Natural polyphenols in themanagement of major depressionLokesh Pathak, Yadvendra Agrawal & Ashish Dhir††Gujarat Forensic Sciences University, Institute of Research & Development, Gujarat, India
Introduction: Natural polyphenols, the non-essential micronutrients, found in
array of plant products, are known to affect various physiological and bio-
chemical functions in the body. Studies have shown the protective effect of
these polyphenols in different neurological and mental disorders. These poly-
phenols modulate monoaminergic neurotransmission in the brain and thus
possess antidepressant-like activity at least in animal models of depression.
Areas covered: The present review discusses the use of these natural polyphe-
nols in the treatment of major depression. The review article discusses the
antidepressant potential of some important polyphenols such as amentofla-
‘Polyphenols’ is a broad category of natural agents comprising tannins, flavonols,flavanols, flavones, anthocyanins, proanthocyanidins, phenolic acids, hydroxyben-zoic acids, hydroxycinnamic acids and their structural variants [1,2]. These are natu-rally occurring substances that are present in fruits and beverages (fruit juice, wine,tea, coffee, chocolate and beer) and, to a lesser extent in vegetables, dry legumes andcereals [3]. Polyphenols have shown several beneficial effects illustrating their prom-ising role as therapeutic agents in various acute and chronic conditions of the bodysuch as cardiovascular and metabolic disorders [4,5], inflammation and cancer [6],oxidative stress [7,8], cerebral ischemia [9] and obesity [10,11]. Numerous studieshave shown that natural polyphenols play an important role in proper functioningof the brain [12-14]. These micronutrients, for example, are involved in learningand memory process, prevent neuroinflammation and possess antioxidantpotential [15-17]. These polyphenols are known to modulate various neurotransmittersystems in the brain. For example, curcumin found in Curcuma longa modulatesserotoninergic and dopaminergic neurotransmission in the brain and thereforecould be useful as an antidepressant agent [16]. The fact that these polyphenols alterdifferent neurotransmitters has prompted researchers to explore their usefulness inthe treatment of major depression.
Major depression is a serious medical illness that affects both developed anddeveloping countries [18,19], and has an estimated lifetime prevalence of about15 -- 20% [20-22]. It has been estimated that by the year 2020, depression will reachin second place in the ranking of disability-adjusted life-years [23]. The monoaminetheory of major depression has been well-accepted by researchers. According to thistheory, there is a decrease in the levels of various monoaminergic neurotransmitterssuch as norepinephrine, serotonin and dopamine in brains of depressed patients.
Molecules that reverse this deficiency are known to possessantidepressant activity [24]. Various new antidepressants suchas venlafaxine and triple reuptake inhibitors have beendiscovered based on this theory [25].More than 25 antidepressant agents are available commer-
cially (Figure 1) that has allowed treatment of depressedpatients in an efficient manner. However, acute or chronicadministration of these antidepressants could lead to seriousside effects, adverse drug reactions and drug--drug and food--drug interactions [26]. Unfortunately, about 10 -- 30% ofdepressed patient population still continues to have depressiveepisodes besides the availability of these wonderful drugs [27].All these factors justify a need for newer antidepressant agentspossessing better efficacy and minimal side effects [24,28].With this background, the present review attempts to dis-
cuss some of the polyphenols that are being tested extensivelyin animal models of major depression. The review alsoincludes the mechanism of action of these polyphenols fortheir antidepressant activity. Some of the polyphenols thathave been tested for their antidepressant activity are illustratedin Table 1 with their chemical structures representedin Figure 2. Based on the preclinical data, it is hypothesizedthat these polyphenols might be useful as an adjuvant therapywith already established antidepressant agents for the treatmentof major depression.
2. Animal models of behavioral despair
The discovery of various new molecular entities (NMEs) asantidepressants requires appropriate animal models withexcellent face, construct and predictive validity [29]. These ani-mal models should mimic human condition of major depres-sion. Various animal models have been proposed so far toevaluate the antidepressant-like activity of new molecules.Out of these models, forced swim test (FST) and tail-suspension test (TST) are majorly used. Although these mod-els do not mimic the human condition of major depression,however, antidepressants acting through modulating mono-aminergic neurotransmission are active in these test mod-els [30]. In a FST, animals are forced to swim inside a jar(with specific dimensions) filled with water (maintained at25�C) up to a certain height. During an initial 1 -- 2 min,animal struggles to get out of the water and remain mobile.After this struggling phase has passed, animal gives up to the
situation, and remain floating (immobile) inside the jar withvery little limb movements. This condition correlates withthe state of behavioral despair and various antidepressantsare known to reverse this immobility period [24]. Similarly,in a TST, an animal (mice or rat) is suspended by its tail ata certain height and for a definite period of time and itsimmobility period is assessed. Although both of these modelsmeasure immobility period in animals, however, they differeach other on neurochemical basis [31]. NMEs that reversethis immobility period in these two tests are studied furtherfor their antidepressant action. Some of the other modelsthat are routinely used for testing antidepressant-like activityof new molecules include olfactory bulbectomy, sucrose pref-erence, intracranial self-stimulation task and others. In thesebehavioral paradigms of despair, locomotor activity is alsoassessed simultaneously with the antidepressant activity. Ithas been seen that amphetamine-like psychostimulants arealso active in these animal models [32]. Therefore, researchersoften times use locomotor activity as a criterion to distinguishantidepressant and psychostimulatory activities in thesebehavioral paradigms of despair.
