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Antidepressant-like properties of cocoa's polyphenols The role of flavanoids and flavanols on depression



In the last ten years, cocoa and bitter chocolate with a high content of cocoa have received much attention due to their significant polyphenol contents, and thus, have been recognized as significant sources of phytochemicals with healthful effects. Increasing evidence from experimental preclinical and clinical studies using cocoa polyphenols extracts or dark chocolate suggest an important role for these high-flavanol-containing products in various human pathologies. In fact, cocoa's polyphenols are susceptible to induce stimulant, relaxant, euphoriant, tonic and antidepressant effects. This article reviews the various cocoa's flavanols, aiming to establish their implications on mood state, particularly on depression, a major public health problem affecting about 12 percent of the world population.
Supplement to AgroFOOD industry hi-tech - November/december 2009 - vol 20 n 6
Focus on Chocolate
Antidepressant-like properties
of cocoa's polyphenols
The role of flavanoids and flavanols
on depression
*Corresponding author
1. ETAP - Centre de Recherche en Pharmacologie, Cancérologie et Nutrition-Santé, Vandoeuvre-lès-Nancy, France
2. Faculté de Médecine de Nancy, Université Henri Poincaré, Vandoeuvre-lès-Nancy, France
3. Hôpital Brabois Adultes, Service Pharmacie, CHU Nancy, Vandoeuvre-lès-Nancy, France
4. Equipe de Neurosciences Comportementales, URAFPA, INRA UC340, INPL-UHP, Vandoeuvre-lès-Nancy, France
Cocoa (Theobroma cacao) and bitter chocolate with a
cocoa content of 70 percent or higher are widely known
for their effects on mood state, particularly depression
related symptoms (1). These products contain a complex
mixture of essential nutrients like carbohydrates, lipids,
proteins, vitamins, minerals, and several biologically active
compounds, including caffeine, theobromine, tryptophan,
phenylethylamine and cannabinoid-like fatty acids. Besides
these constituents, polyphenols are a quantitatively
important group in cocoa and may also represent
promising beneficial therapeutic agents, in particular in
cardiovascular diseases, cancer, diabetes and
neurodegenerative pathologies (2).
This review presents some generalities regarding cocoa and
its antidepressant-like effects, and outlines more specifically
the potential biofunctional activity of flavanols.
Carbohydrates, phenylethylamine, methylxanthines,
anandamides and magnesium
Among active compounds present in cocoa,
carbohydrates are probably closely related to well-being
described after eating chocolate. Important data have
been mentioned by Parker and collaborators (1) relating to
carbohydrates: their abilities to promote a feel-good
sensation during atypical depression and the possibility to
identify the phenomenon of craving as a form of self
medication in different types of depression, particularly in
Phenylethylamine is chemically and pharmacologically
related to catecholamines and amphetamine and the
deficit in this endogenous compound may contribute to
depression state (3).
The most important methylxanthines found in cocoa
and chocolate are caffeine and theobromine.
Like carbohydrates, caffeine could be a self-medication for
pe op le who suffered from de pr es si ve sy mp to ms . For
example, sedation is an important symptom in depression
and methylxanthines can induce a benefit arousal through
an interaction with adenosine receptors (4).
Cocoa and chocolate contain several unsaturated
N-acylethanolamines, which are structurally related to
anandamide (5). High levels of these latter substances
could interact with other active compounds of chocolate
and provoked a well-being sensation.
Finally, magnesium, one of the most quantitatively
important mineral in cocoa, is potentially effective to treat
depression in relation with the intraneuronal magnesium
deficits in depressive patients (6).
Polyphenols and flavanols
The antidepressant properties of polyphenols could be
closely related to their antioxidant effects. Oxidative stress
caused numerous damages during several
psychopat ho logies (7) . Depressi on is assoc ia ted with
elevated antioxidative enzyme activities and lipid
peroxidation, and interestingly, the most common
antidepressant agents, like selective serotonin re-uptake
inhibitors (SSRIs) and tricyclic antidepressants (TCAs), are
able to counteract these deleterious effects (8-10). In this
way, it must be noted the high antioxidant properties of
flavanols of cocoa. Lee and collaborators had compared
the phenolic and flavonoid contents and total antioxidant
capacities of red wine, tea and cocoa (11), and then
concluded: (i) that cocoa contained much higher levels of
total phenolics and flavonoids (expressed in epicatechin
equivalents) per serving than black or green tea and red
wine and (ii) that cocoa exhibits the higher antioxidant
activity (cocoa > red wine > green tea > black tea).
