteins, where the glycan chains
are modulator elements and lectins are proteins, these recognize and bind carbohydrate
complexes. The antidepressant and neuroprotective effects of concanavalin Br may thus
be dependent on carbohydrate interaction. Rieger et al. [104] demonstrated that this lectin improves BDNF expression, probably through a mechanism
dependent on CREB activation mediated by PKA, ERK1, and Akt. In addition, this lectin
inhibited the NMDA receptor and reduced NO and cGMP synthesis [105], which could justify in part the antidepressant-like effect of concanavalin Br in
the FST. Zhao et al. [106] found that the ethanolic extract of the flowers
of Carthamus tinctorius inhibited 5-HT uptake in Chinese hamster ovary cells. Following an activity-guided
isolation, these researchers identified N
1,N
5-(Z)-N
10-(E)-tri-p-coumaroylspermidine (81, Fig. 8S, Supplementary Information) as the active principle. After more testing, this compound
was found to be a novel 5-HT transporter inhibitor, with IC50 values of 0.74 µM (S6 cells) and 1.07 µM (synaptosomes), and with a reversible competitive
property for the inhibition of 5-HT-uptake [106]. Qazi et al. [107] studied the petal extract with similar results in an FST [107] while Abbasi-Maleki et al. [108] studied the flower extract in a TST model and described the involvement of both
dopaminergic (D1 and D2) and serotonergic
(5-HT1A and 5-HT2A) receptors. They postulated a relevant role for N-hexadecanoic acid as the major compound found in the extract (about 20%) [108]. Casimiroa edulis reduced the immobility time with respect to the controls, increasing the climbing
behavior in a similar way as the selective 5-HT reuptake inhibitor fluoxetine; however,
the authors did not cite any active principles [109]. Han et al. [110] isolated 7 flavonoids from a methanol extract of Cayratia japonica through an activity-guided isolation using a MAO inhibition assay model. Of these,
apigenin, luteolin, and quercetin were the most potent MAO inhibitors, with specificity
against MAO-A vs. MAO-B.
Centella asiatica contains pentacyclic triterpenes, mainly asiatic acid (11), asiaticoside (12), madecassic acid (13), and madecasosside (14, Fig. 2S, Supplementary Information) [111]. Many clinical studies of these compounds have been carried out, especially against
dermatological disorders [112], but different experiments with animals have demonstrated the potential of the total
triterpenes fraction as an antidepressant, reducing the immobility time in the FST
in mice [113], ameliorating the function of the HPA axis, increasing the neuronal monoamine neurotransmitters
(DA, 5-HT, NA) and their metabolites, and reducing the corticosterone levels in serum
[114]. In subsequent research, Ceremuga et al. [115] investigated the anxiolytic and antidepressant effects of asiatic acid and its
potential modulation of the GABAA receptor using the EPM and the FST in rats. The results were significant with regard
to the ratio of open arm time, maximum speed, and time spent mobile in the asiatic
acid group as well as in the group treated with asiatic acid combined with midazolam.
Flumazenil counteracted the anxiolytic effects. From these results, the authors concluded
that asiatic acid acts on the GABAA receptor [115]. Polyphenols from Ceratonia siliqua have been shown to exert antidepressant-like effects in both the FST and TST in mice.
Their activity is due to their α-adrenoceptor and D2 antagonist properties, as clearly indicated by the fact that the effects are mediated
by DA and NA [116]. Different species of Rutaceae have edible fruits, such as bitter orange (Citrus × aurantium), pomelo (Citrus maxima), and grapefruit (Citrus
paradisi). Bitter orange and pomelo were studied in both the FST and OFT whereas pomelo was
also studied with a TST. The anti-immobility effect of orange fruits observed in the
FST was prevented by pretreating test rats with various specific antagonists (but
not prazosin), which led to the hypothesis that the active extracts act through the
participation of 5-HT1A, 5-HT2A, D1, D2, and α
2 receptors but not their α
1-adrenergic counterparts [117]. In the case of C. maxima, the extract reduced the immobility time in both tests, indicating that the mechanism
may involve a possible increase in NA levels in the synapses [118]. In the third species, the flavonoids were proposed as the potential active agents
[119].
Clitoria ternatea has been used in Ayurvedic medicine for centuries to treat various nervous system
diseases, including as an antidepressant [120], but an early study concluded that the alcoholic extract only acts at high doses
[121]. Some year later, Jain et al. [122] observed that the extract decreased the duration of immobility in the TST. It also
showed a tendency to reduce the intensity of behavior mediated by 5-HT and ACh whereas
its effect on behavior mediated by DA and NA was not significant [122]. Malik et al. [123] further corroborated these findings and evaluated the activity in the TST in mice.
In another study, the immobility time of rats was also reduced in a dose-dependent
manner in both the FST and TST, leading the authors to hypothesize that the effects
may be due to the presence of flavonoids and that
the mechanism could involve an interaction with the GABAA receptors [124]. Dhingra and Valecha [125] assayed different extracts of Convolvulus prostratus, but only the chloroform fraction was found to significantly reduce the immobility
time in both the FST and TST by interacting with the adrenergic, dopaminergic, and
serotonergic systems. However, the methanolic extract showed antidepressant-like effects
in the SPT, FST, and CUMS. Moreover, the extract reduced the increased levels of pro-inflammatory
cytokines IL-1β, IL-6, TNF-α, and the liver biomarkers ALT and AST in CUMS-exposed rats. Furthermore, the extract
restored the NA and 5-HT levels in the hippocampus as well as in the PFC of CUMS-exposed
rats. The authors thus concluded that C. prostratus exerted its antidepressant-like effect through its anti-inflammatory properties,
restoring liver biomarkers and monoaminergic
responses in the stressed rats [126].
The main components of Crocus sativus are its essential oil (with safranal, 15, Fig. 3S (Supplementary Information), as the most abundant component), bitter principles,
dye material, and other minor compounds, such as the phenolic fraction, made up of
flavonoids, cyanidins, and anthraquinones [127], [128], [129], [130], [131]. Saffron has been used and assessed as a medicinal agent, and different properties
have been described for both saffron and its principles [127], [132], [133], [134], [135], [136], [137], [138]. However, the principal interest in saffron could be due to
its anticonvulsant, anti-anxiety, and hypnotic properties [139], [140]. In addition, antioxidant properties have been attributed to saffron and its various
compounds [141], [142], which may partly justify its neuroprotective effects. Several recent studies have
demonstrated that saffron not only inhibits reuptake of monoamines (DA, NA, 5-HT),
but that it also exhibits both NMDA receptor antagonism and GABAA agonism, which seem to be responsible for its antidepressant-like and anxiolytic
effects demonstrated in animal models (EPM and OFT) [143], [144], [145]. Two extracts of Cucurbita pepo were studied in an FST model in rats and found to decrease immobility time, with
the antioxidant properties of the aqueous extract being responsible for this effect
[146]. The total furocoumarin extract of Cullen corylifolium was likewise tested with the FST and was found to reduce the immobility time and
inhibit both MAO-A and MAO-B, with a more potent effect on the latter. The extract
also blocked plasma-elevated cortisol levels and decreased liver SOD activity and
MDA levels. The authors concluded that the antidepressant-like effects of furocoumarin
extract are mediated by MAO activity, HPA axis action, and oxidative stress [147]. A similar study was performed by Xu et al. [148] and Yi et al. [149], but in these experiments, the authors concentrated on psoralen (49, Fig. 6S, Supplementary Information), the major compound found in the furanocoumarins [148] and psoralidin (51, Fig. 6S, Supplementary Information) [149]. Psoralen reversed
FST-induced alterations in 5-HT levels in the frontal cortex and hippocampus in
mice while attenuating FST-induced elevations in serum CRF and corticosterone [148]. Not only did psoralidin affect 5-HT, CRF, and corticosterone levels, but it also
changed DA levels in the striatum of mice exposed to FST while elevating ACTH in serum
[149]. These results point to an implication of both the monoamine neurotransmitter and
the HPA axis systems [148], [149].