It has been found that natural polyphenols are active inthese animal models of despair. Neurochemical estimationhas shown that some of these polyphenols modulate variousneurotransmitters in the brain that are involved in the patho-physiology of various neuropsychiatric and neurodegenerativedisorders [33]. The details describing the antidepressant activ-ity of some of the natural polyphenols in these behavioralmodels of despair are explained in separate sub-headings.
3. Polyphenols in animal models ofbehavioral despair
The present section discusses the antidepressant-like activityof various natural polyphenols. These polyphenols could beused as an adjuvant therapy in the treatment of major depres-sion. However, it is strongly recommended that clinical trialsdescribing the efficacy and safety profile of these moleculesshould be carried out before these drugs are considered to beuseful in the treatment of major depression.
3.1 CurcuminCurcumin, a polyphenol, is the major active ingredient ofCurcuma longa [24]. Curcumin is known for its diverse biolog-ical actions and widely used in Indian system of medicine [34].A recent review on curcumin has elaborately described theeffect of curcumin in various neurodegenerative disorders [35].Curcumin is known to modulate the activity of various neuro-transmitter systems in the body via regulating the levels ofmonoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B) enzymes [16]. Xu et al. in 2007 showed thatcurcumin enhanced hippocampal neurogenesis in chronicallystressed mice and the effect was similar to imipramine, a stan-dard tricyclic antidepressant agent [36]. Curcumin showedantidepressant-like action in FST in both mice and rats.
Article highlights.
. Natural polyphenols in major depression
. Preclinical studies of natural polyphenols in animalmodels of depression
. Mechanism of action of polyphenols as anantidepressants
. Side effects of natural polyphenols
This box summarizes key points contained in the article.
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Xu et al. in 2005 showed that curcumin at doses of 5 and10 mg/kg., p.o. was active in mouse FST and TST [37].Further, it has been shown that there is an increased level ofnoradrenaline and serotonin in frontal cortex and hippocam-pal brain regions following curcumin administration at a doseof 10 mg/kg., p.o. compared with control group [37]. Inanother similar kind of study, it has been shown that curcu-min is antidepressant in olfactory bulbectomy animal modelof major depression [38]. Curcumin totally reversed olfactorybulbectomy-induced reduced levels of serotonin, noradrena-line and increased levels of 5-hydroxyindoleacetic acid and4-dihydroxyphenylacetic acid in the hippocampus region ofmouse brain in this animal model [38].
The antidepressant activity of curcumin according toWang et al. is linked to modulation of serotoninergic system [39].
It has been shown that there is an involvement of 5-HT1A/1B
and 5-HT2C serotonin receptors in the antidepressant-likeactivity of curcumin [39]. Serotoninergic receptors producephysiological response via adenyl cyclase/cyclic adenosinemonophosphate (AC/cAMP) pathway. Li et al. have shownthat curcumin modulates AC/cAMP pathway and cAMPresponse element binding protein and the effect is mediatedthrough suppressing central 5-HT1A/1B/7 receptors [40].
Besides serotoninergic receptors, other receptor systems arealso involved in the antidepressant-like effect of curcumin.Glutamate, an excitatory neurotransmitter, is known to playan important role in the antidepressant-like action ofcurcumin [41]. Lin et al. have shown that curcumin couldinhibit the release of glutamate induced by 4-aminopyridine(a potassium channel blocker) [41]. Further, it has been
Figure 1. Structures of approved drug molecules for the treatment of major depression.
Natural polyphenols in the management of major depression
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demonstrated that curcumin could inhibit the release of gluta-mate by acting through presynaptic voltage-gated Cav2.2 andCav2.1 calcium channels [41]. Interestingly, the authors havealso demonstrated that the inhibitory effect of curcumin on4-aminopyridine-induced glutamate release and the effectwas completely blocked by fluoxetine, a selective serotoninreuptake inhibitor. This finding suggests that both curcuminas well as fluoxetine share some common mechanisms ofaction that involve inhibition of glutamate release [41].In another study, it has been demonstrated that glutamate
N-methyl-D-aspartate (NMDA) GluN2B receptors areinvolved in the antidepressant-like activity of curcumin. Var-ious agonists and antagonists of NMDA glutamate receptorswere used to prove the hypothesis [42].
The antidepressant activity of curcumin is also linked to itsmodulatory effect on neurotrophic factors. In a study,curcumin reversed a decrease in the levels of brain-derivedneurotrophic factor (BDNF) induced by glutamate [43]. Fur-ther, Wang et al. have depicted that the neuroprotective effectof curcumin involves activation of BDNF and its receptors
NN N
O
ClN
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O O
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Imipramine
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Clomipramine
N
NH N NO
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Amoxapine Paroxetine
Protriptyline Fluvoxamine
Vilazodone
Duloxetine
NHHN O
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Isocarboxazid Tranylcypromine Phenelzine
Minacipran
Figure 1. Structures of approved drug molecules for the treatment of major depression (continued).
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TrkB-dependent MAP kinase (mitogen-activated proteinkinase) and PI3K (phosphatidylinositol 3-kinase) cascadewhen checked in rodent cortical neurons [44].
In one of the studies, curcumin has shown to increase thelevels of serotonin and dopamine neurotransmitters andinhibits the activity of MAO isoenzymes. Further, curcumindecreases immobility period in mouse FST [16]. It has beendemonstrated that curcumin could enhance the antidepressant-like activity of various standard antidepressants such as fluoxetine,venlafaxine or bupropion but not imipramine [16].