Flavanols, also chemically defined by flavan-3-ols, are an
important subclass of polyphenols, included in flavonoids.
Typical flavanols consist in catechin, epicatechin,
epigallocatechin and epigallocatechin gallate. Cocoa
contains only (+)−catechin and (−)−epicatechin, while tea
contains mainly (−)−epicatechin gallate and
(−)−epigallocatechin gallate (12). The procyanidins are the
oligomeric counterparts of the flavanols and are constituted
exclusively of the monomers epicatechin and catechin.
ABSTRACT: In the last ten years, cocoa and bitter chocolate with a high content of cocoa have received much attention due to their
signific ant poly phenol contents, and thus, have been recognized as significant sources of phytochemicals with he althful effects.
Increasing evidence from experimental preclinical and clinical studies using cocoa polyphenolic extracts or dark chocolate suggest
an important role for these high-flavanol-containing products in various human pathologies. In fact, cocoa's polyphenols are
suscept ible to induce sti mulant, relaxant , euphori ant, to ni c and antidepres sant effe cts. This articl e reviews the vari ous coc oa's
flavanols, aiming to establish their implications on mood state, particularly on depression, a major public health problem affecting
about 12 percent of the world population.
Hervé Javelot
KEYWORDS: cocoa composition, polyphenols, flavanols, depression,
oxidative stress, neuroinflammation.
Focus on Chocolate
Supplement to AgroFOOD industry hi-tech - November/December 2009 - vol 20 n 6
a relation between ROS production and lipid peroxidation
(28), and abnormalities in lipids and depression, on the other
hand (29).
Today, the interest of compounds like flavanols for the
treatment of depression is reinforced by numerous reports
concerning antioxidant status of antidepressants. Zafir et al.
(30) have recently demonstrated that a chronic
administration of different antidepressant agents in rats
(fluoxetine, imipramine and venlafaxine) induced: (i) a
de cl ine in the activ it y of sever al enz ym es, su ch as
superoxide dismutase and catalase; (ii) a normalization of
lipid peroxidation. In addition, Bilici et al. have presented
results in human indicating that several SSRIs were able to
regulate antioxidative enzyme activities and lipid
peroxidation (8).
Besides oxidative stress, prolonged exposure to inflammatory
cytokines in the brain may underlay a heightened
neuroinflammatory response that may lead to impairments
such as depression (31). Interestingly, Li et al. had shown
that catechin and epigallocatechin gallate attenuate
microglia and/or astrocyte mediated neuroinflammation,
notably via an inhibition of cytokine release (32).
Taking together all these complementary data strongly
suggest that flavanols, through their hight antioxidant
activities, could regulate oxidative stress, such as the well-
characterized pharmacological antidepressant
drugs. Their role in the CNS could be more complex
in relation, specially, with the modulation of
intracellular signalling cascades, gene expression,
interactions with mitochondria or
Polyphenols and flavonoids in general,
and flavanols in particular, appear
today as a new and interesting
opportunities to regulate mood
disorders. Thus, cocoa flavanols could
be a useful possibility that permit to
have the benefit of chocolate as
therapy, without an excessive and
potentially adverse effects linked to
carbohydrates and lipids.
Today , th e main deve lopment of
flavonoids and flavanols is turned to
neurodegenerative disorders, like
Alzheimer or Parkinson syndromes
(23). This situation corresponds to the
great interest developed around
activities of flavonoids to assure a
protection against neuronal injury
induced in neurodegenerative diseases
(33). However, there is a growing body of
evidence to suggest that flavonoids and
flavanols may be able to play a role in the
prevention and/or the treatment of mood
disorders by (i) the demonstration of their high
an tio xid ant ca pac iti es, an d t he abi lit y o f
pharmacological antidepressant agents, i.e. SSRIs
and TCAs, to exert neuroprotective effects on the CNS
oxidative damage, (ii) their effects on the more complex
phenomenon of neuroinflammation, which could be
predominant in the chronic development of depression.