Turmeric (Curcuma longa) is used as a condiment and flavor corrector, although its use in phytotherapy is
also well-established. The European Pharmacopoeia recognizes the entire rhizome as
a phytotherapeutic agent [150], [151], [152], [153], [154]. The species C. aromatica and C. zanthorrhiza are also used for the same purposes [150], [151], [155], [156], [157], [158]. Of its various pharmacological properties, the anti-inflammatory [155] and neuroprotective [156], [157] properties are the most remarkable. Different researchers have focused
their efforts on demonstrating the properties of curcumin (57, Fig. 6S, Supplementary Information), the main active component, and its potential as a therapeutic
agent, especially in CNS pathologies. Consequently, interest in this compound as a
possible antidepressant has grown in recent years, with studies focusing on its antidepressant
activity in relation to its anti-inflammatory properties. Indeed, both the anti-inflammatory
and antioxidant properties of curcumin have been demonstrated in various studies [12], [158], [159] using different experimental protocols; this has favored the jump to its clinical
use. Among the antidepressant effects of curcumin observed in animal models, the most
notable are its action on the neurotransmitters involved in depression, its modification
of the response of the HPA axis, and its reduction of oxidative stress and mitochondrial
damage [160] due to its anti-inflammatory and antioxidant properties. More than 40 studies have
been conducted in animals using the aforementioned protocols, including the FST or
TST, although other more specific techniques have also been used, such as sleep deprivation,
immobilization stress, and cold stress, all as models of chronic stress. Surgical
procedures including bilateral olfactory bulbectomy and ligation of sciatic nerves
have also been employed [6]. In all cases, the findings have indicated a possible antidepressant effect. For
example, it was demonstrated that the administration of curcumin to rats and mice
improves the study parameters, both in acute and chronic depression models, with similar
effects to those obtained with fluoxetine and imipramine [6], [160], [161]. The results also demonstrated that the antidepressant
mechanism of curcumin involves both the serotonergic system [162] and the AC-cAMP pathway [163]. Curcumin has also been shown to improve the anti-immobility effect of subliminal
doses of various antidepressant drugs such as fluoxetine, venlafaxine, or bupropion
[164], while the combination of curcumin with piperine (a bioavailability enhancer) significantly
increased the anti-mobility effects, the potentiation of the neurotransmitters 5-HT
and DA, and the inhibitory effects of MAO-A with respect to curcumin administered
alone [165]. Other studies established the effect of curcumin in rats with bilateral olfactory
bulbectomy, which causes behavioral changes that lead to characteristics similar to
those observed in patients with depression. Bulbectomy causes important dysfunction
in the cortico-hippocampal-amygdaloidal circuit similar to that observed in
depressed people [166]; however, researchers found that the administration of curcumin modifies the changes
provoked by bulbectomy as effectively as antidepressants, reducing the immobility
time and reversing the behavioral abnormalities induced by the procedure [167]. Curcumin also attenuated the depletion of monoamines and the reserpine-induced
increase of oxidative stress [168] along with the behavioral changes induced by corticosterone [169]. In addition, curcumin was shown to revert or protect rat hippocampal neurons from
damage in response to chronic stress via positive regulation of 5-HT1A and BDNF receptors, 2 molecules involved in the neurogenesis of the hippocampus [170]. Ceremuga et al. [171] studied the anxiolytic and antidepressant-like effects of curcumin in various
selective tests and concluded that curcuminʼs effects were not due to its interaction
with the benzodiazepine site of the GABAA receptor. This means that the observed effects are likely due to the modulation of
other subunits on the GABAA receptor or even interactions with other CNS neurotransmitter systems, thereby confirming
the mechanisms previously cited for curcumin [171]. [Table 1] contains a concise summary of the main results obtained in vivo, with reference to the possible mode of action and the mediators involved in the
mechanism of action of curcumin as an antidepressant. The total glycoside-fraction
of Cynanchum auriculatum was also tested with the FST, TST, and LAT. In addition, the authors tested for the
inhibition of 5-HT reuptake in rat brain synaptosomes to conclude that the antidepressant-like
effects are due to the inhibitory effect on serotonin reuptake [172].
Table 1 Some relevant in vivo studies on the antidepressant-like activity of curcumin.
|
Dose
|
Effect
|
Ref.
|
|
i. p., intraperitoneal; p. o., per os (orally); s. c., subcutaneous
|
|
10 – 80 mg/kg, i. p., mice
|
Reduced the period of immobility and increased levels of 5-HT and DA (at higher doses)
and inhibited both MAO-A and MAO-B
|
[164]
|
|
20 and 40 mg/kg, i. p., 21 days with piperine (2.5 mg/kg, i. p., 21 days), rats
|
Increased the anti-mobility effect, potentiation of the neurotransmitters 5-HT and
DA, and the inhibitory effects of MAO-A with respect to curcumin administered alone
|
[165]
|
|
1.25 – 10.0 mg/kg for 14 days, rats
|
Reduced the immobility time and reversed the behavioral abnormalities induced by said
procedure
|
[167]
|
|
100 – 300 mg/kg, i. p., rats
|
Attenuates depletion of monoamines and the increase of oxidative stress with reserpine
(1 mg/kg, s. c., 3 days)
|
[168]
|
|
20 mg/kg, p. o. and corticosterone (40 mg/kg, s. c.) for 3 weeks, rats
|
Reduce the alteration of the behavior of the rats after an injection of corticosterone.
There was a 46% increase in sucrose consumption and 57% reduction in immobility time
versus negative control (only corticosterone).
|
[169]
|
|
10 and 20 mg/kg, p. o., rats
|
Revert or protect hippocampal neurons from increased damage via positive regulation
of 5-HT1A and BDNF receptors
|
[170]
|
Eleutherococcus senticosus is used with similar indications to those of Panax ginseng, although in the latter, other organs such as leaves are also employed [173], including for the treatment of mental and emotional problems, as well as an antistress
agent [174]. This has prompted several research groups to investigate its efficacy as an antidepressant
in animals, but no studies in humans have been reported. In this context, Jin et al.
studied the antidepressant-like activity at very high doses using FST and TST protocols.
The higher dose elevated the levels of 5-HT, NA, and DA in the whole mouse brain.
Moreover, the extract upregulated the level of CREB protein at both doses, leading
the authors to hypothesize that the antidepressant effects of E. senticosus are mediated by the central monoaminergic neurotransmitter system and CREB protein
expression [174]. In a
complementary study, Wu et al. [175] demonstrated the protective effects of E. senticosus on corticosterone-induced neurotoxicity (PC12 cells) as an in vitro model of depression. They observed that the extract increased cell viability, decreased
lactate dehydrogenase release, suppressed the apoptosis of PC12 cells, attenuated
intracellular Ca2+ overloading, and upregulated BDNF mRNA levels and CREB protein expression in comparison
with the control group. One year later, Gaire and Lim [176] studied the antidepressant effects of E. senticosus in rats (TST and FST) and evaluated the serum corticosterone levels. They noted that
at the higher dose, the extract ameliorated depressive behaviors and restored HPA
activity [176].
Icariin (44, Fig. 5S, Supplementary Information), a prenyl-flavonoid glycoside isolated from Epimedium brevicornu, was tested in a CUMS model of depression in rats. Administration of icariin reversed
the CUMS-induced sucrose intake reduction and CRF elevation, which affected the HPA
axis functions but not the hypothalamus-pituitary-thyroid (HPT) axis [177]. Two species of Eugenia, E. brasiliensis and E. uniflora, were tested both for their antidepressant-like effects and to assess the implication
of the monoaminergic systems in the mechanism of action. In the case of E. brasiliensis, the effect in the TST was mediated by the serotoninergic (5-HT1A and 5-HT2), noradrenergic (α
1), and dopaminergic (D1 and D2) systems [178], whereas in the case of E. uniflora, the activity was attributed to the serotoninergic
(5-HT2A/2C) and noradrenergic (α
1/2) receptors; the dopaminergic system was not involved [179].