Huang et al. developed a novel model of depression. Theauthors in the present study administered corticosterone exog-enously chronically for 3 months. As a result, rats developeddepression-like state. In these rats, a decrease in the levels ofBDNF was found. Pretreatment of curcumin reversed thisdepression-like pattern in this animal model [45]. In a veryrecent study, the antidepressant-like activity of curcumin wasstudied in WKY rat model of depression. Curcumin waseffective both in acute and chronic dosing profiles and theresults were correlated with an increase in the levels of BDNFfollowing curcumin administration in this animal model [46].
3.2 ApigeninApigenin is one of the bioflavonoids abundantly found in cit-rus fruits [47]. The molecule has shown promising activity in
central nervous system (CNS) disorders such as anxiety andinsomnia [48,49]. Apigenin is also protective in cerebral ische-mia reperfusion injury in rats [50] suggesting that the moleculecould easily cross blood--brain barrier. Apigenin has shownanti-inflammatory activity in cultured microglia cells andtherefore the molecule is hypothesized to display neuroprotec-tive/disease-modifying properties in various neurodegenera-tive disorders including Alzheimer’s disease [51]. A recentstudy has shown the protective effect of apigenin in amy-loid-b25-35-induced toxicity in mice [52] suggesting that apige-nin could be useful in the treatment of Alzheimer’s disease.Apigenin has also shown antioxidant effect in kainate modelof excitotoxicity in mice [53]. In this study, apigenin preventedkainic acid-induced excitotoxicity via quenching reactiveoxygen species as well as inhibiting glutathione depletion inhippocampal neurons [53].
Antidepressant-like effect of apigenin was first shown byNakazawa et al. in various behavioral despair test models [54].Further, the central noradrenergic, dopaminergic and seroto-ninergic modulatory activities of apigenin was demonstratedin mice [54]. Apigenin when administered via intraperitonealroute in mice at doses of 12.5 and 25 mg/kg displayed signif-icant anti-immobility action in the FST. Further, at a higherdose of 100 mg/kg, the immobility period in apigenin-treated mice was similar to that of control or vehicle-treated
Table 1. Details of various polyphenols known for their antidepressant activity along with their biological source
and mechanisms of action.
S. no. Polyphenol Biological source Possible mechanism of
antidepressant action
Refs.
1 Curcumin Curcuma longa MAO inhibitory action, modulating BDNF,acting through glutamate receptors,antioxidative effect
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animals. The authors of this study have also measured neuro-transmitters turnover in mouse brain after 40 min stressinduced by forced swimming and its modulation by apigenin.It was found that apigenin at a dose of 25 mg/kg reversed adecrease in dopamine turnover in the amygdale region andincrease in dopamine turnover in the hypothalamus regionof the mouse brain [54]. This study signifies that there is arole of dopamine in the antidepressant-like action of apigenin.Further, the antidepressant-like action of apigenin wasreversed by haloperidol, a dopamine D2 receptor blocker.The antidepressant-like activity of apigenin is not completelyunderstood, however, the molecule has shown to inhibit
MAO enzyme activity with an IC50 value of 6.5 µM. Apige-nin is more effective in inhibiting MAO-A as comparedwith MAO-B activity [55]. MAO inhibitors are effective anti-depressant agents; however, the use of this class of drugs islimited due to their adverse food--drug interactions [24].Besides FST, apigenin was also evaluated in other animalmodels of depression such as chronic mild stress (CMS) [56].Apigenin in this study was administered via oral route. Ithas been found that chronic administration of apigeninreversed CMS-induced decrease in sucrose intake as comparedwith control animals [56]. Furthermore, it was shown thatCMS raised the levels of corticosterone in Wistar rats which
Figure 2. Structures of natural polyphenols known for their antidepressant activity.
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was reversed by chronic administration of apigenin [56]. Thestudy concluded that there are multiple mechanisms withregard to the antidepressant-like activity of apigenin [56].
3.3 AmentoflavoneAmentoflavone is a unique bioflavonoid consisting of apige-nin dimer. It has been shown that amentoflavone could easilycross blood--brain barrier when tested in vitro in primary cellcultures of porcine brain capillary endothelial cells [57]. How-ever, when tested in vivo in a mouse model, amentoflavonehas shown poor blood--brain barrier penetrability [58]. Limitedconcentration of amentoflavone was detected only after intra-peritoneal administration of the molecule at 10 mg/kg. Anin vitro study has suggested that amentoflavone extractedfrom different Hypericum species could inhibit flumazenilbinding to rat brain benzodiazepine binding sites at GABAA
receptor with an IC50 value of 14.9 ± 1.9 nM [59]. The studyfurther demonstrated that amentoflavone binds to the benzo-diazepine site of GABAA receptors [59]. A recent study hasevaluated the antidepressant-like action of amentoflavone.Amentoflavone isolated from root decoction of Cnestis ferrugi-nea (a traditional African herbal medicine often prescribed forpsychiatric disorders) was evaluated for its antidepressant-like activity in mice [60]. The antidepressant-like effect wasstudied using behavioral despair models such as FST andTST in 8-week-old naıve Swiss albino mice. Amentoflavone(6.25 -- 50 mg/kg, p.o.) or imipramine (20 mg/kg, p.o.) wasadministered to mice 1 h prior to the FST. It was foundthat the methanolic extract of C. ferruginea at 12.5 mg/kg,reduced immobility period and simultaneously enhancedswimming behavior in mice subjected to FST [60]. Similarly,the effect of oral administration of amentoflavone in FST,starting from 6.25 mg/kg was found to be more pronouncedand potent in reducing immobility period when comparedwith imipramine (20 mg/kg), a tricyclic antidepressant [60].It is suggested that attempts should be made to enhance theblood--brain barrier penetrability of amentoflavone.
