Natural polyphenols in the management of major depression

Abstract

Introduction:
Natural polyphenols, the non-essential micronutrients, found in array of plant products, are known to affect various physiological and biochemical functions in the body. Studies have shown the protective effect of these polyphenols in different neurological and mental disorders. These polyphenols 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 polyphenols in the treatment of major depression. The review article discusses the antidepressant potential of some important polyphenols such as amentoflavone, apigenin, chlorogenic acid, curcumin, ferulic acid, hesperidin, rutin, quercetin, naringenin, resveratrol, ellagic acid, nobiletin and proanthocyanidins. The mechanism of action of these polyphenols in the treatment of major depression is also discussed in detail.

Expert opinion:
There is an exciting prospect in the discovery of natural polyphenols as therapeutic agents in the treatment of major depression.

Full text

1. Introduction
2. Animal models of behavioral
despair
3. Polyphenols in animal models
of behavioral despair
4. Expert opinion
Review
Natural polyphenols in the
management of major depression
Lokesh 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-
vone, apigenin, chlorogenic acid, curcumin, ferulic acid, hesperidin, rutin,
quercetin, naringenin, resveratrol, ellagic acid, nobiletin and proanthocyani-
dins. The mechanism of action of these polyphenols in the treatment of major
depression is also discussed in detail.
Expert opinion: There is an exciting prospect in the discovery of natural
polyphenols as therapeutic agents in the treatment of major depression.
Keywords: antidepressants, antioxidant, monoaminergic neurotransmission, polyphenols
Expert Opin. Investig. Drugs [Early Online]
1. Introduction
‘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 and
cereals [3]. Polyphenols have shown several beneficial effects illustrating their prom-
ising role as therapeutic agents in various acute and chronic conditions of the body
such as cardiovascular and metabolic disorders [4,5], inflammation and cancer [6],
oxidative stress [7,8], cerebral ischemia [9] and obesity [10,11]. Numerous studies
have shown that natural polyphenols play an important role in proper functioning
of the brain [12-14]. These micronutrients, for example, are involved in learning
and memory process, prevent neuroinflammation and possess antioxidant
potential [15-17]. These polyphenols are known to modulate various neurotransmitter
systems in the brain. For example, curcumin found in Curcuma longa modulates
serotoninergic and dopaminergic neurotransmission in the brain and therefore
could be useful as an antidepressant agent [16]. The fact that these polyphenols alter
different neurotransmitters has prompted researchers to explore their usefulness in
the treatment of major depression.
Major depression is a serious medical illness that affects both developed and
developing countries [18,19], and has an estimated lifetime prevalence of about
15 -- 20% [20-22]. It has been estimated that by the year 2020, depression will reach
in second place in the ranking of disability-adjusted life-years [23]. The monoamine
theory of major depression has been well-accepted by researchers. According to this
theory, there is a decrease in the levels of various monoaminergic neurotransmitters
such as norepinephrine, serotonin and dopamine in brains of depressed patients.
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Molecules that reverse this deficiency are known to possess
antidepressant activity [24]. Various new antidepressants such
as venlafaxine and triple reuptake inhibitors have been
discovered based on this theory [25].
More than 25 antidepressant agents are available commer-
cially (Figure 1) that has allowed treatment of depressed
patients in an efficient manner. However, acute or chronic
administration of these antidepressants could lead to serious
side effects, adverse drug reactions and drug-- drug and food--
drug interactions [26]. Unfortunately, about 10 -- 30% of
depressed patient population still continues to have depressive
episodes besides the availability of these wonderful drugs [27].
All these factors justify a need for newer antidepressant agents
possessing 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 extensively
in animal models of major depression. The review also
includes the mechanism of action of these polyphenols for
their antidepressant activity. Some of the polyphenols that
have been tested for their antidepressant activity are illustrated
in Table 1 with their chemical structures represented
in Figure 2. Based on the preclinical data, it is hypothesized
that these polyphenols might be useful as an adjuvant therapy
with already established antidepressant agents for the treatment
of major depression.
2. Animal models of behavioral despair
The discovery of various new molecular entities (NMEs) as
antidepressants requires appropriate animal models with
excellent 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 to
evaluate 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 at
25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 with
very little limb movements. This condition correlates with
the state of behavioral despair and various antidepressants
are known to reverse this immobility period [24]. Similarly,
in a TST, an animal (mice or rat) is suspended by its tail at
a certain height and for a definite period of time and its
immobility period is assessed. Although both of these models
measure immobility period in animals, however, they differ
each other on neurochemical basis [31]. NMEs that reverse
this immobility period in these two tests are studied further
for their antidepressant action. Some of the other models
that are routinely used for testing antidepressant-like activity
of new molecules include olfactory bulbectomy, sucrose pref-
erence, intracranial self-stimulation task and others. In these
behavioral paradigms of despair, locomotor activity is also
assessed simultaneously with the antidepressant activity. It
has been seen that amphetamine-like psychostimulants are
also active in these animal models [32]. Therefore, researchers
often times use locomotor activity as a criterion to distinguish
antidepressant and psychostimulatory activities in these
behavioral paradigms of despair.
It has been found that natural polyphenols are active in
these animal models of despair. Neurochemical estimation
has shown that some of these polyphenols modulate various
neurotransmitters in the brain that are involved in the patho-
physiology of various neuropsychiatric and neurodegenerative
disorders [33]. The details describing the antidepressant activ-
ity of some of the natural polyphenols in these behavioral
models of despair are explained in separate sub-headings.