Gastrodia elata has previously been studied as an antidepressant in different tests in which the
serotonergic and dopaminergic systems were implicated [180], [181]. In addition, when it was tested in the CSDS model, it ameliorated depression-like
behaviors and stress-induced elevations of corticosterone. It also increased the expression
of BDNF and promoted the hippocampal protein phosphorylation ratio of CREB and Akt
as a possible mechanism of action [182], whereas in the CUMS protocol this extract restored the cerebral turnover rates
of DA and 5-HT and decreased serum corticosterone levels [183]. Gentiana acaulis and its major compound, gentiacaulein, inhibited MAO-A activity in a crude brain
mitochondrial fraction of mice treated with the extract [184]. The standardized extract (Ginkgolon-24) of Ginkgo
biloba reduced the immobility time in both the FST and TST, prompting researchers to assign
its antidepressant-like activity to flavonoid-glycosides; however, other compounds
were also implicated, including ginkgolides and bilobalide. The most likely mechanism
involves the extractʼs effects on monoamines and MAPKs in the brain [185]. In the case of the EGb761 standardized extract, Rojas et al. [186] suggested that the antidepressant-like effect may be partly due to its observed
neuroprotective effects through its antioxidant properties [186]. Recently, Zhang et al. [187] described the compoundʼs antidepressant-like activities and the improved cardiac
function in mice with heart failure (SPT and OFT), with the compound reducing levels
of TNF-α, IL-1β, and 5-HT in the hippocampus, blocking the release of 5-HT in peripheral blood and
triggering HIF-1-induced anti-apoptotic pathways [187]. Glycyrrhiza glabra (liquorice) reduced the immobility times of mice in both the FST and TST, with various
monoamine receptor antagonists (D2 and α
1) reducing the effect, indicating that the extractʼs antidepressant-like effects are
due to an increase of DA and NA (but not of 5-HT) activity in the brain, [188]. In the case of G. uralensis, similar effects were observed in the same tests when the isolated compounds liquiritin
(40) and isoliquiritin (41, Fig. 5S, Supplementary Information) were used, but in these experiments, the mechanism of
action for both compounds was attributed to the increase of 5-HT and NA in the mouse
hippocampus, hypothalamus, and cortex, with no effect on DA [189].
Handroanthus impetiginosus was studied for its antidepressant-like effect (FST, TST, OFT), with the anti-immobility
effect being related to the serotonergic (5-HT2A), adrenergic (α
1, α
2, and β), and dopaminergic (D1 and D2) systems [190] as it increased not only both CREB and ERK1 phosphorylation but also BDNF signaling
pathways in olfactory bulbectomized rats [191]. Moreover, it reduced NO levels in the cerebral cortex, an effect that is dependent
on a blockade of NMDA receptor activation and inhibition of NO-cGMP synthesis [192]. Hedyosmum brasiliense also exerted an antidepressant-like effect (FST and TST), as did its isolated sesquiterpenoid,
podoandin (20, Fig. 3S, Supplementary Information). The activity was reported to be dependent on the serotonergic,
noradrenergic, and dopaminergic
systems but not on the GABAergic, opioid and oxidonitrergic systems [193]. Hemerocallis citrina reduced the immobility time in both the FST and TST models for depression in mice
with no concomitant changes in locomotor activity observed in the OFT. These results
were found to be dependent on the serotonergic (5-HT1A and 5-HT2), noradrenergic (α
1, α
2, and β), and dopaminergic (D2) systems, as well as on the elevation of 5-HT, NA, and DA levels in the mouse brain
[194]. Moreover, the extract reversed the aforementioned changes and upregulated the BDNF
and TrkB receptor protein expression in both the frontal cortex and hippocampus [195] while reversing the decreased sucrose preference in the SPT and inhibiting IL-1β, IL-6, and TNF-α expression [196]. When the
potential neuropharmacological components of a standardized mixture of its principal
flavonoids rutin (45) and hesperidin (46) (Fig. 5S, Supplementary Information) were tested, the activity was attributed to the serotonergic
and dopaminergic systems [197]. Xu et al. [198] tested the total phenol fraction of H. citrina using a CUMS model and described a potential mechanism mediated by regulation of
neurotransmitters and BDNF levels in the brain and alleviation of both the corticosterone
levels and oxidative stress [198]. The flavonoid hesperidin has also been shown to exert an antidepressant-like effect
mediated in an ERK-dependent manner [199]. Hibiscus rosa-sinensis decreased the immobility time (TST and FST) and attenuated the duration of immobility
induced by D2 and α
1 antagonists, and
acted as an 5-HT inhibitor synthesis in both tests. These results indicate the
implication of the dopaminergic, noradrenergic, and serotonergic systems [200]. In the case of Hippeastrum vittatum, the alkaloid montanine (73, Fig. 7S, Supplementary Information), isolated from fresh bulbs, was found to increase the
time spent struggling in the FST model, but no mechanism was proposed [201]. Hordeum vulgare showed an antidepressant-like effect in the FST, reducing both the duration of immobility
and the expression of mRNA for nerve growth factor in the hippocampus in a dose-dependent
manner, which could also be the mechanism for its antidepressant activities [202]. Both the CO2 extract and the α-acid-enriched fraction of Humulus lupulus reduced immobility time during the behavioral despair test, but neither of them affected
the locomotor
activity in the OFT or exerted an anxiolytic effect [203].
The genus Hypericum includes over 500 species, which often leads to confusion for some authors, since
different species are used around the world. The species Hypericum perforatum is known as St. Johnʼs wort, and its flowering tops have traditionally been used
in Europe as a first‐line treatment of major depressive disorder [12], [204]. There are 2 main groups of principles, naphthodianthrones (hypericin 55 and similar) and phloroglucinols (hyperforin 56 and others) (Fig. 6S, Supplementary Information), but other constituents are also relevant. The presence
of pyrrolizidines is not natural in the plant, although they may appear during the
harvesting process [205]. Several in vitro studies have established that St. Johnʼs wort could be an inhibitor of MAO-A and
MAO-B activity while also inhibiting the neuronal reuptake of serotonin, dopamine,
and
noradrenaline; however, it also has a significant affinity for adenosine, GABAA, GABAB, and glutamate receptors. Other studies have demonstrated a relationship between
the activity of St. Johnʼs wort extract and the downregulation of β-adrenergic receptors with a concomitant upregulation of 5-HT2 receptors. Recent research has also established the implication of several compounds
(most likely hypericin, hyperforin, and several flavonoids) in the regulation of genes
that control HPA axis function. With regard to the antidepressant effects of St. Johnʼs
wort extract, many of the pharmacological activities appear to be attributable to
hypericin, hyperforin, and several flavonoids [206]. In this last case, one study has shown that the absence of rutin reduced the antidepressant
activity of St. Johnʼs wort, and that hyperforin was the only plant compound present
in the brains of rodents after oral
administration of the alcoholic extracts, unlike hypericins and flavonoids, which
were not present [207]. Bukhari and Dar [208] tested a standardized extract of H. perforatum using the FST as an animal model of depression and found that the antidepressant-like
properties were related to selective 5-HT reuptake inhibitors. Recently, Zirak et
al. [209] reviewed this species and established that H. perforatum and its principal compounds, hypericin and hyperforin, possess antidepressant properties
similar to those of tricyclic antidepressants and SSRI and that their mechanism is
due to inhibition of MAO-A, modulation of the concentrations of DA, 5-HT, and NA in
the brain and peripheral tissues, inhibition of synaptosomal reuptake of amines, inhibition
of monoamine transporters, and upregulation of 5-HT1A and 5-HT2A receptors. Apparently, hypericin is the
main active principle from the extract [209]. Other species of Hypericum have also been studied as potential antidepressant-like agents, including H. canariense
[210], H. caprifoliatum
[211], [212], [213], [214], [215], [216], [217], H. glandulosum
[210], [211], H. grandifolium
[211], H. perfoliatum
[218], [219], H. polyanthemum
[220], and H. reflexum
[211]. All were studied in similar protocols, but H. caprifoliatum was the most extensively
researched, with both the extract and the phloroglucinol fraction evaluated in
an FST model. The activity was associated with an increase in monoaminergic transmission
due to the inhibition of monoamine uptake [212], along with the inhibition of Na+ influx, which increases hippocampal and cortical Na+K+-ATPase activities [213] by the phloroglucinol compounds. The lipophilic extract was also found to prevent
stress-induced corticosterone increases in the mouse frontal cortex but not in plasma,
exerting an antinociceptive effect mediated indirectly by the opioid system [214]. It was also shown to reduce immobility time and the FST-induced increase of serum
and cortical corticosterone levels while modifying the HPA axis reactivity to stress
[215]. Other studies have focused on the flavonoid hyperoside, the antidepressant-like
effect of which in rats was prevented by sulpiride, a D2 antagonist, thus implicating the dopaminergic system [216]. But recently, Stolz et al. [217] tested the effect of the dimeric phloroglucinol uliginosin B (54, Fig. 6S, Supplementary Information) using various protocols and observed that uliginosin
B inhibited monoamine reuptake, activated DA receptors, and indirectly stimulated
the opioid system [217].