3.4 Chlorogenic acidChlorogenic acid, a polyphenol, has been reported as an anti-oxidant and neuroprotectant in a number of previous stud-ies [61,62]. Chlorogenic acid is abundantly found incoffee [63]. A study showing anxiolytic and antioxidant proper-ties of chlorogenic acid at a dose level of 20 mg/kg has beenreported; the anti-anxiety effect was blocked by flumazenilsuggesting that the anti-anxiety effect of chlorogenic acid isdependent on its activity on GABAA-benzodiazepine recep-tors [62]. Various studies have shown protective effect ofchlorogenic acid in animal models of Alzheimer’s diseaseand cerebral ischemia [63-66]. In one study, chlorogenic acidwas found to inhibit the activity of acetylcholinesteraseenzyme (an enzyme involved in the degradation of acetylcho-line) with an IC50 value of 98.17 µg/ml [63]. Further, themolecule possesses free radical scavenging property with anIC50 value of 3.09 µg/ml [63].
There are not enough studies depicting the antidepressant-like profile of chlorogenic acid. Interestingly, there is a clinicalstudy demonstrating that decaffeinated coffee rich inchlorogenic acid could elevate mood in 39 healthy volunteersdepicting that chlorogenic acid could be useful as an antide-pressant/mood-elevator agent [67]. In one study, chlorogenicacid isolated from Artemisia capillaris Thunb. has shownantidepressant-like activity in chronically restrained mice(2 h/day for 14 days and rest for 14 days without any stress)when tested in mouse FST and TST. The mechanism ofantidepressant action of chlorogenic acid is not clear buthypothesized to act through opioidergic pathway [13].
3.5 Ellagic acidEllagic acid is a polyphenolic compound that occurs in plantssuch as raspberries, pomegranate, the stem and bark of euca-lyptus species and nuts [68]. This bioflavonoid has shown anti-oxidant, antifibrotic, anti-inflammatory, cardioprotective andanticancer properties [68,69]. Few studies have been carried outdemonstrating the antidepressant-like profile of ellagic acid.Girish et al. have shown that ellagic acid at doses of25 -- 100 mg/kg., p.o. when administered both in an acuteand chronic fashion reduces immobility period in both FSTand TST [70]. The effect of ellagic acid in these animal modelswas comparable with fluoxetine, a selective serotonin reuptakeinhibitor [70]. Further, the authors have shown the involve-ment of monoaminergic neurotransmitter receptors (bothserotonin and adrenergic) in the antidepressant-like actionof ellagic acid [70]. The authors further confirmed that thereis no role of opioidergic receptors in the antidepressant-like action of ellagic acid [70]. In another study carried byDhingra and Chhillar, the antidepressant-like activity of ella-gic acid was confirmed in immobilization-induced stress inmice. The authors in the present study induced stress inmice by immobilizing them once for a total of 150 min. Itwas shown that ellagic acid at 17.5 and 35 mg/kg reducedthe immobility period in stressed mice when checked inboth FST and TST animal models. The authors concludedthat there might be involvement of adrenergic, serotoninergicand/or nitric oxide (NO) system in the antidepressant-like action of ellagic acid in these animal models [71]. Thereare no clinical studies to prove the antidepressant-like effectof ellagic acid in major depression.
3.6 Ferulic acidFerulic acid (4-hydroxy-3-methoxycinnamic acid; FA) is aplant constituent known to scavenge free radicals in thebody and thus act as a powerful antioxidant agent [72]. Themolecule has been known to possess multiple pharmacologicaleffects including anti-inflammatory, anticancer, antidiabeticand anti-atherogenic and neuroprotective [73-76]. FA improveslearning and memory in rat model of vascular dementia [77].The authors have concluded three mechanisms of action inthe protective effect of FA in dementia. These mechanismsinclude i) antioxidative potential of FA, ii) improvement of
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cholinergic system by FA and iii) antagonizing the action ofexcitatory amino acid [77]. It has been shown that long-term administration of FA prevents brain damage frombeta-amyloid protein and thus could be useful to preventthe occurrence of Alzheimer’s disease [78]. Sodium ferulate, asodium salt of FA is also known to possess sedative activity [79],and the plant extract containing this molecule has found itsusefulness in the treatment of headache and irritability, apo-plexy, stasis, etc. [80,81]. A very recent study has shown theeffect of FA on the proliferation of neural progenitor cellboth in vitro and in vivo [82]. When administered orally inmice, FA enhances the number of newly generated cells inthe dentate gyrus of the hippocampus of corticosterone-treated mice [82]. FA has been shown to possess antidepressantand prokinetic properties [83]. The molecule reduces immobil-ity period in rat FST, its anti-immobility effect was preventedby PCPA (p-chlorophenylalanine; serotonin depleter),WAY-100635 (selective serotonin 5-HT1A antagonist), ketan-serin (selective serotonin 5-HT2 antagonist), sulpiride (adopamine D2 receptor antagonist), SCH233390 (a dopamineD1 receptor antagonist), haloperidol (dopamine D2 receptorantagonist) and yohimbine (selective adrenergic alpha-2antagonist), respectively. In another recent study, FA(0.01 -- 10 mg/kg, p.o.) is active in behavioral despair modelsincluding FST and TST. It has been found that theantidepressant-like activity of this molecule is not dependenton changes in the locomotor activity. Some of the conven-tional antidepressants such as fluoxetine, paroxetine, sertraline(all selective serotonin reuptake inhibitors) enhance theantidepressant-like action of FA, thus demonstrating animportant role of serotonin in the antidepressant actionof this molecule. Further, it is confirmed that bothWAY-100635 (0.1 mg/kg, s.c., a selective 5-HT1A receptorantagonist) or ketanserin (5 mg/kg, i.p., a 5-HT2A receptorantagonist) reverse the antidepressant-like effect of FA inthis animal model [84].
