Content uploaded by Hervé Javelot
Author content
All content in this area was uploaded by Hervé Javelot on Sep 21, 2017
Content may be subject to copyright.
Supplement to AgroFOOD industry hi-tech - November/december 2009 - vol 20 n 6
Focus on Chocolate
19
Antidepressant-like properties
of cocoa's polyphenols
The role of flavanoids and flavanols
on depression
HERVE JAVELOT1,2,3*, MICHAËL MESSAOUDI1, CECILE JACQUELIN2, NICOLAS VIOLLE1,
JEAN-FRANÇOIS BISSON1, AMINE NEJDI1, PASCALE ROZAN1, DIDIER DESOR4
*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
INTRODUCTION
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.
COCOA COMPOSITION
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
chocolate.
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
20
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
neuroinflammation.
CONCLUSION
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).
ANTIDEPRESSANT-LIKE EFFECTS OF COCOA
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
neuroinflammation
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
21
Psychoneuroendocrinology, PMID: 19631474 (2009).
22. M. Messaoudi, J.F. Bisson et al., “Antidepressant-like effects of a
cocoa polypheno lic ext ract in Wis tar -Unileve r ra ts” , Nutr
Neurosci., 11(6), pp. 269-276 (2008).
23. J.P. Spencer, “The interactions of flavonoids within neuronal
signalling pathways”, Genes Nutr., 2(3), pp. 257-273 (2007).
24. K.A. Youdim, J.A. Joseph, “A possible emerging role of
phytochemicals in improving age-related neurological
dysfunctions: a multiplicity of effects”, Free Radic Biol Med.,
30(6), pp. 583-594 (2001).
25. M.M. Abd El Mohsen, G. Kuhnle et al., “Uptake and metabolism
of epicatechin and its access to the brain after oral ingestion”,
Free Radic Biol Med., 33(12), pp. 1693-7102 (2002).
26. G. Juergenliemk, K Boje et al. “In vitro studies indicate that
miquelianin (quercetin 3-O-beta-D-glucuronopyranoside) is able
to reach the CNS from the small intestine”, Planta Med., 69(11),
pp. 1013-1017 (2003).
27. A. Sluzewska, “Indicators of immune activation in depressed
patients”, Adv Exp Med Biol., 461, pp. 59-73 (1999).
28. H. Efe, O. Değer et al., “Decreased neutrophil antioxidative
enzyme activities and increased lipid peroxidation in
hyperlipoproteinemic human subjects”, Clin Chim Acta., 279(1-
2), pp. 155-165 (1999).
29. M. Maes, A. Christophe et al., “Lowered omega3
polyunsaturated fatty acids in serum phospholipids and
cholesteryl esters of depressed patients”, Psychiatry Res., 85(3),
pp. 275-291 (1999).
30. A. Zafir, A. Ara et al., “In vivo antioxidant status: a putative target
of antidepressant action”, Prog Neuropsychopharmacol Biol
Psychiatry, 33(2), pp. 220-228 (2009).
31. J.P. Godbout, R.W. Johnson, “Age and neuroinflammation: a
lifetime of psychoneuroimmune consequences”, Immunol
Allergy Clin North Am., 29(2), pp. 321-337 (2009).
32. R. Li, Y.G. Huang et al., “(-)-Epigallocatechin gallate inhibits
lipopolysaccharide-induced microglial activation and protects
against inflammation-mediated dopaminergic neuronal injury”,
J Neurosci Res., 78(5), pp. 723-731 (2004).
33. S. Mandel, M.B. Youdim, “Catechin polyphenols:
neurodegeneration and neuroprotection in neurodegenerative
diseases”, Free Radic Biol Med., 37(3), pp. 304-317 (2004).
REFERENCES AND NOTES
1. G. Parker, I. Parker et al.,
“Mood state effects of
choco late ”, J A ffe ct
Di so rd ., 92(2-3), p p.
149-159 (2006).
2. H. Tapiero, K.D. Tew et
al., “Polyphenols: do
they play a role in the
prevention of human
pathologies?”, Biomed
Pharmacother., 56(4), pp.