Further studies are necessary to identify the active
constituents with antidepressant-like activity among the
various cocoa’s polyphenols and to understand their
mechanism of action in the brain.
The polyphenol content of raw cocoa beans differs from
that of cocoa powder or chocolate. Raw cocoa beans are
rich in flavanol monomers and epicatechin-based
procyanidin oligomers from dimers to decamers. Finally,
chocolate type also influences the content of flavanols,
such as dark chocolate contains more than three times as
much catechin as milk chocolate (13).
Many flavonoids have been reported to exert
antidepressant-like activity in different animal models. For
example, among the compounds evaluated in the forced
swimming test (FST) we can note: flavonoids contained in
Hypericum perforatum (14, 15), hyperoside and isoquercitrin
presents in Apocynum venetum (16), quercetin (17), the
aqueous extract of Cecropia glazioui Sneth, rich in
catechins, procyanidins and others flavonoids (18) or rutin
isolated from the ethanolic extract from Schinus molle (19).
Alternative methods of evaluation, like chronic mild stress,
had showed similar results with others flavonoids: liquiritin
extracted from Glycyrrhiza uralensis (20) or icariin, isolated
from Epimedium brevicornum (21).
In a recent work, we have demonstrated that a cocoa
polyphenolic extract, containing high levels of flavonoids,
exhibits an antidepressant-like effect in the FST paradigm in
rats (22). In this study we were not able to determine the
specificity of polyphenols involved in the antidepressants-
like effect of cocoa; however, the results pave the
way to a reflection on the impact of flavanols
in the regulation of oxidative stress.
Ability of flavonoids to cross the blood-
brain barrier
Today, the biological actions of
flavanols, like flavonoids, appear more
related to the modulation of
intracellular signalling cascades and
gene expression or the interactions
with mitochondria, rather than a
simply influence on the intracellular
redox status (23). So an important
preliminary question is the ability of
flavanols to interact with the central
nervous system (CNS). Youdim et al.
(24) had studied interaction between
flavonoids and the blood-brain
barrier and had demonstrated that a
higher lipophilicity of compounds is
associated with a better penetration.
So the more polar flavonoid, such as
epicatechin and their glucuronidated
metabolites may not be able to access
the brain. However, the study of Abd El
Mohsen and collaborators (25) had
previously demonstrated the presence of
epicatechin glucuronide and its
3′-O-methylated epicatechin glucuronide in the
brain tissue. Similar results had been observed with
miquelianin, a quercetin found in Hypericum
perforatum (26).
Pathogenesis of depression, oxidative stress and
The existence of an immunological activation during
depression is well-established (27) and the activation of
immune cells is associated with overproduction of reactive
oxygen species (ROS). Moreover, on the one hand, there is
Supplement to AgroFOOD industry hi-tech - November/december 2009 - vol 20 n 6
Focus on Chocolate
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... Cocoa has been found to contains (+)-catechin and (−)-epicatechin (Figures 42 and 43). In a study, polyphenolic extract of cocoa, containing high levels of flavanols, has been found to exhibit antidepressant-like action in mice evaluated using forced swim test paradigm [140]. Recently, Zafir et al., have proved that chronic administration of various antidepressants to mice has caused a decrease in the activity of antioxidant enzymes, such as catalase and superoxide dismutase and also, reduced the normalization of lipid peroxidation. ...