3.7 FisetinFisetin (3,3¢,4¢,7-tetrahydroxyflavone) is a naturally occurringflavonoid and is found abundantly in strawberries and otherfruits and vegetables. Fisetin has a strong anti-inflammatoryproperty in brain microglia cells [85]. In a study carried outby Zheng et al., it was shown that fisetin suppressed the levelsof various inflammatory markers such as TNF-a, NO andprostaglandin E2 (PGE2) in lipopolysaccharide-stimulatedBV-2 microglia cells or primary microglia cultures [85]. Fisetinplays an important role in regulating brain functions [86-91].Antidepressant-like effect of fisetin in behavioral models ofdespair was recently investigated and the results suggestedthat fisetin (10 and 20 mg/kg, p.o.) dose dependently inhib-ited the immobility period in FST and TST without affectingthe locomotor activity [92]. Further, fisetin reversed hypother-mia induced by reserpine (a neurotransmitter-depletingagent). Neurochemical analysis revealed that fisetin couldenhance the levels of noradrenaline and serotonin in the
frontal cortex and hippocampal regions of mouse brain [92].Further, fisetin inhibits the activity of MAO-A enzyme with-out affecting the activity of MAO-B. This suggests that thecompound acts by modulating levels of both noradrenalineand serotonin and possesses no action toward dopaminelevels [92].
3.8 QuercetinQuercetin (3,3¢,4¢,5,7-pentahydroxyflavone) is a bioflavonoidwidely distributed in plant products and exists as glyco-sides [93]. There are numerous findings depicting the antide-pressant activity of food rich in quercetin and its glycosidessince last decade [94-98]. Dixon Clarke and Ramsay havereported that diet rich in quercetin could inhibit MAO activ-ity in brain [99]. This could further prevent neurotransmitterbreakdown [99]. The first study demonstrating theantidepressant-like profile of quercetin was conducted byAnjaneyulu et al. [100]. In this study, quercetin per se wasineffective in mouse FST. However, quercetin showedantidepressant-like action in streptozotocin-induced diabeticmice when tested in FST. The antidepressant-like effect ofquercetin (50 and 100 mg/kg) was comparable with fluoxe-tine (5 mg/kg., i.p.) or imipramine (15 mg/kg., i.p.) instreptozotocin-induced diabetic mice [100]. A similar kind ofstudy was published in 2007 by the same group demonstrat-ing that quercetin could induce depression-like phase andthis property involves the participation of alpha-2 adrenergicreceptors in its mechanism of action [101]. Yohimibine, analpha-2 adrenergic receptor blocker inhibited the behavioraldespair induced by quercetin [101].
Recently, an interesting study has been published depictingthe antistress effect of quercetin. Animals in this study were sub-jected to water immersion-restraint stress [102]. Animals werefound to have activated hypothalamic--pituitary--adrenal (HPAaxis) that was normalized with the treatment of quercetin [102].Quercetin in this study significantly suppressed elevated levelsof plasma corticosterone and adrenocorticotropic hormone.Results have shown that quercetin suppresses the expression ofcorticotrophin-releasing factor (CRF) mRNA [102]. The findingshave been confirmed by another group where CRF was injectedin animals to induce anxiety and depression-like stage and thepretreatment of quercetin reversed the effect of exogenouslyadministered CRF [103]. Quercetin is an interesting compoundto study in various brain disorders. Quercetin has shown to bea weak inhibitor of MAO-A enzyme in brain; however, thecompound does not affect MAO-A activity in mouse intestinalmitochondria. This study reflects that various drug--foodinteractions (e.g., hypertensive crisis observed with tyramine-containing food) that are commonly seen with the use ofcommercially available MAO inhibitors are not seen with theuse of quercetin [104]. Similarly, Yoshino et al. have shownthat quercetin inhibits MAO-A enzyme in mouse brainmitochondria and thus inhibits the breakdown of serotoninneurotransmitter [105]. Quercetin metabolite, quercetin 3-glucu-ronide, has powerful antioxidant activity as shown by
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Yoshino et al. [105]. Beside MAO inhibiting and antioxidantproperties of quercetin, other factors may also contribute tothe antidepressant-like activity of quercetin. Quercetin is neuro-protective in focal cerebral ischemia model via activation ofBDNF-TrkB-PI3K/Akt signaling pathway. Therefore, querce-tin antidepressant-like activity relates to its ability to modulatelevels of BDNFs [105]. Thus, quercetin seems to be a viablecandidate to be included in antidepressant drug therapy.