3. Polyphenols in animal models of
behavioral despair
The present section discusses the antidepressant-like activity
of various natural polyphenols. These polyphenols could be
used as an adjuvant therapy in the treatment of major depres-
sion. However, it is strongly recommended that clinical trials
describing the efficacy and safety profile of these molecules
should be carried out before these drugs are considered to be
useful in the treatment of major depression.
3.1 Curcumin
Curcumin, a polyphenol, is the major active ingredient of
Curcuma 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 the
effect 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 of
monoamine oxidase-A (MAO-A) and monoamine oxidase-
B (MAO-B) enzymes [16].Xuet al. in 2007 showed that
curcumin enhanced hippocampal neurogenesis in chronically
stressed mice and the effect was similar to imipramine, a stan-
dard tricyclic antidepressant agent [36]. Curcumin showed
antidepressant-like action in FST in both mice and rats.
Article highlights.
.Natural polyphenols in major depression
.Preclinical studies of natural polyphenols in animal
models of depression
.Mechanism of action of polyphenols as an
antidepressants
.Side effects of natural polyphenols
This box summarizes key points contained in the article.
L. Pathak et al.
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Xu et al. in 2005 showed that curcumin at doses of 5 and
10 mg/kg., p.o. was active in mouse FST and TST [37].
Further, it has been shown that there is an increased level of
noradrenaline and serotonin in frontal cortex and hippocam-
pal brain regions following curcumin administration at a dose
of 10 mg/kg., p.o. compared with control group [37].In
another similar kind of study, it has been shown that curcu-
min is antidepressant in olfactory bulbectomy animal model
of major depression [38]. Curcumin totally reversed olfactory
bulbectomy-induced reduced levels of serotonin, noradrena-
line and increased levels of 5-hydroxyindoleacetic acid and
4-dihydroxyphenylacetic acid in the hippocampus region of
mouse brain in this animal model [38].
The antidepressant activity of curcumin according to
Wang et al. is linked to modulation of serotoninergic system [39].
It has been shown that there is an involvement of 5-HT
1A/1B
and 5-HT
2C
serotonin receptors in the antidepressant-like
activity of curcumin [39]. Serotoninergic receptors produce
physiological response via adenyl cyclase/cyclic adenosine
monophosphate (AC/cAMP) pathway. Li et al. have shown
that curcumin modulates AC/cAMP pathway and cAMP
response element binding protein and the effect is mediated
through suppressing central 5-HT
1A/1B/7
receptors [40].
Besides serotoninergic receptors, other receptor systems are
also involved in the antidepressant-like effect of curcumin.
Glutamate, an excitatory neurotransmitter, is known to play
an important role in the antidepressant-like action of
curcumin [41]. Lin et al. have shown that curcumin could
inhibit the release of glutamate induced by 4-aminopyridine
(a potassium channel blocker) [41]. Further, it has been
NH
ONO
O
ONH
H
Cl
Cl
NH
H
Nortriptyline Venlafaxine Doxepin Raboxetine Sertraline
O
N
N
F
Escitalopram
O
N
N
F
Citalopram
N
Amitriptyline
Desipramine Fluoxetine Mirtazapine Trimipramine Mianserin
Cl
O
NH
N
O
NH N N
N
N
N
NN
Cl
O
Bupropion Minaprine Trazodone
Maprotiline
NH
N
NH
NH O
F
F
F
N
N
N
N
N
N
N
N
O
OH
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 Ca
v
2.2 and
Ca
v
2.1 calcium channels [41]. Interestingly, the authors have
also demonstrated that the inhibitory effect of curcumin on
4-aminopyridine-induced glutamate release and the effect
was completely blocked by fluoxetine, a selective serotonin
reuptake inhibitor. This finding suggests that both curcumin
as well as fluoxetine share some common mechanisms of
action that involve inhibition of glutamate release [41].
In another study, it has been demonstrated that glutamate
N-methyl-D-aspartate (NMDA) GluN2B receptors are
involved in the antidepressant-like activity of curcumin. Var-
ious agonists and antagonists of NMDA glutamate receptors
were used to prove the hypothesis [42].
The antidepressant activity of curcumin is also linked to its
modulatory effect on neurotrophic factors. In a study,
curcumin reversed a decrease in the levels of brain-derived
neurotrophic factor (BDNF) induced by glutamate [43]. Fur-
ther, Wang et al. have depicted that the neuroprotective effect
of curcumin involves activation of BDNF and its receptors
N
NN
O
Cl
N
H
N
H
N
F
OO
O
Imipramine
NH
FF
F
O
N
O
H2N
N
N
Cl
Clomipramine
N
NH NNO
O
NH2
NH2
N
O
Cl
O
NH N
O
Moclobemide
O
S
NH
HN NH2
Amoxapine Paroxetine
Protriptyline Fluvoxamine
Vilazodone
Duloxetine
NH
HN O
N
O
NH2
Isocarboxazid Tranylcypromine Phenelzine
Minacipran
Figure 1. Structures of approved drug molecules for the treatment of major depression (continued).
L. Pathak et al.
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TrkB-dependent MAP kinase (mitogen-activated protein
kinase) and PI3K (phosphatidylinositol 3-kinase) cascade
when checked in rodent cortical neurons [44].