Macranthol (60, Fig. 6S, Supplementary Information) from Illicium dunnianum was tested in the FST, TST, and CUMS models, attenuating the reduction of serotonergic
neurotransmission in the frontal cortex and hippocampus regions of the brain and ameliorating
the chronic but not acute, treatment-enhanced BDNF expression [221]. This antidepressant-like action was associated with BDNF-TrkB and downstream activation
of the PI3K/Akt-Bcl-2/caspase-3 signaling pathway [222]. In addition, this lignan decreased the levels of elevated pro-inflammatory cytokines
such as IL-1β, IL-6, and TNF-α in serum and the PFC, indicating that the antidepressant-like properties may be mediated
by the suppression of microglia-related neuro-inflammation in the PFC [223]. The compound 1,3,7-trihydroxy-2-(3-methylbut-2-enyl)-xanthone (62, Fig. 6S, Supplementary Information) from
Kielmeyera coriacea acts as an antagonist of 5-HT1A autoreceptors in the intra-median raphe nucleus while increasing 5-HT availability
in projection regions [224]. Lafoensia pacari reduced immobility time in antidepressant-like tests (FST, TST, and OFT) in mice
without affecting motor activity; however, no mechanism or active compounds were cited
[225]. In a second study, it exerted the effect by acting on the serotonergic and catecholaminergic
systems and increased hippocampal BDNF levels without affecting MAO activity, with
the phytochemical analysis indicating the presence of saponins, tannins, steroids,
and triterpenes [226].
Different species of Lavandula and their essential oils have been reviewed by Cavanagh and Wilkinson [227], who noted that aromatherapy with these oils could be effective due to both the
psychological and the physiological effects of the inhaled volatile compounds because
of the participation of both the amygdala and hippocampus. Although the mechanism
is unknown, some authors have suggested that the essential oil of lavender (Lavandula angustifolia) may have a similar action to that of benzodiazepines, enhancing the effects of GABA
in the amygdala. Other authors have cited the effect of linalool (18, Fig. 3S, Supplementary Information), which serves as an ACh release inhibitor and alters
ion channel function at the neuromuscular level [227]. Hritcu et al. [228] used the EPM and FST to evaluate the effects of the essential oils of lavender on
neurological capacity
in a scopolamine-induced dementia model in rats, demonstrating that these essential
oils exert antidepressant activity. In a similar study, the hydro-alcoholic extract
ameliorated scopolamine-induced memory impairment and depression-like behavior in
a dose-dependent manner [229]. Lavender oil and linalool also modulate the neuroendocrine system by interfering
with activation-induced tryptophan breakdown and indoleamine 2,3-dioxygenase activity
[230]. López et al. [231] established that lavender essential oil exerts its effects by modulating the NMDA
receptor. Caputo et al. [232] analyzed both the essential oil and linalool, demonstrating that both compounds
reversed social aversion behaviors, while linalool also inhibited the expression of
phosphorylated-ERK and kinase A, which are involved in the transmission of nerve signals
[232]. The oral administration of lavender essential oil attenuated nerve injury-induced
neuropathic pain symptoms in mice while simultaneously exerting an antidepressant-like
activity through the inhibition of spinal ERK and JNK phosphorylation, along with
the reduction of iNOS expression [233]. Lepidium meyenii (Maca) has been used to treat various maladies, including depression. It was tested
in the CUMS model of depression in mice and was found to decrease immobility time
in the TST; it also reduced corticosterone levels in serum. In addition, DA and NA
levels increased and ROS were inhibited in the mouse brain tissue [234]; however, MAO-A was not inhibited [235]. Lycium barbarum’s (wolfberry) antidepressant-like effect is due to the enhancement of synaptic plasticity
but not hippocampal neurogenesis [236].
Marsilea minuta reduced immobility in the FST and TST in rodents, with the activity due to the downregulation
of 5-HT2A receptors in the frontal cortex [237]. Melissa officinalis is also used as an antidepressant [238], with its extracts and essential oil showing antidepressant-like effects in mice
and rats [239], [240], [241]. In 2015, Lin et al. [242] tested rosmarinic acid (58, Fig. 6S, Supplementary Information), and found that both extract and rosmarinic acid modulated
serotonergic neurotransmission and down-regulated the turnover of 5-HT in the FST
model. Mimosa pudica reduced immobility time in both the FST and TST, but exhibited no effects in the
OFT (locomotor activity) and increased DA and NA levels in the brain. In addition,
the extract showed
anti-anxiety and memory enhancing activities [243]. In the case of Mitragyna speciosa, the major alkaloid (mitragynine 67, Fig. 1S, Supplementary Information) was tested and shown to reduce the immobility time of
mice in both the FST and TST, with no concomitant effect on locomotor activities.
The alkaloid also reduced the release of corticosterone in mice. The authors hypothesized
that mitragynineʼs antidepressant-like effects are most likely due to its interaction
with the neuroendocrine HPA axis systems [244]. Momordica charantia also reduced the duration of immobility in the FST and TST; in this case, the antidepressant-like
effect was found to be dependent on the monoamine receptors (5-HT2, α
1, α
2, and D2), but the muscarinic cholinergic systems and benzodiazepine-type receptor also seem
to be implicated in the plantʼs anxiolytic
activity [245].
Morinda officinalis has antidepressant and anti-inflammatory activities [246]. Zhang et al. [247] studied its effects in an FST animal model of depression, as well as in a behavioral
screening known to be both selective and sensitive to antidepressant drugs, namely
the DRL 72-s schedule. The plant extract exerted effects similar to those of the antidepressant
drug desipramine in rats in the DRL 72-s test, reducing the response rate and efficiency
ratio and increasing the reinforcement rate. In the FST, the extract also elicited
a significant reduction in the duration of immobility, as did the reference drug [247]. Other research has focused on the inulin-type oligosaccharides MW-97 (1 glucose
and 3 to 6 fructose) and P6 (6 units, 1 glucose and 5 fructose) obtained from this plant, finding that they both
increased 5-HT levels in the brains of reserpinized mice while
normalizing the hyperactive state of the HPA axis induced by chronic stress in
mice or rats [248]. In a subsequent study, the same authors demonstrated that P6 and desipramine antagonize the apoptosis induced by corticosterone in PC12 cells,
which may be one of the cellular mechanisms behind their antidepressant effects. In
addition, MW-97 increased both the 5-HT levels and the activity of the Gs protein-AC-cAMP
pathway, with both leading to an increase in the neurotrophic factors. This hypothesis
explains why MW-97 increases the activity of AC in vivo, while having no effect in vitro. This inulin-type hexasaccharide (P6, but referred to as IHS in this paper) decreased intracellular Ca2+ overloading, thereby upregulating nerve growth factor mRNA expression in corticosterone-treated
PC12 cells. This cytoprotective and neuroprotective action may be part of the mechanism
behind its antidepressant
effects [249], [250]. Xu et al. [251] described the positive effects of a mixture of oligosaccharides from M. officinalis on chronic, unpredictable stress-induced depression-like behavior in the SPT and
FST. Indeed, the mixture attenuated chronic, unpredictable stress-induced abnormalities
in the BDNF-GSK-3β-β-catenin pathway and ameliorated synaptic protein deficits in the medial–but not the
orbitofrontal–PFC. However, the phosphoinositide-3 kinase inhibitor LY294002 reversed
the antidepressant-like effects of these oligosaccharides in the FST, most likely
because of the activation of GSK-3β by the inhibitor. In addition, naïve rats treated with oligosaccharides exhibited
resistance to CUMS, accompanied by increases in the expression of BDNF, phosphorylated-Ser9-GSK-3β, and β-catenin in the medial PFC [251].