3.9 ResveratrolResveratrol (3,4¢,5-trihydroxystilbene), is a natural phenoliccompound present in peanuts, red grapes and wine [106]. Itexists as cis- or trans-isomers [107,108]. It has been found thatresveratrol possesses an inhibitory effect on the uptake of[3H] NA (noradrenaine) and [3H]5-HT (serotonin) in ratsynaptosomes, prevents the uptake of [3H]5-HT in humanplatelets and inhibits MAO isoform activity [109]. The firststudy to demonstrate the antidepressant-like effect of trans-resveratrol in behavioral despair model was carried out byXu et al. [110]. The authors have shown that trans-resveratrol(20 -- 80 mg/kg, p.o.) significantly decreased the immobilityperiod in mouse models of behavioral despair without affect-ing the locomotor activity. Neurochemical analysis has shownthat trans-resveratrol at doses of 40 and 80 mg/kg produces asignificant increase in the levels of noradrenaline and seroto-nin. The mechanism is yet not clear, however, the authorshave demonstrated that trans-resveratrol could significantlyinhibit the activity of MAO-A enzyme [110]. Resveratrol isknown to upregulate the production of astroglia-derivedneurotrophic factors via activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP responsiveelement-binding protein (CREB) [111]. By contrast, it hasbeen shown recently that resveratrol inhibits hippocampalneurogenesis when tested in healthy adult mice [112]. Also, ithas been shown that resveratrol inhibits the proliferation andsurvival of cultured neural progenitor cells [112]. Therefore,the exact mechanism regarding the antidepressant-like actionof resveratrol is not clear. Moreover, it was demonstrated byDi Liberto et al. that the antidepressant action of resveratrolis sex specific. Resveratrol structure is similar to diethylstilbes-trol, a synthetic estrogen. It was shown that resveratrol signif-icantly increased dopamine transporters in striatal region offemale mice and not in male mice [113]. It is yet not clearhow this will influence the activity of resveratrol in treatingpatients suffering from major depression.
3.10 HesperidinHesperidin is a flavanone glycoside abundantly found in thecitrus fruits [114]. Hesperidin decreases capillary permeabilityand fragility: it is also known as vitamin P [115]. There are sev-eral pharmacological reports on the action of hesperidin thatinclude its sedative potential [116,117], antioxidant ability [118],anti-inflammatory and analgesic properties [119]. Souza et al.demonstrated the antidepressant-like activity of hesperidinin mouse FST and TST [120]. In this study, it was observed
that hesperedin (0.1 -- 1 mg/kg., i.p.) reduced the immobilityperiod in both the tests and the antidepressant-like activitywas independent of alterations in locomotor activity [120]. Ithas been found that hesperidin is effective in TST at a subef-fective dose of 0.01 mg/kg [120]. Further, authors concludedthat the antidepressant-like effect of hesperidin in TST wasdependent on its interaction with the serotoninergic 5-HT1A
receptors. Another study has shown the involvement of kappaopioidergic receptors in the antidepressant-like effect of hesper-idin [121]. The antidepressant-like effect of hesperidin in FSTwas prevented by pretreatment of naloxone (a non-selectiveopioidergic receptor antagonist) and 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide (DIPPA (1 mg/kg), a selective k-opioidreceptor antagonist) suggesting the involvement of kappa recep-tors in its antidepressant-like action [121]. Other actions of hes-peridin might also contribute toward its antidepressant-like activity. For example, hesperidin has shown anti-inflammatory and antioxidant activity in an experimental modelof stroke [122]. Interestingly, hesperidin reduced the levels ofinflammatory biomarkers such as TNF-a, IL-1b levels, induc-ible nitric oxide synthase (iNOS) expression and glial fibrillaryacidic protein (GFAP) in middle cerebral artery occluded ratsas compared with their respective controls [122]. In one of thestudies, hersperidin has been shown to enhance neuronal popu-lation when neuronal progenitor cells were treated with hesper-idin. There was an 80% increase in the number of b-tubulin IIIcells in this study [123]. Hesperidin seems to be a viable candidatefor the treatment of major depression.
3.11 RutinRutin, a diglycoside flavonol, is extensively found in manyplants including Hypericum perforatum. St. John’s wort, anextract of H. perforatum, is a traditional remedy for the treat-ment of depression since ages [124]. It has been found thatrutin is an important constituent of the Hypericum extractand is essential for its antidepressant activity [125]. This flavo-nol has been shown to exert several other biological activitiesincluding antimicrobial [126] anti-inflammatory [127], antioxi-dant [128], neuroprotective [129] and antiulcerogenic [130]
potentials. Rutin is observed to be absorbed slowly and lessefficiently as compared with quercetin on the basis of areaunder the plasma concentration--time curve values and rela-tive urinary excretions [131]. In order to study theantidepressant-like profile of rutin, Machado et al. carriedout a study exploring the effect of ethanolic extract of aerialpart of Schinus molle using FST and TST in mice [132]. Theauthors found that administration of rutin reduced the immo-bility period in the TST (0.3 -- 3 mg/kg, p.o.), but not in theFST. Further, pretreatment of mice with PCPA (inhibitor ofserotonin synthesis) or AMPT (a-methyl-p-tyrosine; inhibitorof noradrenaline synthesis) prevented the anti-immobilityeffect of rutin suggesting the involvement of neurotransmit-ters in its antidepressant-like action [132]. Rutin enhanced spa-tial memory in aged rats and further augmented the levels of
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noradrenaline and dopamine neurotransmitters in hippocam-pus and hypothalamus regions of aged rat brains, respec-tively [133]. Similar to hesperidin and other polyphenols,rutin has also shown antioxidant and anti-inflammatoryactivities when tested in rats [134]. In streptozotocin-inducedinflammatory rat model, rutin prevented the overexpressionof inflammatory biomarkers such as cyclooxygenase-2(COX-2), GFAP, IL-8, iNOS, nuclear factor-kappaB(NF-kB) [134]. In repeated cerebral ischemic rats, rutin pre-vented spatial memory impairment and neuronal death inhippocampal CA1 region [135]. In contrast to these studies,Silva et al. have shown that rutin has a capacity to induceTNF-a and NO in primary glial cell culture [136]. Also,Boyle et al. conducted a 6-week randomized single-blind placebo controlled trial on 18 healthy female volunteersfor studying the pharmacokinetics of rutin (quercetin-3-O-b-rutinoside [137]. The authors in this study concluded that after6-week administration of rutin, there was no significant anti-oxidant effect observed in the plasma [137]. This might berelated to bioavailability issues associated with rutin. Morestudies are required to establish the use of rutin in braindisorders including its use in major depression.