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Depression is one of the most frequently observed psychological disorders, affecting thoughts, feelings, behavior and a sense of well-being in person. As per the WHO, it is projected to be the primitive cause of various other diseases by 2030. Clinically, depression is treated by various types of synthetic medicines that have several limitations such as side-effects, slow-onset action, poor remission and response rates due to complicated pathophysiology involved with depression. Further, clinically, patients cannot be given the treatment unless it affects adversely the job or family. In addition, synthetic drugs are usually single targeted drugs. Unlike synthetic medicaments, there are many plants that have flavonoids and producing action on multiple molecular targets and exhibit anti-depressant action by affecting multiple neuronal transmissions or pathways such as noradrenergic, serotonergic, GABAnergic and dopaminergic; inhibition of monoamine oxidase and tropomyosin receptor kinase B; simultaneous increase in nerve growth and brain-derived neurotrophic factors. Such herbal drugs with flavonoids are likely to be useful in patients with subclinical depression. This review is an attempt to analyze pre-clinical studies, structural activity relationship and characteristics of reported isolated flavonoids, which may be considered for clinical trials for the development of therapeutically useful antidepressant.
Cocoa intake enhances antioxidant defenses quickly and over a short period after ingestion. Epidemiological studies indicate that cocoa has a cardioprotective effect by improving endothelial function and decreasing platelet aggregation and blood pressure. Clinical evidence suggests that cocoa can be a new and interesting food for regulating mood and brain disorders. Cocoa flavonoids have in vitro anti-inflammatory effects, and preclinical studies show this potential. The immunomodulatory power of cocoa, demonstrated preclinically, may be beneficial in reducing certain states of autoimmunity and hypersensitivity. Although in vitro studies have shown that cocoa flavonoids exert antitumoral effects, further studies are needed.
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Caffeine is the most widely consumed centralnervous-system stimulant. Three main mechanisms of action of caffeine on the central nervous system have been described. Mobilization of intracellular calcium and inhibition of specific phosphodiesterases only occur at high non-physiological concentrations of caffeine. The only likely mechanism of action of the methylxanthine is the antagonism at the level of adenosine receptors. Caffeine increases energy metabolism throughout the brain but decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion. Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Many of the alerting effects of caffeine may be related to the action of the methylxanthine on serotonine neurons. The methylxanthine induces dose-response increases in locomotor activity in animals. Its psychostimulant action on man is, however, often subtle and not very easy to detect. The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue. Caffeine exerts obvious effects on anxiety and sleep which vary according to individual sensitivity to the methylxanthine. However, children in general do not appear more sensitive to methylxanthine effects than adults. The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.
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Depression is a major public health problem affecting about 12% of the world population. Drugs exist but they have many side effects. In the last few years, natural substances (e.g. flavonoids) have been tested to cure such disorders. Cocoa polyphenolic extract is a complex compound prepared from non-roasted cocoa beans containing high levels of flavonoids. The antidepressant-like effect of cocoa polyphenolic extract was evaluated using the forced swimming test in rats. Cocoa polyphenolic extract significantly reduced the duration of immobility at both doses of 24 mg/kg/14 days and 48 mg/kg/14 days, although no change of motor dysfunction was observed with the two doses tested in the open field. The results of the forced swimming test after a subchronic treatment and after an additional locomotor activity test confirm the assumption that the antidepressant-like effect of cocoa polyphenolic extract in the forced swimming test model is specific. Further, it can be speculated that this effect might be related to its content of active polyphenols.
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Emerging evidence suggests that dietary phytochemicals, in particular flavonoids, may exert beneficial effects in the central nervous system by protecting neurons against stress-induced injury, by suppressing neuroinflammation and by promoting neurocognitive performance, through changes in synaptic plasticity. It is likely that flavonoids exert such effects in neurons, through selective actions on different components within a number of protein kinase and lipid kinase signalling cascades, such as phosphatidylinositol-3 kinase (PI3K)/Akt, protein kinase C and mitogen-activated protein kinase. This review details the potential inhibitory or stimulatory actions of flavonoids within these pathways, and describes how such interactions are likely to affect cellular function through changes in the activation state of target molecules and/or by modulating gene expression. Although, precise sites of action are presently unknown, their abilities to: (1) bind to ATP binding sites on enzymes and receptors; (2) modulate the activity of kinases directly; (3) affect the function of important phosphatases; (4) preserve neuronal Ca(2+) homeostasis; and (5) modulate signalling cascades lying downstream of kinases, are explored. Future research directions are outlined in relation to their precise site(s) of action within the signalling pathways and the sequence of events that allow them to regulate neuronal function in the central nervous system.