In one of the studies, curcumin has shown to increase the
levels of serotonin and dopamine neurotransmitters and
inhibits the activity of MAO isoenzymes. Further, curcumin
decreases immobility period in mouse FST [16]. It has been
demonstrated 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. The
authors in the present study administered corticosterone exog-
enously chronically for 3 months. As a result, rats developed
depression-like state. In these rats, a decrease in the levels of
BDNF was found. Pretreatment of curcumin reversed this
depression-like pattern in this animal model [45]. In a very
recent study, the antidepressant-like activity of curcumin was
studied in WKY rat model of depression. Curcumin was
effective both in acute and chronic dosing profiles and the
results were correlated with an increase in the levels of BDNF
following curcumin administration in this animal model [46].
3.2 Apigenin
Apigenin 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 and
insomnia [48,49]. Apigenin is also protective in cerebral ische-
mia reperfusion injury in rats [50] suggesting that the molecule
could easily cross blood-- brain barrier. Apigenin has shown
anti-inflammatory activity in cultured microglia cells and
therefore the molecule is hypothesized to display neuroprotec-
tive/disease-modifying properties in various neurodegenera-
tive disorders including Alzheimer’s disease [51]. A recent
study has shown the protective effect of apigenin in amy-
loid-b
25-35
-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 model
of excitotoxicity in mice [53]. In this study, apigenin prevented
kainic acid-induced excitotoxicity via quenching reactive
oxygen species as well as inhibiting glutathione depletion in
hippocampal neurons [53].
Antidepressant-like effect of apigenin was first shown by
Nakazawa et al. in various behavioral despair test models [54].
Further, the central noradrenergic, dopaminergic and seroto-
ninergic modulatory activities of apigenin was demonstrated
in mice [54]. Apigenin when administered via intraperitoneal
route in mice at doses of 12.5 and 25 mg/kg displayed signif-
icant anti-immobility action in the FST. Further, at a higher
dose 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
[16,36-39]
2 Apigenin Citrus family, leaves
of Perilla frutescens
Central noradrenergic, dopaminergic and
serotoninergic activity, MAO-A inhibition,
acting through hypothalamic pituitary adrenal axis
[56-58]
3 Chlorogenic acid Artemisia capillaris Thunb. Opioidergic pathway [13,67]
4 Amentoflavone Cnestis ferruginea MAO inhibitory action, modulating BDNF,
acting via glutamate receptors, antioxidative effect,
modulation of GABA-A receptors
[60]
5 Ellagic acid Raspberries, the stem and bark
of eucalyptus species and nuts
Adrenergic, serotoninergic and/or NO system [70]
6 FA Ubiquitous plants Serotoninergic pathway [83,84]
7 Fisetin Strawberries and other
fruits and vegetables
Selective MAO-A inhibition,
serotoninergic/noradrenergic
[92]
8 Hesperidin Citrus fruits Modulation of kappa opioidergic receptors [120,121]
9 Naringenin Citrus fruits Serotoninergic, noradrenergic [143,144]
10 Nobiletin Citrus fruits Serotoninergic, noradrenergic or dopaminergic [164,165]
11 Proanthocyanidins Grape seed extract,
Hibiscus rosa-sinensis
Serotoninergic, noradrenergic and dopaminergic [154]
12 Cis/trans-resveratrol Polygonum cuspidatum, wine MAO-A inhibition [109,110]
13 Rutin Schinus molle Serotoninergic, noradrenergic pathways [132,125]
14 Quercetin St. John’s wort, Gingko biloba Serotoninergic, MAO-A inhibition, modulation of
BDNF-TrkB-PI3K/Akt pathways
[99-101]
BDNF: Brain-derived neurotrophic factor; FA: Ferulic acid; GABA-A: Gamma-aminobutyric acid type A; MAO: Monoamine oxidase; NO: Nitric oxide.
Natural polyphenols in the management of major depression
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animals. The authors of this study have also measured neuro-
transmitters turnover in mouse brain after 40 min stress
induced by forced swimming and its modulation by apigenin.
It was found that apigenin at a dose of 25 mg/kg reversed a
decrease in dopamine turnover in the amygdale region and
increase in dopamine turnover in the hypothalamus region
of the mouse brain [54]. This study signifies that there is a
role of dopamine in the antidepressant-like action of apigenin.
Further, the antidepressant-like action of apigenin was
reversed by haloperidol, a dopamine D
2
receptor blocker.
The antidepressant-like activity of apigenin is not completely
understood, however, the molecule has shown to inhibit
MAO enzyme activity with an IC
50
value of 6.5 µM. Apige-
nin is more effective in inhibiting MAO-A as compared
with MAO-B activity [55]. MAO inhibitors are effective anti-
depressant agents; however, the use of this class of drugs is
limited due to their adverse food-- drug interactions [24].
Besides FST, apigenin was also evaluated in other animal
models of depression such as chronic mild stress (CMS) [56].