3.12 NaringeninNaringenin (4,5,7-trihydroxyflavanone) is one of the mostabundant flavanones in citrus fruits [138]. Neuroinflammationhas been speculated to play a major role in the pathophysiol-ogy of major depression. Neuroinflammatory signalingpathways have emerged as new targets for antidepressantdrugs [139]. The fact that naringenin is known to reduceneuroinflammatory injuries in glial cells via inhibiting pro-inflammatory mediators such as p38 signaling cascades andthe STAT-1 transcription factor, it was hypothesized that nar-ingenin might be useful in the treatment of major depres-sion [140]. Like other flavonoids, naringenin also possessesantioxidant and anti-inflammatory properties [141]. Naringe-nin suppressed NF-kB signaling pathway in ischemic strokemodel, suggesting anti-inflammatory property [141]. Naringe-nin has a good oral bioavailability [142]. Naringenin has shownto inhibit the activity of MAO enzyme [143]. Antidepressant-like action of naringenin was investigated by Yi et al. Theauthors in this article have demonstrated that naringenin(10 -- 50 mg/kg) treatment could significantly decrease theimmobility period in the mouse TST but not in the FST.Moreover, pretreatment with PCPA or AMPT significantlyinhibited the anti-immobility effect of naringenin in theTST suggesting the role of serotoninergic and noradrenergicsystems in its antidepressant action [144].
3.13 ProanthocyanidinsProanthocyanidins polyphenols are the major component ofgrape seed extract [145,146]. Proanthocyanidins have demon-strated various pharmacological actions such as antioxi-dant [147], antinociceptive [148] and cardioprotective [149].Lu et al. found that proanthocyanidins-rich grape seed extract
improved the condition of diabetic neuropathy in rats viaacting through cellular signaling pathways such as advancedglycation product (AGEs), nuclear factor-kappa B p65(NF-kB65) [150]. Wang et al. demonstrated that metabolitesof monomeric proanthocyanidins could selectively reach brainand improve cognition by modulating synaptic plasticity inthe brain [151]. When tested in rat hippocampal cells, grapeseed proanthocyanidins inhibited glutamate-induced celldeath via inhibiting calcium signals and NO formation [152].In earlier findings, proanthocyanidins-rich dietary food con-stituents inhibited the activity of MAO enzyme in C6 glialcells [153]. However, the antidepressant-like activity of theproanthocyanidins in animal models was first demonstratedby Xu et al. [154]. The authors demonstrated effectiveness ofproanthocyanidins in animal models of behavioral despairafter oral administration in mice at dose range of 25 and50 mg/kg for 7 days. The antidepressant-like activity in thisanimal model is devoid of alterations in the locomotor activityof mice [154]. Further, neurochemical evidences revealedthat proanthocyanidins increases the levels of serotonin,noradrenaline and dopamine in various regions of the brainsuggesting the role of central monoaminergic system in itsantidepressant-like action [154].
3.14 NobiletinNobiletin is a polymethoxylated flavone abundantly found incitrus fruits [155,156]. Nobiletin has vast pharmacologicalactions including its applications in various clinical conditionssuch as cataract [157], obesity [158], metastasis [159], neuroin-flammation [160] and hyperglycemia [161]. Nobiletin has alsoshown activity in various animal models of CNS disorders.In one of the studies, nobiletin exerted neuroprotectiveeffects on ischemia-induced neuronal cell death in hippocam-pal CA1 region of the brain [162]. In another study,Matsuzaki et al. demonstrated neurotrophic property of nobi-letin in murine hippocampus [163]. The antidepressant-like activity of the nobiletin was demonstrated for the firsttime in animals by Yi et al. [164]. The authors in this studyadministered nobiletin to mice and observed a decrease inimmobility period in both FST and TST at a dose range of25 -- 100 mg/kg per oral. The antidepressant-like action ofnobiletin in this study was devoid of alterations in thelocomotor activity of mice as assessed by open-field test [164].Further, it has been shown that pretreatment of mice withWAY-100635 (a serotonin 5-HT1A receptor antagonist),cyproheptadine (a serotonin 5-HT2 receptor antagonist), pra-zosin (an a1-adrenoceptor antagonist), SCH23390 (a dopa-mine D1 receptor antagonist) or sulpiride (a dopamineD2 receptor antagonist) prevented the anti-immobility effectof nobiletin in TST. By contrast, pretreatment of animalswith yohimbine (an a2-adrenoceptor antagonist) or proprano-lol (a b-adrenoceptor antagonist) did not affect theantidepressant-like action of nobiletin in this animal model [164].The study confirmed the involvement of serotoninergic, norad-renergic or dopaminergic systems in antidepressant action of
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nobiletin [164]. Nobiletin (oral administration for 11 days) alsoreversed memory impairment in olfactory-bulbectomizedmice [165] suggesting its antidepressant potential.
Polyphenols which were investigated during last decade fortheir antidepressant and anxiolytic activities are summarizedin Table 1.