Moringa oleifera also produced significant changes in FST, TST, and LAT models, with the activity
involving the noradrenergic-serotonergic systems [252]. In the case of Morus alba, it decreased immobility in the FST in rats, decreasing the HPA axis response to
stress in the hippocampal and hypothalamic paraventricular nucleus region [253]. In contrast, the antidepressant-like activity (FST, TST, and CUMS in mice) of Mucuna pruriens involved the dopaminergic system [254]. Myristica fragrans also decreased the immobility period of mice in FST and TST models, with no effect
on locomotor activity. Different selective inhibitors of monoamine activity/receptor/synthesis
reduced or abolished the effects, which led to the hypothesis that the antidepressant-like
effect of nutmeg is mediated by its interaction with the adrenergic (α
1) and
dopaminergic (D2) receptors, along with 5-HT synthesis [255]. Moinuddin et al. obtained similar results working with rats [256], but no mechanisms were proposed.
The activity of Nardostachys jatamansi was studied in silico. The docking results prompted the authors to propose that the compounds of this plant
can modify depression through multiple molecular targeting of different compounds
[257]. Other authors studied these compounds in vivo and observed that they produced a decrease in brain MAO-A and MAO-B activities, consequently
increasing monoamine levels. In addition, the extract also interacted with GABAB receptors, resulting in a decrease in GABA levels in the mouse brain [258]. Working with Nelumbo nucifera, researchers isolated the bisbenzylisoquinoline alkaloids neferine (68), liensinine (69), and isoliensinine (70, Fig. 7S, Supplementary Information), which were studied for their antidepressant-like activity
(FST) in mice. The effect in this case was mediated by the 5-HT1A receptor, whereas
other subtypes of 5-HT and adrenergic receptors (α
1) were not implicated [259], [260]. Extracts enriched in flavonoids, saponins, alkaloids, tannins, and terpenoids were
also tested and likewise showed antidepressant-like activity in the FST as well as
anxiolytic effects in the EPM, but no mechanisms were elucidated [261]. Ocimum tenuiflorum shortened the immobility time in both the TST and FST while also decreasing anxiety
in different models but had no effects on the motor coordination of mice. No mechanisms
or active compounds were proposed [262].
Paeonia lactiflora reduced the duration of immobility in mice, with the effect being related to the
central monoaminergic neurotransmitter system [263], the modulation of the function of the HPA axis, the inhibition of oxidative stress,
and the up-regulation of neurotrophins [264]. To identify the potential active principles, the total glycosides of peony were
tested in the same protocols. The results suggested that the antidepressant-like effects
are mediated by the inhibition of MAO [265]. Albiflorin (19, Fig. 3S, Supplementary Information) from this plant exhibited activity in both the FST and
in a CUMS-induced model of depression in rats. This monoterpene-glycoside reversed
both the immobility and the reduced SPT while increasing 5-HT levels in serum and
those of its metabolite 5-HIAA in the hypothalamus. It also abolished the over-expression
of 5-HT1A and
5-HT2A receptors in the hypothalamus caused by CUMS. In addition, albiflorin enhanced DA
and NA concentration in the serum and hypothalamus, while increasing levels of tyrosine
hydroxylase, enhancing the D2 receptor and reducing DAT expression in the hypothalamus, thus demonstrating that
not only the serotonergic system but also the dopaminergic system is involved in the
antidepressant-like effect of albiforin [266].
Panax ginseng has been used for generations in Asian countries to combat various maladies, including
neurodegenerative diseases and cognitive dysfunctions [267]. It was shown to reduce immobility time in both the FST and TST [268]. The molecular and cellular mechanisms of ginseng include the modulation of the
monoamine neurotransmitter system, the upregulation of the expression of neurotrophic
factors, the regulation of HPA axis function, anti-inflammatory effects [269], and antioxidant activity through the Nrf2/heme oxygenase-1 system [270]. Several studies have focused on the pharmacological effects of different samples,
such as the ginseng extract G115 [271], the sesquiterpene fraction [272], or saponins [273], which are the most relevant chemicals in the
roots. The ginsenosides are the principal active group of chemicals found in this
plant; of these, the ginsenoside Rg1 (9) has been shown to exert antidepressant-like effects in mice via activation of the
hippocampal BDNF signaling pathway [274]. Indeed, treatment with ginsenoside Rb1 (10, Fig. 2S, Supplementary Information) attenuated the CUMS-induced decrease in the activities
of BDNF, TrkB, Akt, ERK, and CREB in the mouse hippocampal CA3 region and PFC. These
results suggest that BDNF-TrkB-CREB signaling may be involved in the antidepressant
mechanism of the action of Rb1 [269]. This compound also exhibited a significant antidepressant-like effect in behavioral
tests in mice (FST and TST), chronic animal models, and drug interactions. Its mechanism
is mainly mediated by central neurotransmitters with a significant upregulation of
5-HT, NA, and DA levels in CUMS rat brains [275]. However, not only is the monoaminergic system implicated; the glutamatergic and
GABAergic receptors may also be involved in the antidepressant-like effect of Rb1,
mainly because ginsenoside Rb1 has been shown to up-regulate the levels of the monoaminergic
and GABAergic systems while decreasing the level of glutamate in the mouse hippocampus
CA3 region and PFC [276]. Ginsenoside Rg1 (9) also modulated HPA and the hypothalamic-pituitary-gonadal axis in research carried
out by Mou et al. [277], who proposed this new mechanism for the antidepressant-like effects of ginsenoside
Rg1. The compound downregulated serum corticosterone levels while increasing androgen
receptor protein levels in the PFC of gonadectomized-treated mice, a result that provides
theoretical clues for potential clinical therapies [277]. Another mechanism proposed for ginsenoside Rg1 is its effect on
the corticosterone-induced Gap junction intercellular communication dysfunction
in astrocytes from the PFC and hippocampus, which may have clinical significance in
the treatment of depression, as observed by Xia et al. [278]. With a chemical structure similar to that of ginsenoside Rg1, ginsenoside Rg5 (8, Fig. 2S, Supplementary Information) likewise has antineuroinflammatory effects and leads
to cognitive improvements. Xu et al. [279] studied the antidepressant-like effects of ginsenoside Rg5 using different models
of depression. Ginsenoside Rg5 exhibited antidepressant-like activity in both the
FST and TST without affecting locomotor activity. It was also effective in the CSDS
model of depression, restoring the CSDS-induced decrease in the hippocampal BDNF signaling
cascade. The authors thus concluded that ginsenoside Rg5 exerts its antidepressant
activities via the activation of the hippocampal BDNF
system [279]. Panax notoginseng has been used to achieve the same objectives as true ginseng. It is similar in composition,
pharmacological make-up, and mechanisms for its effects [280]. For example, saponins found in the plant exerted antidepressant-like activity in
CUMS, FST, and TST models through regulation of 5-HT, DA, and NA; modulation of GABA
neurotransmission, the glutamatergic system, the HPA axis, and BDNF and its intracellular
signaling pathways in the CNS; and by producing neuronal protection by means of anti-inflammatory,
antioxidant, and anti-apoptotic effects [280], [281].
Paullinia cupana was assayed and compared with caffeine. It reduced the duration of immobility in
the FST but had no effect on ambulation in the OFT. These results seem to indicate
that the mechanism of guaraná does not involve the adenosinergic system [282]. Peganum harmala inhibited MAO-A due to its high content in the β-carboline alkaloids harmaline (71) and harmine (72, Fig. 7S, Supplementary Information) [235]. Perilla frutescens oil reduced immobility time in an FST rat model, increasing both BDNF and 5-HT levels
in the brain, thus partly explaining the antidepressant-like properties of this oil
[283]. In contrast, the essential oil reversed the alterations in the concentrations of
5-HT and 5-HIAA and reduced the IL-6, IL-1β, and TNF-levels in mice with CUMS-induced depression. The antidepressant-like activity
in this case is
related to the alteration of serotonergic responses and anti-inflammatory effects
[284]. Phyllanthus emblica was tested with the FST and TST in mice; its observed activity may come about through
its interaction with GABAB, α
1-, and D2-receptors, along with 5-HT synthesis [285]. Different species of Piper have been studied for their antidepressant-like effects in specific protocols in vivo and in vitro
[286], [287], [288], [289], [290], [291]. Piper laetispicum was shown to decrease IL-6 and TNF-α (pro-inflammatory), upregulate the expression of BDNF mRNA, and downregulate caspase-3
mRNA [286]. An amide alkaloid, laetispicine
(82, Fig. 8S, Supplementary Information) decreased the immobility time (FST) [287], with a complementary study revealing another antidepressant-like compound identified
as leatispiamide A (83, Fig. 8S, Supplementary Information) [288]. Piper nigrum decreased swimming time while increasing immobility time in the FST; the mechanism
involved attenuation of the oxidative stress in the rat amygdala [289]. Piper sarmentosum activity seems to be mediated by the modulation of the HPA axis along with phosphorylation
and expression of BDNF, CREB, and ERK in the hippocampus [290]. Piplartine, (84, Fig. 8S, Supplementary Information) an amide alkaloid, was isolated from Piper tuberculatum and shown to exhibit significant anxiolytic and antidepressant activities, but no
mechanisms were proposed for the latter effect [291]. Other species of Piper, such as P. longum L. and P. methysticum have also been described as antidepressants [292].