Apigenin in this study was administered via oral route. It
has been found that chronic administration of apigenin
reversed CMS-induced decrease in sucrose intake as compared
with control animals [56]. Furthermore, it was shown that
CMS raised the levels of corticosterone in Wistar rats which
O
O
HO
HO
OH
O
HO
OH
O
OH
O
OO
O
O
OO
O
O
OH
O
OH
OH
OH
OH
OH
OH
OH
HO
OH
OH
OH
OH
HO O
O
OH
OH
HO
HO
O
OH
O
O
OH
OH
O
O
O
OH
OH
O
HO
HO
O
HO
OO
OH
O
O
HO
OH
O
HO O
O
OH
OH
OH
Amentoflavone
cis-Resveratrol Apigenin Chlorogenic acid Curcumin
Ferulic acid
Ellagic acid Fisetin Hesperidin
Rutin Quercetin Gallic acid
Naringenin
Nobiletin Proanthocyanidins Trans-Resveratrol
O
OH
O
O
HO
O
OH
O
O
O
HO
HO
HO
HO
HO
OH
OHO
O
OH O
O
HO
OH
OH
OH
O
O
OH
OH
OHO
O
OH
OHHO
O
OH
OOH
HO
OH
OH OOH
HO
OH
OH
Figure 2. Structures of natural polyphenols known for their antidepressant activity.
L. Pathak et al.
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was reversed by chronic administration of apigenin [56]. The
study concluded that there are multiple mechanisms with
regard to the antidepressant-like activity of apigenin [56].
3.3 Amentoflavone
Amentoflavone is a unique bioflavonoid consisting of apige-
nin dimer. It has been shown that amentoflavone could easily
cross blood-- brain barrier when tested in vitro in primary cell
cultures of porcine brain capillary endothelial cells [57]. How-
ever, when tested in vivo in a mouse model, amentoflavone
has shown poor blood-- brain barrier penetrability [58]. Limited
concentration of amentoflavone was detected only after intra-
peritoneal administration of the molecule at 10 mg/kg. An
in vitro study has suggested that amentoflavone extracted
from different Hypericum species could inhibit flumazenil
binding to rat brain benzodiazepine binding sites at GABA
A
receptor with an IC
50
value of 14.9 ± 1.9 nM [59]. The study
further demonstrated that amentoflavone binds to the benzo-
diazepine site of GABA
A
receptors [59]. A recent study has
evaluated the antidepressant-like action of amentoflavone.
Amentoflavone isolated from root decoction of Cnestis ferrugi-
nea (a traditional African herbal medicine often prescribed for
psychiatric disorders) was evaluated for its antidepressant-
like activity in mice [60]. The antidepressant-like effect was
studied using behavioral despair models such as FST and
TST in 8-week-old naı
¨ve Swiss albino mice. Amentoflavone
(6.25 -- 50 mg/kg, p.o.) or imipramine (20 mg/kg, p.o.) was
administered to mice 1 h prior to the FST. It was found
that the methanolic extract of C. ferruginea at 12.5 mg/kg,
reduced immobility period and simultaneously enhanced
swimming 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 pronounced
and potent in reducing immobility period when compared
with imipramine (20 mg/kg), a tricyclic antidepressant [60].
It is suggested that attempts should be made to enhance the
blood-- brain barrier penetrability of amentoflavone.
3.4 Chlorogenic acid
Chlorogenic 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 in
coffee [63]. A study showing anxiolytic and antioxidant proper-
ties of chlorogenic acid at a dose level of 20 mg/kg has been
reported; the anti-anxiety effect was blocked by flumazenil
suggesting that the anti-anxiety effect of chlorogenic acid is
dependent on its activity on GABA
A
-benzodiazepine recep-
tors [62]. Various studies have shown protective effect of
chlorogenic acid in animal models of Alzheimer’s disease
and cerebral ischemia [63-66]. In one study, chlorogenic acid
was found to inhibit the activity of acetylcholinesterase
enzyme (an enzyme involved in the degradation of acetylcho-
line) with an IC
50
value of 98.17 µg/ml [63]. Further, the
molecule possesses free radical scavenging property with an
IC
50
value of 3.09 µg/ml [63].
There are not enough studies depicting the antidepressant-
like profile of chlorogenic acid. Interestingly, there is a clinical
study demonstrating that decaffeinated coffee rich in
chlorogenic acid could elevate mood in 39 healthy volunteers
depicting that chlorogenic acid could be useful as an antide-
pressant/mood-elevator agent [67]. In one study, chlorogenic
acid isolated from Artemisia capillaris Thunb. has shown
antidepressant-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 of
antidepressant action of chlorogenic acid is not clear but
hypothesized to act through opioidergic pathway [13].
3.5 Ellagic acid
Ellagic acid is a polyphenolic compound that occurs in plants
such as raspberries, pomegranate, the stem and bark of euca-
lyptus species and nuts [68]. This bioflavonoid has shown anti-
oxidant, antifibrotic, anti-inflammatory, cardioprotective and
anticancer properties [68,69]. Few studies have been carried out
demonstrating the antidepressant-like profile of ellagic acid.
Girish et al. have shown that ellagic acid at doses of
25 -- 100 mg/kg., p.o. when administered both in an acute
and chronic fashion reduces immobility period in both FST
and TST [70]. The effect of ellagic acid in these animal models
was comparable with fluoxetine, a selective serotonin reuptake
inhibitor [70]. Further, the authors have shown the involve-
ment of monoaminergic neurotransmitter receptors (both
serotonin and adrenergic) in the antidepressant-like action
of ellagic acid [70]. The authors further confirmed that there
is no role of opioidergic receptors in the antidepressant-
like action of ellagic acid [70]. In another study carried by
Dhingra and Chhillar, the antidepressant-like activity of ella-
gic acid was confirmed in immobilization-induced stress in
mice. The authors in the present study induced stress in
mice by immobilizing them once for a total of 150 min. It
was shown that ellagic acid at 17.5 and 35 mg/kg reduced
the immobility period in stressed mice when checked in
both FST and TST animal models. The authors concluded
that there might be involvement of adrenergic, serotoninergic
and/or nitric oxide (NO) system in the antidepressant-
like action of ellagic acid in these animal models [71]. There
are no clinical studies to prove the antidepressant-like effect
of ellagic acid in major depression.