4. Expert opinion
Major depression is a serious psychiatric disorder that requirespharmacological intervention. Besides the availability of someof the wonderful antidepressant molecules, research is stillgoing on to explore novel antidepressant molecules withunique mechanism of action. These novel antidepressantsare expected to possess better efficacy and safety profiles com-pared with existing ones. As discussed in previous sections ofthis review article, polyphenols have shown antidepressant-like activity in various animal models of major depression.Various mechanisms have been put forward to justify the anti-depressant potential of these molecules. These include:i) modulation of various neurotransmitters such as norepi-nephrine, serotonin and dopamine, ii) antioxidant property,iii) anti-inflammatory potential, iv) ability to modulate the
activity of MAO enzyme and v) acting on neurotransmitterreceptor systems. These mechanisms are listed in Figure 3.
Despite an extensive research on the use of natural polyphe-nols in neurological and psychiatric disorders, we have not yetreached to a stage that could lead to prescription of these pol-yphenols for the treatment of major depression. Research inthis potential area is much slower and ineffective due to thefollowing reasons: i) none of the animal models mimic anexact state of human major depression. An animal model ofmajor depression should possess all the cardinal features ofthe disease condition; ii) the exact pathophysiology of majordepression is not yet known because of the complex natureof human brain and iii) there are not enough clinical eviden-ces demonstrating the antidepressant profile of these polyphe-nols. It is proposed that these polyphenols could be useful inthe treatment of major depression provided proper preclinicaland clinical studies are carried out to understand their phar-macokinetic and pharmacodynamic properties.
Curcumin is considered as a wonder molecule that is exten-sively studied for its use in various body disorders includingits effectiveness in major depression. Curcumin has showneffective antidepressant-like action in various animal modelsof depression. Researchers are preparing various analogs of
MAO inhibition
Modulating BDNF
Acting through glutamatereceptors
Anti-oxidative effect
Serotoninergic,nor-adrenergic ordopaminergic
Selective MAO-Ainhibition
Serotoninergic/nor-adrenergic
Serotoninergic,noradrenergicpathways
Serotoninergic
MAO-A inhibition
Modulation of BDNF-TrκB-Pi\I3K/Akt pathways
MAO-Ainhibition
Modulation of GABA-Areceptors
Anti-oxidative effect
Modulation of BDNF
MAO inhibition
Acting throughhypothalamic pituitaryadrenal axis
Modulation ofnitric oxide system
Serotoninergic
Adrenergic
Serotoninergicpathway
Serotoninergicnor-adrenergicordopaminergic
Serotoninergic, nor-adrenergic
Modulation ofκ opioidergicreceptors
Curcumin
Proanthocyanidins
Fisetin
Rutin
Quercetin Resveratrol
Opioidergicpathway
MAO-A inhibition
Central noradrenergic,dopaminergic andserotoninenergic activity
Amentoflavone
Apigenin
Ellagic acid
Ferulic acid
Chlorogenic acidHesperidin, Naringenin and Nobiletin
Naturalpolyphenols
Acting via glutamatereceptors
Figure 3. Mechanism of action of various polyphenols depicting antidepressant activity.
Natural polyphenols in the management of major depression
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curcumin that could enhance its bioavailability and blood--brain barrier penetrability. The bioavailability of these moleculescould be enhanced by using different approaches such as makingwater-soluble analogs of aqueous insoluble polyphenols or viausing nanotechnological intervention. Another important issuewith the use of polyphenols is their short half-life. For example,green tea polyphenols have a short half-life of about 3 h. There-fore, it will be necessary to drink green tea at least 8 times in aday to have antidepressant action. It is very important toenhance the half-life of such polyphenols either by making novelanalogs or by preventing their metabolism. It is a common myththat natural compounds are very safe. Some of these polyphenolsat higher doses have potential side effects that are listedin Table 2. Therefore, it is mandatory to perform clinical studiesto extract out the side-effect profile of these natural polyphenols.
It is expected that these polyphenols might be prescribed asan adjuvant therapy with already existing antidepressant mol-ecules in the treatment of major depression. Alternatively,these molecules could be prescribed in pharmacoresistantpatients where 3 or > 3 drugs are found to be ineffective inrelieving the symptoms. In summary, polyphenols researchis an exciting field to study and there are lots of opportunitiesin this upcoming area of research.
Declaration of interest
A Dhir is a Fellow of Department of Biotechnology, NewDelhi. The authors state no conflict of interest and havereceived no payment in preparation of this manuscript.
Table 2. Potential side effects of natural polyphenols listed for antidepressant activity.
S. no. Polyphenol Side effects Refs.
1 Curcumin Cytotoxic and genotoxic potential on human peripheral lymphocytes athigh doses are observed
[166]
2 Apigenin - -3 Chlorogenic acid Inflammation at high doses when tested in rats [167]
4 Amentoflavone Mutagenic when tested in Salmonella typhimurium [168]
5 Ellagic acid - -6 Hesperidin - -7 FA - -8 Fisetin - -9 Naringenin Known to induce expression of CYP1A1 in the colon tissue and thus
could promote colorectal carcinomas[169]
10 Nobiletin - -11 Resveratrol Inhibit various metabolizing enzymes leading to food--drug interactions [170]
12 Proanthocyanidins Inhibits iron absorption and therefore toxic when given in iron deficiency anemia [171]
13 Quercetin Depletion of intracellular glutathione content, total RNA amount and cellregulating genes, induction of CYP1A1 in colon and liver microsomes
[169,172]
14 Rutin - -
CYP1A1: Cytochrome 1A1; FA: Ferulic acid.
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AffiliationLokesh Pathak1, Yadvendra Agrawal1 &
Ashish Dhir†1,2 MPharm PhD†Author for correspondence1Scientist D,