The genus Polygala has 4 species with antidepressant-like properties, all of which have been tested
by different authors using similar protocols (FST, OFT). In the case of Polygala paniculata, the activity was mediated by an interaction with the serotonergic (5-HT2A), adrenergic (α
2 and β), and dopaminergic (D1 and D2) receptors [293], as occurs in the case of scopoletin (50, Fig. 6S, Supplementary Information) isolated from Polygala sabulosa; however, in the latter case the effect involved the α
1 but not the β-adrenoceptor [294]. In the case of Polygala sibirica, the activity was related to the normalization of the deficit in hippocampal neurogenesis
with inhibition of newborn neuron apoptosis [295]. A mechanism similar for Polygala tenuifolia has likewise been
cited [296], with a relevant role for the HPA axis, but in this species, researchers studied
a particular isolated compound, 3,6′-disinapoyl sucrose (61, Fig. 6S, Supplementary Information), and found that its antidepressant-like properties were
mediated by the inhibition of MAO-A, MAO-B, the HPA axis, and the oxidative systems,
all through increases in SOD activity, inhibition of lipid peroxidation, and decreases
in the production of MDA [297]. The antidepressant effects of a mixture of α-amyrin (2) and β-amyrin (3, Fig. 1S, Supplementary Information) isolated from Protium heptaphyllum were evaluated in the standard protocol of antidepressant-like effects, and their
activity was attributed to a noradrenergic mechanism [298]. In contrast, the activity of Ptychopetalum olacoides seems to be mediated by β-adrenergic and
D1 receptors [299] along with the prevention of stress-induced HPA hyperactivity [300]. Pueraria montana var. lobata was tested against depressive-like behaviors of mice exposed to cerebral ischemia
reperfusion and was found to modify the disturbance of DA and NA systems in both the
hippocampus and striatum; this activity was more important in the development of depressive-like
behavior in mice than that of the 5-HT system [301].
Rhazya stricta
[302], [303], along with Rosa × damascena
[304], [305] were both studied and found to possess antidepressant properties. There are many
papers on the potential of Rosmarinus officinalis as an antidepressant drug, but no relevant clinical studies have been performed.
Machado et al. [306] observed a marked antidepressant-like effect in mice (FST and TST). Pretreatment
with a 5-HT synthesis inhibitor and receptor antagonists (5-HT2A, 5-HT3, α
1, D1, and D2)–but not with an α
2-adrenoceptor antagonist–reversed the anti-immobility effect. The authors concluded
that the antidepressant effect of rosemary is mediated by an interaction with the
monoaminergic system. These same authors [307]
established the effect of this extract in olfactory bulbectomized mice, observing
an increase in hippocampal AChE activity. They hypothesized that rosemary extract
could thus be used in the treatment of depression [307]. In 2 complementary studies, these same researchers established that the potential
active compounds of this extract, tested in the same protocols, were ursolic acid
(4) [308], betulinic acid (5) (Fig. 1S, Supplementary Information), and carnosol (25, Fig. 3S, Supplementary Information), [309]. However, other authors have cited luteolin (28, Fig. 4S, Supplementary Information), carnosic acid (26, Fig. 3S, Supplementary Information), and rosmarinic acid (58, Fig. 6S, Supplementary Information) as potential active compounds because they were shown
to regulate DA, NA, 5-HT, and ACh, as well as the gene expression of tyrosine
hydroxylase and pyruvate carboxylase, 2 major genes involved in dopaminergic,
serotonergic, and GABAergic pathway regulation [310]. Rosmarinic acid, luteolin-7-O-glucuronide (39, Fig. 5S, Supplementary Information), and caffeic acid (48, Fig. 6S, Supplementary Information), all of which are AChE inhibitors [311], as well as salvigenin (29), cirsimaritin (30, Fig. 4S, Supplementary Information), and rosmanol (27, Fig. 3S, Supplementary Information), which produce biphasic modulation of GABAA receptors [312], have also been proposed as active constituents. In one interesting study, Guo et
al. [313] investigated the antidepressant effects of rosemary extracts on chronic restraint
stress mice along with the inflammatory mechanisms related to the gut microbiome.
The results showed that the extract
significantly ameliorates depressive-like behaviors in chronic restraint stress
mice. This effect was due to the inhibition of inflammatory reactions in the hippocampus
and serum, as well as in microglia cells (BV-2), and the promotion of BDNF and p-Akt/Akt
expression in the hippocampus, along with a rebalance of gut microbiota. This data
is of interest because there is a clear relationship between depression and abundance
of Lactobacillus, Bacteroidetes, Firmicutes, and Proteobacteria. The rosemary extracts were found to decrease the proportion of both Bacteroidetes and Proteobacteria while promoting an abundance of Lactobacillus and Firmicutes. With respect to the pro-inflammatory mediators, the extract reduced IL-1β, TNF-α, and p-NF-κB, indicating a protective effect for rosemary extract in mice and its
implication in the antidepressant-like properties of the plant [313]. A lipid
extract (D-004) of Roystonea regia increased mouse immobility in both the FST and TST but showed no effects in other
behavioral tests [314].
Three species of Salvia have been tested as potential antidepressant-like agents in rodents. Salvinorin A
(23, Fig. 3S, Supplementary Information), the major compound from Salvia divinorum, was isolated and tested in EPM, FST, and TST rodent models. The authors concluded
that the anxiolytic- and antidepressant-like effects of salvinorin A are mediated
by both opioid and endocannabinoid systems but that the compound had a very weak affinity
for cannabinoid CB1 receptors [315]. Salvia elegans was also tested, but no significant activities were described [316]. In the case of Salvia sclarea, the essential oil showed antidepressant-like effects in the FST in rats. This property
seems to be closely associated with modulation of the dopaminergic pathway [317]. Sceletium tortuosum is also used as an antidepressant, with different studies in
animals demonstrating its activity [318], [319], [320]. The active compounds have been identified as mesembrine alkaloids [321]. Of these, both mesembrine (74) and mesembrenone (75, Fig. 7S, Supplementary Information) are 5-HT reuptake inhibitors, but mesembrenone also has
a reasonably potent inhibitory effect on phosphodiesterase-4 [321] while mesembrine was shown to be the most active alkaloid against SERT [322]. While this species has antidepressant properties, it also produces ataxia, which
may limit its usefulness as an antidepressant [318]. The activity of Schinus molle was shown to be due to its interaction with the serotonergic (synthesis and 5-HT1A, 5-HT2A/2C, 5-HT3 receptors), noradrenergic
(α
1- and α
2-adrenoceptors), and dopaminergic (D1 and D2 receptors) systems. Although the extract contains triterpenoids as major compounds,
no principles specifically responsible for these effects have been identified. Further
chemical analysis of the extract is planned in order to isolate and characterize the
active compounds responsible for the observed effects [323]. In addition, rutin (45, Fig. 5S, Supplementary Information) was also tested, and authors justified that the antidepressant-like
effect of Schinus molle was due to rutin, which acts by increasing the availability of 5-HT and NA
in the synaptic cleft [324].
