Review Article Psychiatric Disorders and Polyphenols: Can...

Review ArticlePsychiatric Disorders and Polyphenols Can TheyBe Helpful in Therapy

Jana Trebatickaacute1 and Zde^ka gturaIkovaacute2

1Department of Child and Adolescent Psychiatry Faculty of Medicine Comenius University and Child University Hospital833 40 Bratislava Slovakia2Institute of Medical Chemistry Biochemistry and Clinical Biochemistry Faculty of Medicine Comenius University813 72 Bratislava Slovakia

Correspondence should be addressed to Zdenka Durackova zdenkadurackovafmedunibask

Received 23 September 2014 Revised 6 February 2015 Accepted 10 February 2015

Academic Editor Cristina Angeloni

Copyright copy 2015 J Trebaticka and Z Durackova This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

The prevalence of psychiatric disorders permanently increases Polyphenolic compounds can be involved in modulation of mentalhealth including brain plasticity behaviour mood depression and cognition In addition to their antioxidant ability otherbiomodulating properties have been observed In the pathogenesis of depression disturbance in neurotransmitters increasedinflammatory processes defects in neurogenesis and synaptic plasticity mitochondrial dysfunction and redox imbalance areobserved Ginkgo biloba green tea and Quercus robur extracts and curcumin can affect neuronal system in depressive patientsADHD patients treated with antipsychotic drugs especially stimulants report significant adverse effects therefore an alternativetreatment is searched for An extract from Ginkgo biloba and from Pinus pinaster bark Pycnogenol could become promisingcomplementary supplements in ADHD treatment Schizophrenia is a devastating mental disorder with oxidative stress involved inits pathophysiologyThedirect interference of polyphenolswith schizophrenia pathophysiology has not been reported yetHoweverincreased oxidative stress caused by haloperidol was inhibited ex vivo by different polyphenols Curcumin extract from green teaand fromGinkgo bilobamay have benefits on serious side effects associatedwith administration of neuroleptics to patients sufferingfrom schizophrenia Polyphenols in the diet have the potential to becomemedicaments in the field ofmental health after a thoroughstudy of their mechanism of action

1 Introduction

The prevalence of psychiatric disorders permanently in-creases In the WHO European Region nearly 4 out of 15people suffer from major depression and anxiety Neuropsy-chiatric disorders are the second cause of disability in Europeand account for 19 in comparison to cardiovascular disor-ders with only 4 In 28 countries of EU with a populationof 466 million at least 21 million people were affected bydepression out of which almost 80 are men The treatmentof psychiatric disorders is very expensive The total annualcost of depression in Europe was estimated at Euro 118billion in 2004 which corresponds to a cost of Euro 253per inhabitant The cost of depression corresponds to 1 ofthe total economy of Europe These reasons provide supportfor the importance of increased research efforts in this field

better detection prevention based on improvement of life-style factors including diet and effectiveness of treatment [1]

Results of many animal and human studies support therole of different natural polyphenolic compounds in modu-lation of mental health including brain plasticity behaviourmood through anxiolytic antidepressant-like properties andcognition Research demonstrates that dietary factors andexercise can affect the maintenance and development ofneurons and protect the brain from insult associated withneurological illnesses or injuries [2ndash7]

2 Polyphenolic Compounds

Polyphenols (known as polyhydroxyphenols) are predom-inantly secondary metabolites of plants They belong to

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2015 Article ID 248529 16 pageshttpdxdoiorg1011552015248529