3.6 Ferulic acid
Ferulic acid (4-hydroxy-3-methoxycinnamic acid; FA) is a
plant constituent known to scavenge free radicals in the
body and thus act as a powerful antioxidant agent [72]. The
molecule has been known to possess multiple pharmacological
effects including anti-inflammatory, anticancer, antidiabetic
and anti-atherogenic and neuroprotective [73-76]. FA improves
learning and memory in rat model of vascular dementia [77].
The authors have concluded three mechanisms of action in
the protective effect of FA in dementia. These mechanisms
include i) antioxidative potential of FA, ii) improvement of
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cholinergic system by FA and iii) antagonizing the action of
excitatory amino acid [77]. It has been shown that long-
term administration of FA prevents brain damage from
beta-amyloid protein and thus could be useful to prevent
the occurrence of Alzheimer’s disease [78]. Sodium ferulate, a
sodium salt of FA is also known to possess sedative activity [79],
and the plant extract containing this molecule has found its
usefulness in the treatment of headache and irritability, apo-
plexy, stasis, etc. [80,81]. A very recent study has shown the
effect of FA on the proliferation of neural progenitor cell
both in vitro and in vivo [82]. When administered orally in
mice, FA enhances the number of newly generated cells in
the dentate gyrus of the hippocampus of corticosterone-
treated mice [82]. FA has been shown to possess antidepressant
and prokinetic properties [83]. The molecule reduces immobil-
ity period in rat FST, its anti-immobility effect was prevented
by PCPA (p-chlorophenylalanine; serotonin depleter),
WAY-100635 (selective serotonin 5-HT
1A
antagonist), ketan-
serin (selective serotonin 5-HT
2
antagonist), sulpiride (a
dopamine D2 receptor antagonist), SCH233390 (a dopamine
D1 receptor antagonist), haloperidol (dopamine D2 receptor
antagonist) and yohimbine (selective adrenergic alpha-2
antagonist), respectively. In another recent study, FA
(0.01 -- 10 mg/kg, p.o.) is active in behavioral despair models
including FST and TST. It has been found that the
antidepressant-like activity of this molecule is not dependent
on changes in the locomotor activity. Some of the conven-
tional antidepressants such as fluoxetine, paroxetine, sertraline
(all selective serotonin reuptake inhibitors) enhance the
antidepressant-like action of FA, thus demonstrating an
important role of serotonin in the antidepressant action
of this molecule. Further, it is confirmed that both
WAY-100635 (0.1 mg/kg, s.c., a selective 5-HT
1A
receptor
antagonist) or ketanserin (5 mg/kg, i.p., a 5-HT
2A
receptor
antagonist) reverse the antidepressant-like effect of FA in
this animal model [84].
3.7 Fisetin
Fisetin (3,3¢,4¢,7-tetrahydroxyflavone) is a naturally occurring
flavonoid and is found abundantly in strawberries and other
fruits and vegetables. Fisetin has a strong anti-inflammatory
property in brain microglia cells [85]. In a study carried out
by Zheng et al., it was shown that fisetin suppressed the levels
of various inflammatory markers such as TNF-a, NO and
prostaglandin E2 (PGE2) in lipopolysaccharide-stimulated
BV-2 microglia cells or primary microglia cultures [85]. Fisetin
plays an important role in regulating brain functions [86-91].
Antidepressant-like effect of fisetin in behavioral models of
despair was recently investigated and the results suggested
that fisetin (10 and 20 mg/kg, p.o.) dose dependently inhib-
ited the immobility period in FST and TST without affecting
the locomotor activity [92]. Further, fisetin reversed hypother-
mia induced by reserpine (a neurotransmitter-depleting
agent). Neurochemical analysis revealed that fisetin could
enhance 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 the
compound acts by modulating levels of both noradrenaline
and serotonin and possesses no action toward dopamine
levels [92].
3.8 Quercetin
Quercetin (3,3¢,4¢,5,7-pentahydroxyflavone) is a bioflavonoid
widely 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 glycosides
since last decade [94-98]. Dixon Clarke and Ramsay have
reported that diet rich in quercetin could inhibit MAO activ-
ity in brain [99]. This could further prevent neurotransmitter
breakdown [99]. The first study demonstrating the
antidepressant-like profile of quercetin was conducted by
Anjaneyulu et al. [100]. In this study, quercetin per se was
ineffective in mouse FST. However, quercetin showed
antidepressant-like action in streptozotocin-induced diabetic
mice when tested in FST. The antidepressant-like effect of
quercetin (50 and 100 mg/kg) was comparable with fluoxe-
tine (5 mg/kg., i.p.) or imipramine (15 mg/kg., i.p.) in
streptozotocin-induced diabetic mice [100]. A similar kind of
study was published in 2007 by the same group demonstrat-
ing that quercetin could induce depression-like phase and
this property involves the participation of alpha-2 adrenergic
receptors in its mechanism of action [101]. Yohimibine, an
alpha-2 adrenergic receptor blocker inhibited the behavioral
despair induced by quercetin [101].