Schisandra chinensis produces an antidepressant-like effect in corticosterone-induced depression in mice;
the effect seems to be mediated by the modification of the stress-based HPA axis dysfunction
and upregulation of the BDNF/TrkB/CREB signaling pathway [325], [326] along with the PI3K/Akt/GSK-3β pathways [326]; however, the modification of noradrenergic, dopaminergic, GABAergic, and glutamatergic
systems may also play a role [327]. Scrophularia ningpoensis has also been described as an antidepressant-like medicinal plant in an LHT model
of depression [328]. Scrophularia striata exerts its anxiolytic and antidepressant effects through modulation of the GABAergic
system, most probably GABAA, as was demonstrated in EPM and FST models, as well as through modulation of the
intracerebroventricular administration of an agonist or antagonist, which was
shown to enhance or block the effect of the ethanol extract [329]. Scutellaria baicalensis reduced immobility time (FST and TST), increased sucrose consumption (SPT), alleviated
the damage from CUMS-induced neurogenesis, and improved depressive-like behavior through
the regulation of the cAMP/PKA neurogenesis pathway. The authors identified wogonin
(31), baicalein (32, Fig. 4S, Supplementary Information), baicalin (42), and wogonoside (43, Fig. 5S, Supplementary Information) as the principal compounds responsible for these effects
[330]. Of these, baicalin has been studied as an isolated compound and was shown to increase
sucrose consumption in the SPT as well as the number of crossings in the OFT. It also
attenuated immobility time in the TST, with its mechanism seemingly related to the
promotion of
neuron differentiation via the Akt/FOXG1 pathway [331]. In addition, baicalin increased DA levels in the rat striatum, hippocampus, and
cortex and ameliorated the synaptogenesis associated with GABAA receptor downregulation following abnormal stimulation of D1 receptors [332]. Securidaca longepedunculata probably exerts its antidepressant-like effects through the opioidergic pathway [333].
Sedum roseum is used as an adaptogen, antidepressant, and anti-inflammatory agent [334], [335], [336]. A wide variety of preclinical in vivo and ex vivo studies with laboratory animals suggests the presence of several biochemical and
pharmacological antidepressant-like actions [337]. Different studies in animals established that golden root extract and its principal
constituent, salidroside (59, Fig. 6S, Supplementary Information), interact with different mediators implicated in several
molecular networks of the neuroendocrine and neurotransmitter systems involved in
the pathophysiology of depression. It was shown to improve depressive-like behaviors
through its anti-inflammatory effects (reducing TNF-α and IL-1β levels in the hippocampus) and the regulation of HPA axis activity (increasing glucocorticoid
receptor
and BDNF expression in the hippocampus, attenuating CRH expression in the hypothalamus,
and reducing corticosterone in serum) in olfactory bulbectomized rats [338]. In summary, the principal targets and pathways that have been established for these
extracts are the CREB/microphthalmia-associated transcription factor/tyrosinase pathway,
the 5-HT/5-HT1A receptors, and MAO-A, p-JNK, NO, cortisol and neuropeptide Y [337], [339], [340]. In the case of salidroside, the principal targets are BDNF, CREB, TrkB, the glucocorticoid
receptor, CRH, NA, p-JNK, NO, neuropeptide Y, heat shock factor 1, and heat shock
protein-70 [337], [338]. Two species of the genus Senna have been tested, S. septemtrionalis and S. spectabilis. In the former, the α
2-adrenoceptors
are probably responsible for the plantʼs antidepressant-like effects as observed
in both the FST and TST [341]. As for the latter species, different analogs of the natural piperidine alkaloid
(−)-3-O-acetylspectaline isolated from it were studied for their antidepressant-like activities.
In the end, the derivative ethyl 2-[(3-nitropyridin-2-yl)sulfanyl]acetate was shown
to decrease the immobility time of mice in the FST without affecting locomotor activity;
unfortunately, no mechanism was proposed [342]. Sida tiagii showed activity in the FST and TST, acting through the inhibition of both MAO (more
selectivity on MAO-A than on MAO-B) and lipid peroxidation [343]. Siphocampylus verticillatus was also studied for its potential antidepressant-like effect in 2 models in mice
and against synaptosomal uptake of 5-HT, NA, and DA. The authors concluded that the
extract
elicited its antidepressant-like effect through interaction with the adrenergic,
dopaminergic, glutamatergic, and serotonergic systems [344]. Solanum torvum inhibited the immobility period (FST and TST), increased DA, NA, and 5-HT levels,
and inhibited MAO in mice [345]. In a second study, these same authors examined the effect of torvanol A (36, Fig. 4S, Supplementary Information), and found that it likewise decreased the immobility
period in the specific tests through implication of the noradrenergic, dopaminergic,
serotonergic, and GABAergic systems [346]. In another study, Sonchus oleraceus reduced the immobility time in the FST and TST [347].
Two species of Tagetes have been studied by various researchers. Tagetes erecta inhibited the immobility period in mice (FST), with the serotonergic and nitrergic
pathways, as well as the σ-opioid receptors, all being implicated in the antidepressant-like
activity [348]. Tagetes lucida reduced immobility and increased swimming without affecting climbing behavior in
the FST; in addition, it affected neither motor activity nor male sexual behavior
in rats, which may explain its antidepressant-like properties [349]. The effect seems to be mediated by the serotonergic system [350] and is blocked by HT2A receptor antagonists and serotonin synthesis inhibitors but not by β- and α
2-noradrenergic receptor antagonists, indicating that the extract modulates the release/reuptake
of serotonin [351]. Tanacetum
parthenium has exhibited anxiolytic and antidepressant-like effects in various tests, prompting
the authors to propose the involvement of the GABAergic system [352]. Terminalia bellirica exerted its antidepressant-like effects (FST and TST) in mice through interaction
with the adrenergic (α
1), dopaminergic (D2), and serotonergic (release/reuptake of 5-HT) systems [353]. In the case of Theobroma cacao, the antidepressant-like effect of the polyphenol-enriched extract was studied and
justified in part by the antioxidant effects of its polyphenols; however, the high
amount of magnesium found in the extract could also be implicated, as this mineral
has been reported to be effective against depression-like behavior in mice [354]. The methanol extracts and essential oils from the aerial parts of 3 species of
Thymus–T. fallax, T.
kotschyanus, and T. pubescens–were studied in mice, with all 3 species shortening the duration of immobility in
the FST. In addition, the activities of the essential oils were lower than those of
the extracts, with both the extracts and oils of T. fallax being more active than those of T. kotschyanus and T. pubescens
[355]. The effect of T. kotschyanus extract was corroborated in FST and TST mouse models by Doosti et al. [356]. Tinospora sinensis produced a significant antidepressant-like effect in both the FST and TST, acting
through the α
1-adrenoceptor, D2-receptor, 5-HT release/reuptake, and GABAB reduction while also reducing MAO-A and MAO-B levels overall in mice, leading to
an increase in brain monoamine levels [357]. In a preliminary study, Campos et al. [358]
described the antidepressant-like effects of Trichilia catigua in rodents (FST), inhibiting the uptake and increasing the release of both 5-HT and
DA from rat brain synaptosomes [358]. The content in simple phenolics and tannins could explain this effect as they exert
a strong antioxidant activity [359]. In a complementary study, Bonassoli et al. [360] likewise observed antidepressant-like effects along with the induction of hippocampal
cell proliferation in mice for this same extract, whereas Bernardo et al. [361] demonstrated that the aqueous extract of the bark of this plant inhibited MAO-A
and AChE activities, inhibiting the xanthine/xanthine oxidase pathway and throwing
the oxidative stress out of equilibrium by acting as a SOD anion radical scavenger,
which may account for its antidepressant-like effects. In a screening for antidepressant
and
anti-anxiety plants, 17 plant species were tested for their affinity to the 5-HT
transporter and for inhibition of MAO-A. Of these, Trigonella foenum-graecum was the most active in the MAO-A assay, with no effect on 5-HT reuptake [362]. This property was subsequently confirmed by Khursheed et al. [363] with a similar extract, which exhibited activity in the FST and TST but not in the
OFT, reducing both MAO-A and MAO-B. In addition, the flavonoid-enriched extracts from
the seeds of this plant were shown not only to reverse the CRS-induced behavioral
abnormalities but also to restore the induced changes in serum levels of corticosterone,
as well as those of the neurotransmitters DA, NA, and 5-HT in the PFC and hippocampus,
and those of NA in striatum. The extract also inhibited MAO-A activity as well as
downregulating the KLF11, SIRT1, and MAO-A protein expression levels in the PFC and
hippocampus. These
results justify the role of flavonoids in the antidepressant-like effects of this
species [364]. Uncaria lanosa var. appendiculata was assayed in FST and TST mouse models, increasing the levels of 5-HT and 5-HIAA
in the cortex, striatum, hippocampus, and hypothalamus, as well as increasing NA levels
in the cortex, hippocampus, and striatum along with the 4-dihydroxyphenylacetic acid
levels in striatum [365].