2 Oxidative Medicine and Cellular Longevity

O

A

B

345

6

78

Flavonoid basic structure

O

OH

Flavane-3-ol

O

OFlavanone

OHAnthocyanidin

O

O

OH

Flavone-3-ol

O

OFlavone

2998400

3998400

4998400

5998400

6998400

O+

Figure 1 Basic flavonoid structures

structural class of organic compounds characterized by thepresence of large multiples of phenol structural units Thesephenol structures underlie the unique physical chemical andbiological (metabolic toxic therapeutic etc) properties ofparticular members of the class The name derives from theancient Greek word 120587o120582 120592120589 (polus meaning ldquomany muchrdquo)and the word phenol which refers to a chemical structureformed by attaching a hydroxyl (ndashOH) group to an aromaticphenyl ring They are divided into three groups accordingto their hydrolytic cleavage products (i) tannins derivativesof catechin or gallic acid with mostly antioxidant properties[8] (ii) phenylpropane derivatives (lignans ellagitanninscinnamic acid derivatives and others) for example higherdietary intake of lignans is associated with better cognitivefunctions in postmenopausal women [9] or extract of ellag-itannins from oak wood reduced many of key symptomsof chronic fatigue [10] and (iii) flavonoids phenolic com-pounds spread in the plant kingdomThey includemore than4000 different derivatives and their list constantly increasesFormation of so many derivatives is possible due to thesubstitution of hydrogen atoms by hydroxyl methoxyl andother groups at different sites of the basic structures Thebasic flavonoid structures include the following flavan-3-ols (epicatechin and gallocatechin) flavanones (naringeninand hesperidin) flavones (apigenin and luteolin) flavone-3-ol (quercetin and myricetin) anthocyanidins (cyanidin andpelargonidin) and isoflavones (genistein and daidzein) [11](Figure 1)

Polyphenols occur in food (vegetables and fruits) eitheras free monomers (quercetin and catechin) or oligomers(procyanidins) They are bound to saccharides as glycosidesor occasionally they are found as free aglycones Afteringestion flavonoids can undergo biotransformation to theirmetabolites which can be detected in plasma reaching con-centration of about 1120583molsdotLminus1 [12 13]

Consumption of polyphenol-rich foods is associated witha lower incidence of coronary heart disease myocardialinfarction [14] cancer [15] neurodegenerative diseases [16]

psychiatric disorders (like ADHD) [17] and other chronicdiseases [18] Since in the pathology of these diseases inaddition to other factors oxidative stress has been assumedto play a role dietary flavonoids have been suggested toexert health benefits through antioxidant mechanisms Inexperiments in vitro flavonoids exert a significant antioxi-dant [8 19] and redox modulating [20] ability Polyphenolsact as strong antioxidants in vitro through the numerousmechanisms such as radical scavenging metal ions (Fe Cuand others) chelation and the modulation of antioxidantenzyme activities [8 21] In the scavenging ability the positionand the number of phenolic ndashOH groups play a role throughdonation of a hydrogen atom from their hydroxyl groupsto radicals resulting in radical moiety elimination Duringthis reaction phenoxyl radical is formed that can form stablecompound and terminates radical reaction via reaction withanother radical [20]

Upon consumption of food polyphenols are available inthe form of esters glycosides or polymers that cannot beabsorbed in the intestine The original molecules of polyphe-nolic compounds are hydrolyzed by microbial enzymes incolon and transformed via methylation sulfation and glu-curonidation to derivatives of original molecules followed bytheir absorption in the colon and travelling through bloodto various tissues and organs such as the brain Howeverdue to the diverse susceptibilities of phenolic compounds tocolon enzymemetabolism their bioavailability can vary fromvery low to very high [22 23] The low bioavailability andtransformation of polyphenolic compounds in vivo to differ-ent derivatives lead to their low direct antioxidant activity incomparison to other low-molecularweight antioxidants suchas vitamins C and E and uric acid [24]

However in addition to antioxidant activities polyphe-nols at low concentration can exert also other biologicaleffects in vivo Polyphenols can participate in modulationof different signaling pathways thus influencing the fateof cells [25] including nerve cells via influencing theneuronal survival regeneration development or death [26]

Oxidative Medicine and Cellular Longevity 3

Polyphenolic compounds possess also antimutagenic ability[27] vasodilating [28] antithrombic [29] antiapoptotic [30]and anti-inflammatory [31] effects