Neurodegeneration in Parkinson's, Alzheimer's, and other neurodegenerative diseases seems to be multifactorial, in that a complex set of toxic reactions including inflammation, glutamatergic neurotoxicity, increases in iron and nitric oxide, depletion of endogenous antioxidants, reduced expression of trophic factors, dysfunction of the ubiquitin-proteasome system, and expression of proapoptotic proteins leads to the demise of neurons. Thus, the fundamental objective in neurodegeneration and neuroprotection research is to determine which of these factors constitutes the primary event, the sequence in which these events occur, and whether they act in concurrence in the pathogenic process, This has led to the current notion that drugs directed against a single target will be ineffective and rather a single drug or cocktail of drugs with pluripharmacological properties may be more suitable. Green tea catechin polyphenols, formerly thought to be simple radical scavengers, are now considered to invoke a spectrum of cellular mechanisms of action related to their neuroprotective activity. These include pharmacological activities like iron chelation, scavenging of radicals, activation of survival genes and cell signaling pathways, and regulation of mitochondrial function and possibly of the ubiquitin-proteasome system. As a consequence these compounds are receiving significant attention as therapeutic cytoprotective agents for the treatment of neurodegenerative and other diseases.
Depression is associated with a lowered degree of esterification of serum cholesterol, an increased C20:4ω6/C20:5ω3 ratio and decreases in ω3 fractions in fatty acids (FAs) or in the red blood cell membrane. The aims of the present study were to examine: (i) serum phospholipid and cholesteryl ester compositions of individual saturated fatty acids (SFAs), monounsaturated FAs (MUFAs) and polyunsaturated FAs (PUFAs) in major depressed patients vs. healthy volunteers; (ii) the relationships between the above FAs and lowered serum zinc (Zn), a marker of the inflammatory response in depression; and (iii) the effects of subchronic treatment with antidepressants on FAs in depression. The composition of the FAs was determined by means of thin layer chromatography in conjunction with gas chromatography. Lipid concentrations were assayed by enzymatic colorimetric methods. The oxidative potential index (OPI) of FAs was computed in 34 major depressed inpatients and 14 normal volunteers. Major depression was associated with: increased MUFA and C22:5ω3 proportions and increased C20:4ω6/C20:5ω3 and C22:5ω6/C22:6ω3 ratios; lower C22:4ω6, C20:5ω3 and C22:5ω3 fractions in phospholipids; lower C18:3ω3, C20:5ω3 and total (Σ)ω3 FAs, and higher C20:4ω6/C20:5ω3 and Σω6/Σω3 ratios in cholesteryl esters; lower serum concentrations of phospholipids and cholesteryl esters; and a decreased OPI. In depression, there were significant and positive correlations between serum Zn and C20:5ω3 and C22:6ω3 fractions in phospholipids; and significant inverse correlations between serum Zn and the Σω6/Σω3, C20:4ω6/C20:5ω3, and C22:5ω6/C22:6ω3 ratios in phospholipids. There was no significant effect of antidepressive treatment on any of the FAs. The results show that, in major depression, there is a deficiency of ω3 PUFAs and a compensatory increase in MUFAs and C22:5ω6 in phospholipids. The results suggest that: (i) there is an abnormal metabolism of ω3 PUFAs in depression; (ii) the FA alterations in depression are related to the inflammatory response in that illness; and (iii) the disorders may persist despite successful antidepressant treatment.
Chronic mild stress (CMS) is suggested to develop dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) stress circuit. Icariin, a major constituent of flavonoids isolated from Epimedium brevicornum, has been previously confirmed to rescue the HPA axis abnormalities in animal models of depression. However, antidepressant treatment of icariin on corticotropin-releasing factor (CRF) system within the LHPA stress circuit and its interaction with serotonergic receptor are still seldom studied in CMS model of animals. The present study further investigated the effects of CMS procedure and subsequent icariin treatment on mRNA and protein levels of CRF, CRF receptor 1 (CRFR1) and CRF binding protein (CRFBP), as well as sucrose intake in rats. Moreover, the levels of cyclic adenosine 3′,5′-monophosphate (cAMP) response element binding protein (CREB), glucocorticoid receptor (GR) and 5-hydroxytryptamine 1A receptor (5-HTR1A) in hypothalamus, hippocampus and frontal cortex were simultaneously evaluated for their participations in CRF system in this model. We found that CMS procedure significantly increased CRF expression levels in the brain regions, and decreased GR and 5-HTR1A in hippocampus and frontal cortex, with sucrose intake reduction representing the hedonic deficit in rats. Icariin restored these alterations in CMS rats. These results confirmed the hypothesis that icariin exerted antidepressant-like effect via its regulation of central CRF system. And hippocampus was suggested as an important neural area controlling the LHPA stress circuit in icariin-treated CMS rats. These findings for the first time proved that the potential molecular mechanism of antidepressant action of icariin was targeted on the interaction of the LHPA stress circuit and serotonergic function in CMS rats.