Grouped under the common name of valerian, there are about 200 known species of the
genus Valeriana, but V. officinalis is the most commonly used for medicinal purposes and the only one accepted by the
European Medicines Agency to treat insomnia as a sedative-hypnotic, as well as for
its anxiolytic, antidepressant, and anticonvulsant properties [366]. Valerian roots contain volatile oils and the iridoids known as valepotriates (valtrates,
21, Fig. 3S, Supplementary Information). Hattesohl et al. [367] carried out various experiments with 4 commercially available preparations on mice
and rats, finding anxiolytic and antidepressant activities but not sedative or myorelaxant
properties. The extracts increased BDNF levels in vitro, an effect that was completely reversed after removal of valerenic acid (22, Fig. 3S, Supplementary Information) from the extract, indicating that this
compound is crucial for the neuronal activity [368]. Three other species of Valeriana were also tested: V. fauriei
[369], [370], V. glechomifolia
[371], [372], [373], and V. jatamansi
[374]. In the first species, bicyclo[8, 1, 0]5β-hydroxyl-7β-1acetoxyl-5,11,11′-trimethyl-E-1(10)-ene-4,15-olide was identified as the principal active compound, increasing
the immobility time in the FST in mice [369]. The extract enhanced the stimulation of Nrf-2 pathways, in accordance with upregulation
in protein expression of BDNF [370]. In the second assay, a supercritical CO2 extract enriched in valepotriates was tested in TST and FST models and showed an
anti-immobility effect that was reversed by both the α
2-adrenoceptor antagonist and D1 and D2 receptor antagonists, whereas neither α
1-adrenoceptor antagonists nor serotonin synthesis inhibitors had any effect on the
anti-immobility effect of the extract. These results account for the antidepressant-like
activity of valepotriates through their interaction with dopaminergic and noradrenergic
neurotransmission [371]. The synergistic interactions between diene valepotriates (valtrate, acevaltrate,
1-β-acevaltrate, 1-β-aceacevaltrate, and isovaltrate) and various standard antidepressants highlight their
potential as adjuvants because they target different neuronal transporters than those
targeted by standard treatments [372]. Moreover, the activity of diene valepotriates in the FST was reduced by a protein
synthesis inhibitor that works by
inhibiting Trk receptors, which could explain the role of diene valepotriates
in the extractʼs antidepressant-like activity, namely through its reduction of hippocampal
DNA methylation together with increased protein synthesis. Furthermore, BDNF-mediated
TrkB signaling also contributes to the antidepressant-like effect of this extract
[373]. In the third case, the extract increased DA and NA levels in the forebrain [374].
Vanda spathulata inhibit both MAO-A and MAO-B in mouse brains in both the FST and TST [375]. Three flavonoids were isolated from Viola odorata and tested in mice (TST and FST) to compare their antidepressant-like effects with
those of the standard drug, fluoxetine. The compounds were identified as 5,7-dihydroxy-3,6-dimethoxyflavone
(33), 5,7,4′-trihydroxy-3′,5′dimethoxyflavone (34), and 5,7,4′-trihydroxy-3′-methoxyflavone (35, Fig. 4S, Supplementary Information); all exhibited activity on 5-HT1A, 5-HT2A, and 5-HT3 receptors but not on D1 and D2 receptors. There was likewise no effect on 5-HT synthesis, indicating that the antidepressant-like
effects involve the serotonergic system [376].
A glycowithanolide-enriched fraction from Withania somnifera exhibited antidepressant effects in the FST in rats [377]. Shah et al. [378] tested an extract of ashwagandha alone as well as in combination with standard drugs;
in both cases, imipramine and fluoxetine produced a significant decrease in the mean
immobility time in the FST, an effect that seems to be mediated partly through the
α-adrenoceptor and alterations in the levels of central biogenic amines [378]. Ashwagandha also exhibited anxiolytic effects in the EPM [379] as well as anti-inflammatory and antioxidant properties [380], which may strengthen its antidepressant-like effects. Xylopia aethiopica showed antidepressant-like properties through its effects on 5-HT neurotransmission,
but also by a synergistic effect with the glycineB receptor
(possible glutamatergic effect) and NOS inhibition. The adrenergic system was
not involved, as indicated by the fact that catecholamine depletion did not affect
the antidepressant properties [381]. In the case of Xysmalobiyum undulatum, the extract showed activity in mice but not in rats (FST). Moreover, it showed affinity
to SERT, but, when used at a different concentration, had no effect on SERT, NAT,
or DAT transporters, indicating that the effects are most likely due to another mechanism
[41]. In one early study on Zingiber officinale, Sharma et al. [382] described the effect of the ethanol extract in different CNS tests, including the
FST and TST, in which it was shown to decrease time of immobility; this effect was
related to its antioxidant properties. Martínez et al. [383] isolated and studied a phenolic from the rhizomes,
dehydrozingerone (85, Fig. 8S, Supplementary Information), which showed antioxidant activity in the hippocampus,
cortex, and cerebellum of mice, as analyzed in TST and FST models, reducing the immobility
time in both tests with no concomitant effect on locomotor activity in the OFT. Its
activity involved 5-HT2A/2C and 5-HT3 receptors, as well as α
1- and α
2-adrenoceptors. The antidepressant-like effect of ginger thus involves the serotonergic
and noradrenergic systems as well as its antioxidant properties [383]. However, in a study by Kukula-Koch et al. [384], the nonpolar fraction of the oleoresin was as also found to possess antidepressant
activities. Of the different principles, (−)-geraniol (16) and (−)-terpinen-4-ol (17, Fig. 1S, Supplementary Information) were found to be the strongest MAO-A inhibitors [384].
Finally, although other species have been previously described, no studies on them
have been conducted since the year 2000, and, in many cases, the protocols and mediators
have never been described. The principal species in this category are true cinnamon
tree (Cinnamomum verum J.Presl, syn: Cinnamomum zeylanicum Blume, Lauraceae) [28], bindweed (Cissampelos sympodialis Eichler, Menispermaceae) [292], Indian coleus (Coleus forskohlii (Willd.) Briq., Lamiaceae) [292], dodder (Cuscuta sp., Convolvulaceae) [12], red feathers (Echium amoenum Fisch. & C. A.Mey., Boraginaceae) [24], [27], [292], common water hyacinth (Eichhornia crassipes (Mart.) Solms, Pontederiaceae [28], [29], “árnica roja” (Galphimia glauca Cav., Malpighiaceae) [24], Levant cotton (Gossypium herbaceum L., Malvaceae) [292], imperforate St Johnʼs wort (Hypericum maculatum Crantz, Hypericaceae) [29], “xuan fu hua” (Inula japonica Thunb., Compositae) [292], Thai black ginger (Kaempferia parviflora Wall. ex Baker, Zingiberaceae) [292], Indian tobacco (Lobelia inflata L., Campanulaceae) [25], [292], houpu magnolia (Magnolia officinalis Rehder & E. H.Wilson, Magnoliaceae) [23], [25], [292], “gondolosi” (Mondia whitei (Hook.f.) Skeels, Apocynaceae) [41], evening-primrose (Oenothera biennis
L., Onagraceae) [23], wild maracuja (Passiflora foetida L., Passifloraceae) [29], musk willow (Salix aegyptiaca L., Salicaceae) [28], “sanjeevani” (Selaginella bryopteris (L.) Baker, Selaginellaceae) [29], “dhiguthiyara” (Senna occidentalis (L.) Link, syn: Cassia occidentalis L., Leguminosae) [29], wild marigold (Tagetes minuta L., Compositae) [25], yellow trumpetbush (Tecoma stans (L.) Juss. ex Kunth, Bignoniaceae) [29], common nettle (Urtica dioica L., Urticaceae) [29], common grape vine (Vitis vinifera L., Vitaceae) [292], and “katber” (Ziziphus xylopyrus (Retz.) Willd., Rhamnaceae) [385]. Species such as
Eysenhardtia polystachya (Ortega) Sarg. (Leguminosae) [386], Capparis brassii DC (syn: Capparis thonningii Schumach., Capparaceae) [387], and Cnestis ferruginea Vahl ex DC (Connaraceae) [388] could also be of interest for antidepressant studies.