Recently, an interesting study has been published depicting
the antistress effect of quercetin. Animals in this study were sub-
jected to water immersion-restraint stress [102].Animalswere
found to have activated hypothalamic-- pituitary-- adrenal (HPA
axis) that was normalized with the treatment of quercetin [102].
Quercetin in this study significantly suppressed elevated levels
of plasma corticosterone and adrenocorticotropic hormone.
Results have shown that quercetin suppresses the expression of
corticotrophin-releasing factor (CRF) mRNA [102].Thefindings
have been confirmed by another group where CRF was injected
in animals to induce anxiety and depression-like stage and the
pretreatment of quercetin reversed the effect of exogenously
administered CRF [103]. Quercetin is an interesting compound
to study in various brain disorders. Quercetin has shown to be
a weak inhibitor of MAO-A enzyme in brain; however, the
compound does not affect MAO-A activity in mouse intestinal
mitochondria. This study reflects that various drug-- food
interactions (e.g., hypertensive crisis observed with tyramine-
containing food) that are commonly seen with the use of
commercially available MAO inhibitors are not seen with the
use of quercetin [104]. Similarly, Yoshino et al. have shown
that quercetin inhibits MAO-A enzyme in mouse brain
mitochondria and thus inhibits the breakdown of serotonin
neurotransmitter [105]. Quercetin metabolite, quercetin 3-glucu-
ronide, has powerful antioxidant activity as shown by
L. Pathak et al.
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Yoshino et al. [105]. Beside MAO inhibiting and antioxidant
properties of quercetin, other factors may also contribute to
the antidepressant-like activity of quercetin. Quercetin is neuro-
protective in focal cerebral ischemia model via activation of
BDNF-TrkB-PI3K/Akt signaling pathway. Therefore, querce-
tin antidepressant-like activity relates to its ability to modulate
levels of BDNFs [105]. Thus, quercetin seems to be a viable
candidate to be included in antidepressant drug therapy.
3.9 Resveratrol
Resveratrol (3,4¢,5-trihydroxystilbene), is a natural phenolic
compound present in peanuts, red grapes and wine [106].It
exists as cis-ortrans-isomers [107,108]. It has been found that
resveratrol possesses an inhibitory effect on the uptake of
[
3
H] NA (noradrenaine) and [
3
H]5-HT (serotonin) in rat
synaptosomes, prevents the uptake of [
3
H]5-HT in human
platelets and inhibits MAO isoform activity [109]. The first
study to demonstrate the antidepressant-like effect of trans-
resveratrol in behavioral despair model was carried out by
Xu et al. [110]. The authors have shown that trans-resveratrol
(20 -- 80 mg/kg, p.o.) significantly decreased the immobility
period in mouse models of behavioral despair without affect-
ing the locomotor activity. Neurochemical analysis has shown
that trans-resveratrol at doses of 40 and 80 mg/kg produces a
significant increase in the levels of noradrenaline and seroto-
nin. The mechanism is yet not clear, however, the authors
have demonstrated that trans-resveratrol could significantly
inhibit the activity of MAO-A enzyme [110]. Resveratrol is
known to upregulate the production of astroglia-derived
neurotrophic factors via activation of extracellular signal-
regulated kinase 1/2 (ERK1/2) and cAMP responsive
element-binding protein (CREB) [111]. By contrast, it has
been shown recently that resveratrol inhibits hippocampal
neurogenesis when tested in healthy adult mice [112]. Also, it
has been shown that resveratrol inhibits the proliferation and
survival of cultured neural progenitor cells [112]. Therefore,
the exact mechanism regarding the antidepressant-like action
of resveratrol is not clear. Moreover, it was demonstrated by
Di Liberto et al. that the antidepressant action of resveratrol
is 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 of
female mice and not in male mice [113]. It is yet not clear
how this will influence the activity of resveratrol in treating
patients suffering from major depression.
3.10 Hesperidin
Hesperidin is a flavanone glycoside abundantly found in the
citrus fruits [114]. Hesperidin decreases capillary permeability
and fragility: it is also known as vitamin P [115]. There are sev-
eral pharmacological reports on the action of hesperidin that
include its sedative potential [116,117], antioxidant ability [118],
anti-inflammatory and analgesic properties [119]. Souza et al.
demonstrated the antidepressant-like activity of hesperidin
in mouse FST and TST [120]. In this study, it was observed
that hesperedin (0.1 -- 1 mg/kg., i.p.) reduced the immobility
period in both the tests and the antidepressant-like activity
was independent of alterations in locomotor activity [120].It
has been found that hesperidin is effective in TST at a subef-
fective dose of 0.01 mg/kg [120]. Further, authors concluded
that the antidepressant-like effect of hesperidin in TST was
dependent on its interaction with the serotoninergic 5-HT
1A
receptors. Another study has shown the involvement of kappa
opioidergic receptors in the antidepressant-like effect of hesper-
idin [121]. The antidepressant-like effect of hesperidin in FST
was prevented by pretreatment of naloxone (a non-selective
opioidergic 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-opioid
receptor 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 model
of stroke [122]. Interestingly, hesperidin reduced the levels of
inflammatory biomarkers such as TNF-a,IL-1blevels, induc-
ible nitric oxide synthase (iNOS) expression and glial fibrillary
acidic protein (GFAP) in middle cerebral artery occluded rats
as compared with their respective controls [122].Inoneofthe
studies, 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 III
cells in this study [123]. Hesperidin seems to be a viable candidate
for the treatment of major depression.