200-207 (2002).
3. H.C. Sab el li, J. I. Ja vaid ,
“Phenylethylamine
modulation of affect:
therapeutic and diagnostic implications”, J
Neuropsychiatry Clin Neurosci., 7(1), pp.
6-14 (1995).
4. A. Nehlig, J.L. Daval et al., “Caffeine and
the central nervous system: mechanisms of
action, biochemical, metabolic and psychostimulant effects”
Brain Res Brain Res Rev., 17(2), pp. 139-170 (1992).
5. E. di Tomaso, M. Beltramo et al., “Brain cannabinoids in
chocolate”, Nature, 382(6593), pp. 677-678 (1996).
6. G.A. Eby, K.L. Eby, “Rapid recovery from major depression using
magnesium treatment”, Med Hypotheses, 67(2), pp. 362-370
(2006).
7. M. Berk, “Oxidative biology: new intervention opportunities in
psychiatry”, Acta Neuropsychiatr., 19, pp. 259-260 (2007).
8. M. Bilici, H. Efe et al., “Antioxidative enzyme activities and lipid
peroxidation in major depression: alterations by antidepressant
treatments”, J Affect Disord., 64, pp. 43-51 (2001).
9. S.D. Khanzode, G.N. Dakhale et al., “Oxidative damage and
major depression: the potential antioxidant action of selective
serotonin re-uptake inhibitors”, Redox Rep., 8, pp. 365-370 (2003).
10. M.E. Ozcan, M. Gulec et al., “Antioxidant enzyme activities and
oxidative stress in affective disorders”, Int Clin
Psychopharmacol., 19, pp. 89-95 (2004).
11. K. W. Lee, Y.J . Kim et al., “Cocoa has mor e phenol ic
phytochemicals and a higher antioxidant capacity than teas
and red wine”, J Agric Food Chem., 51(25), pp. 7292-7295
(2003).
12. I.C. Arts, P.C. Hollman et al., “Chocolate as a source of tea
flavonoids”, Lancet., 354(9177), pp. 488 (1999).
13. I.E. Dreosti, “Antioxidant polyphenols in tea, cocoa, and wine”,
Nutrition., 16(7-8), 692-694 (2000).
14. V. Butterweck, F. Petereit et al., “Solubilized hypericin and
pseudohypericin from Hypericum perforatum exert
antidepressant activity in the forced swimming test”, Planta
Med., 64(4), pp. 291-294 (1998).
15. V. Butterweck, G Jürgenliemk et al. “Flavonoids from Hypericum
perforatum show antidepressant activity in the forced swimming
test”, Planta Med., 66(1), pp. 3-6 (2000).
16. V. Butterweck, S. Nishibe et al., “Antidepressant effects of
Apocynum venetum leaves in a forced swimming test”, Biol
Pharm Bull., 24(7), pp. 848-851 (2001).
17. M. Anjaneyulu, K. Chopra et al., “Antidepressant activity of
quercetin, a bioflavonoid, in streptozotocin-induced diabetic
mice”, J Med Food., 6(4), pp. 391-395 (2003).
18. F.F. Rocha, M.T. Lima-Landman et al., “Antidepressant-like effect
of Cecropia glazioui Sneth and its constituents - in vivo and in
vitro characterization of the underlying mechanism”,
Phytomedicine, 14(6), pp. 396-402 (2007).
19. D.G. Machado, L.E. Bettio et al., “Antidepressant-like effect of
rutin isolated from the ethanolic extract from Schinus molle L. in
mice: evidence for the involvement of the serotonergic and
noradrenergic systems”, Eur J Pharmacol., 587(1-3), pp. 163-168
(2008).
20. Z. Zhao, W. Wang et al., “Antidepressant-like effect of liquiritin
from Glycyrrhiza uralensis in chronic variable stress induced
depression model rats”, Behav Brain Res., 194(1), pp. 108-113
(2008).
21. Y. Pan, F.M. Wang et al., “Icariin attenuates chronic mild stress-
induced dysregulation of the LHPA stress circuit in rats”,