Many flavonoids extracted from nature plants have been reported to exert antidepressant-like effect in animal studies. The present study was designed to observe the effects of liquiritin, a flavone compound derived from Glycyrrhiza uralensis, on the behaviors of chronic variable stress induced depression model rats and to explore the possible association between its antidepressant-like effect and antioxidative activity by measuring erythrocyte superoxide dismutase (SOD) activity and plasma malondialdehyde (MDA) level of the experimental animals. With the exposure to stressor once daily for consecutive 5 weeks, liquiritin and a positive control drug fluoxetine were administered via gastric intubation to rats once daily for consecutive 3 weeks from the 3rd week. The results showed that CVS reduced open-field activity and sucrose consumption significantly, but increased immobility time in forced swimming test. Treatment of liquiritin could effectively reverse alteration in immobility time and sucrose consumption but did not show significant effect on open-field activity. Moreover, liquiritin could increase SOD activity, inhibit lipid peroxidation, and lessen production of MDA, while fluoxetine did not. In conclusion, the present study demonstrated a potential antidepressant-like effect of liquiritin treatment on chronic variable stress induced depression model rats, which might be related to defense of liquiritin against oxidative stress.
Aging can impair functional interaction that occurs between the brain and the immune system. Recent findings indicate that microglia and astrocytes, innate immune cells of the brain, become more reactive during normal aging. This age-associated increase in innate immune reactivity sets the stage for an exaggerated inflammatory cytokine response in the brain after activation of the peripheral innate immune system. This elevated neuroinflammatory response may lead to more severe long-lasting behavioral and cognitive deficits. This article discusses new evidence that aging creates a brain environment that is permissive to the occurrence of mental health complications following innate immune activation.
Oxidative stress is a critical route of damage in various psychological stress-induced disorders, such as depression. Antidepressants are widely prescribed to treat these conditions; however, few animal studies have investigated the effect of these drugs on endogenous antioxidant status in the brain. The present study employed a 21-day chronic regimen of random exposure to restraint stress to induce oxidative stress in brain, and behavioural aberrations, in rodents. The forced swimming (FST) and sucrose preference tests were used to identify depression-like phenotypes, and reversal in these indices indicated the effectiveness of treatment with fluoxetine (FLU; 20 mg/kg/day, p.o.; selective serotonin reuptake inhibitor), imipramine (IMI; 10 mg/kg/day, p.o.; tricyclic antidepressant) and venlafaxine (VEN; 10 mg/kg/day, p.o.; dual serotonin/norepinephrine reuptake inhibitor) following restraint stress. The antioxidant status was investigated in the brain of these animals. The results evidenced a significant recovery in the activities of superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), glutathione reductase (GR) and glutathione (GSH) levels by antidepressant treatments following a restraint stress-induced decline of these parameters. The severely accumulated lipid peroxidation product malondialdehyde (MDA) and protein carbonyl contents in stressed animals were significantly normalized by antidepressant treatments. The altered oxidative status is implicated in various aspects of cellular function affecting the brain. Thus, it is possible that augmentation of in vivo antioxidant defenses could serve as a convergence point for multiple classes of antidepressants as an important mechanism underlying the neuroprotective pharmacological effects of these drugs observed clinically in the treatment of various stress disorders. Consequently, pharmacological modulation of stress-induced oxidative damage as a possible stress-management approach should be an important avenue of further research.