3.11 Rutin
Rutin, a diglycoside flavonol, is extensively found in many
plants including Hypericum perforatum. St. John’s wort, an
extract of H. perforatum, is a traditional remedy for the treat-
ment of depression since ages [124]. It has been found that
rutin is an important constituent of the Hypericum extract
and is essential for its antidepressant activity [125]. This flavo-
nol has been shown to exert several other biological activities
including antimicrobial [126] anti-inflammatory [127], antioxi-
dant [128], neuroprotective [129] and antiulcerogenic [130]
potentials. Rutin is observed to be absorbed slowly and less
efficiently as compared with quercetin on the basis of area
under the plasma concentration-- time curve values and rela-
tive urinary excretions [131]. In order to study the
antidepressant-like profile of rutin, Machado et al. carried
out a study exploring the effect of ethanolic extract of aerial
part of Schinus molle using FST and TST in mice [132]. The
authors found that administration of rutin reduced the immo-
bility period in the TST (0.3 -- 3 mg/kg, p.o.), but not in the
FST. Further, pretreatment of mice with PCPA (inhibitor of
serotonin synthesis) or AMPT (a-methyl-p-tyrosine; inhibitor
of noradrenaline synthesis) prevented the anti-immobility
effect 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
Natural polyphenols in the management of major depression
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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-inflammatory
activities when tested in rats [134]. In streptozotocin-induced
inflammatory rat model, rutin prevented the overexpression
of 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 in
hippocampal CA1 region [135]. In contrast to these studies,
Silva et al. have shown that rutin has a capacity to induce
TNF-aand 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 volunteers
for studying the pharmacokinetics of rutin (quercetin-3-O-b-
rutinoside [137]. The authors in this study concluded that after
6-week administration of rutin, there was no significant anti-
oxidant effect observed in the plasma [137]. This might be
related to bioavailability issues associated with rutin. More
studies are required to establish the use of rutin in brain
disorders including its use in major depression.
3.12 Naringenin
Naringenin (4,5,7-trihydroxyflavanone) is one of the most
abundant flavanones in citrus fruits [138]. Neuroinflammation
has been speculated to play a major role in the pathophysiol-
ogy of major depression. Neuroinflammatory signaling
pathways have emerged as new targets for antidepressant
drugs [139]. The fact that naringenin is known to reduce
neuroinflammatory injuries in glial cells via inhibiting pro-
inflammatory mediators such as p38 signaling cascades and
the 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 possesses
antioxidant and anti-inflammatory properties [141]. Naringe-
nin suppressed NF-kB signaling pathway in ischemic stroke
model, suggesting anti-inflammatory property [141]. Naringe-
nin has a good oral bioavailability [142]. Naringenin has shown
to inhibit the activity of MAO enzyme [143]. Antidepressant-
like action of naringenin was investigated by Yi et al. The
authors in this article have demonstrated that naringenin
(10 -- 50 mg/kg) treatment could significantly decrease the
immobility period in the mouse TST but not in the FST.
Moreover, pretreatment with PCPA or AMPT significantly
inhibited the anti-immobility effect of naringenin in the
TST suggesting the role of serotoninergic and noradrenergic
systems in its antidepressant action [144].
3.13 Proanthocyanidins
Proanthocyanidins polyphenols are the major component of
grape 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 via
acting through cellular signaling pathways such as advanced
glycation product (AGEs), nuclear factor-kappa B p65
(NF-kB65) [150]. Wang et al. demonstrated that metabolites
of monomeric proanthocyanidins could selectively reach brain
and improve cognition by modulating synaptic plasticity in
the brain [151]. When tested in rat hippocampal cells, grape
seed proanthocyanidins inhibited glutamate-induced cell
death 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 glial
cells [153]. However, the antidepressant-like activity of the
proanthocyanidins in animal models was first demonstrated
by Xu et al. [154]. The authors demonstrated effectiveness of
proanthocyanidins in animal models of behavioral despair
after oral administration in mice at dose range of 25 and
50 mg/kg for 7 days. The antidepressant-like activity in this
animal model is devoid of alterations in the locomotor activity
of mice [154]. Further, neurochemical evidences revealed
that proanthocyanidins increases the levels of serotonin,
noradrenaline and dopamine in various regions of the brain
suggesting the role of central monoaminergic system in its
antidepressant-like action [154].
3.14 Nobiletin
Nobiletin is a polymethoxylated flavone abundantly found in
citrus fruits [155,156]. Nobiletin has vast pharmacological
actions including its applications in various clinical conditions
such as cataract [157], obesity [158], metastasis [159], neuroin-
flammation [160] and hyperglycemia [161]. Nobiletin has also
shown activity in various animal models of CNS disorders.
In one of the studies, nobiletin exerted neuroprotective
effects 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 first
time in animals by Yi et al. [164]. The authors in this study
administered nobiletin to mice and observed a decrease in
immobility period in both FST and TST at a dose range of
25 -- 100 mg/kg per oral. The antidepressant-like action of
nobiletin in this study was devoid of alterations in the
locomotor activity of mice as assessed by open-field test [164].
Further, it has been shown that pretreatment of mice with
WAY-100635 (a serotonin 5-HT
1A
receptor antagonist),
cyproheptadine (a serotonin 5-HT
2
receptor antagonist), pra-
zosin (an a1-adrenoceptor antagonist), SCH23390 (a dopa-
mine D1 receptor antagonist) or sulpiride (a dopamine
D2 receptor antagonist) prevented the anti-immobility effect
of nobiletin in TST. By contrast, pretreatment of animals
with yohimbine (an a2-adrenoceptor antagonist) or proprano-
lol (a b-adrenoceptor antagonist) did not affect the
antidepressant-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
L. Pathak et al.
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nobiletin [164]. Nobiletin (oral administration for 11 days) also
reversed memory impairment in olfactory-bulbectomized
mice [165] suggesting its antidepressant potential.
Polyphenols which were investigated during last decade for
their antidepressant and anxiolytic activities are summarized
in Table 1.
4. Expert opinion
Major depression is a serious psychiatric disorder that requires
pharmacological intervention. Besides the availability of some
of the wonderful antidepressant molecules, research is still
going on to explore novel antidepressant molecules with
unique mechanism of action. These novel antidepressants
are expected to possess better efficacy and safety profiles com-
pared with existing ones. As discussed in previous sections of
this 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 neurotransmitter
receptor 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 yet
reached to a stage that could lead to prescription of these pol-
yphenols for the treatment of major depression. Research in
this potential area is much slower and ineffective due to the
following reasons: i) none of the animal models mimic an
exact state of human major depression. An animal model of
major depression should possess all the cardinal features of
the disease condition; ii) the exact pathophysiology of major
depression is not yet known because of the complex nature
of 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 in
the treatment of major depression provided proper preclinical
and 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 including
its effectiveness in major depression. Curcumin has shown
effective antidepressant-like action in various animal models
of depression. Researchers are preparing various analogs of
MAO inhibition
Modulating BDNF
Acting through glutamate
receptors
Anti-oxidative effect
Serotoninergic,
nor-adrenergic or
dopaminergic
Selective MAO-A
inhibition
Serotoninergic/no
r-adrenergic
Serotoninergic,
noradrenergic
pathways
Serotoninergic
MAO-A inhibition
Modulation of BDNF-
Tr κB-Pi\I3K/Akt pathways
MAO-A
inhibition
Modulation of GABA-A
receptors
Anti-oxidative effect
Modulation of BDNF
MAO inhibition
Acting through
hypothalamic pituitary
adrenal axis
Modulation of
nitric oxide system
Serotoninergic
Adrenergic
Serotoninergic
pathway
Serotoninergic
nor-adrenergic
or
dopaminergic
Serotonine
rgic, nor-
adrenergic
Modulation of
κ opioidergic
receptors
Curcumin
Proanthocyanidins
Fisetin
Rutin
Quercetin Resveratrol
Opioidergic
pathway
MAO-A inhibition
Central noradrenergic,
dopaminergic and
serotoninenergic activity
Amentoflavone
Apigenin
Ellagic acid
Ferulic acid
Chlorogenic acid
Hesperidin, Naringenin and Nobiletin
Natural
polyphenols
Acting via glutamate
receptors
Figure 3. Mechanism of action of various polyphenols depicting antidepressant activity.
Natural polyphenols in the management of major depression
Expert Opin. Investig. Drugs [Early Online] 11
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curcumin that could enhance its bioavailability and blood--
brain barrier penetrability. The bioavailability of these molecules
could be enhanced by using different approaches such as making
water-soluble analogs of aqueous insoluble polyphenols or via
using nanotechnological intervention. Another important issue
with 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 a
day to have antidepressant action. It is very important to
enhance the half-life of such polyphenols either by making novel
analogs or by preventing their metabolism. It is a common myth
that natural compounds are very safe. Some of these polyphenols
at higher doses have potential side effects that are listed
in Table 2. Therefore, it is mandatory to perform clinical studies
to extract out the side-effect profile of these natural polyphenols.
It is expected that these polyphenols might be prescribed as
an adjuvant therapy with already existing antidepressant mol-
ecules in the treatment of major depression. Alternatively,
these molecules could be prescribed in pharmacoresistant
patients where 3 or > 3 drugs are found to be ineffective in
relieving the symptoms. In summary, polyphenols research
is an exciting field to study and there are lots of opportunities
in this upcoming area of research.
Declaration of interest
A Dhir is a Fellow of Department of Biotechnology, New
Delhi. The authors state no conflict of interest and have
received 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 at
high 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 - -
7FA - -
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 cell
regulating genes, induction of CYP1A1 in colon and liver microsomes
[169,172]
14 Rutin - -
CYP1A1: Cytochrome 1A1; FA: Ferulic acid.
L. Pathak et al.
12 Expert Opin. Investig. Drugs [Early Online]
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Affiliation
Lokesh Pathak
1
, Yadvendra Agrawal
1
&
Ashish Dhir
†1,2
MPharm PhD
†
Author for correspondence
1
Scientist D,
Gujarat Forensic Sciences University,
Institute of Research & Development,
DFS Headquarters,
Sector 18-A, Gandhinagar,
Gujarat-382007, India
Tel: +91 79 65735505 06;
E-mail: ashishdhirpu@yahoo.com
2
Department of Biotechnology,
New Delhi, India
L. Pathak et al.
18 Expert Opin. Investig. Drugs [Early Online]
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