Anti-inflammatory effects of polyphenols in cerebraltissue can be realised via binding to various receptorsFlavonoid-induced receptor stimulation can modulate activestate of different kinases such as the mitogen-activated pro-tein (MAP) kinase (naringenin) phosphoinositide-3-(PI3)kinase (curcumin) nuclear factor-kappaB (resveratrol andepigallocatechin gallate) and protein kinase C (PKC) path-ways (resveratrol) Polyphenols can thus influence differen-tiation and apoptosis cell survival (inhibition of apoptosis)inflammatory response learning andmemory and reductionof amyloid plaque formation Polyphenols can affect theactivation of glial cells in brain which are the residenceof macrophages via inhibiting the inflammation mediatedby macrophages through the reduction of proinflammatorycytokines (IL-1 beta TNF-alpha) formation [32]

The neuroprotection of polyphenols can be assigned tothe improvement of cerebral blood flow via stimulation ofNO formation in the endothelium and inhibition of plateletaggregation [32]

The principle question is how and in which form andamount can polyphenols reach the brain and modulate itsfunctionThis problem is not completely solved Results fromanimal experiments indicate that diet supplementation withsome polyphenolic extracts (eg from grapes blueberriesand blackberries) results in deposition and bioavailability ofpolyphenols and their metabolites in the brain of animalswhere they can directly exert their protective effects How-ever we can only assume that a diet rich in vegetables andfruits will result in increased cerebral deposition of these ben-eficial compounds Polyphenols might modify brain functionat three locations (i) outside the CNS by improving cerebralblood flow or by altering signaling pathways from peripheralorgans to the brain (ii) at the blood-brain barrier by alter-ing multi-drug-resistant protein-development influxexfluxmechanisms of different biomolecules and (iii) inside theCNS bymodifying the activity of neurons and glial cells [33]

On the other hand flavonoids could exert also theirprooxidative properties in vitro for example in the presenceof high concentration of Cu2+ ions (25ndash100 120583molsdotLminus1) andoxygen The issue whether prooxidative effects of flavonoidscan be exerted also in vivo has not been addressed yet and theanswer to this question requires further studies [34 35]

3 Psychiatric Disorders

Psychiatric disorders including major depression attentiondeficit hyperactivity disease (ADHD) and schizophreniacontribute largely to mental problems of children adoles-cents and adults

According to the PubMed under the terms ldquopolyphenolsrdquoand ldquomental healthrdquo the number of studies dealing withpolyphenols and mental health is much lower (21 papers)compared with cardiovascular diseases (924 papers) or neu-rodegenerative diseases (291 papers) For this reason any newpaper dealing with this topic is very important

It is believed that in pathology of psychiatric disordersalso oxidative stress plays a role (Figure 2) Oxidative stressis defined as the disbalance between production of freeradicals andor reactive oxygen speciesreactive nitrogenspecies (ROSRNS) and antioxidant defence in favour ofROSRNS leading to oxidative damage to lipids proteins andDNA and thus to the dysfunction of cells and organs [25]Although the brain forms less than 2 of the body weightit consumes about 20 of the oxygen available throughrespiration The brain is also a lipid-rich organ which cancontribute to its susceptibility to oxidative damage [36] Thebrain has a large potential oxidative capacity but a limitedability to counteract oxidative stress Cells in the centralnervous system are more sensitive to toxic effects of ROSthan cells in other organs of the body Moreover in the brainthere is a low activity of catalase insufficient activities ofglutathione peroxidase (both enzymes decompose hydrogenperoxide or organic peroxides) and superoxide dismutase(decomposes superoxide anion radical to hydrogen peroxideand oxygen) and higher level of iron ions and ascorbic acid(together they form optimal conditions for formation of verytoxic hydroxyl radical) in comparison to other cells Thesefacts increase the susceptibility of brain to oxidative andperoxidative damages to biomolecules [25 32]

In addition to antioxidant properties of polyphenolsresearch has shown that polyphenols can exert their neuro-protective properties through modulation of specific cellularsignaling pathways involved in cognitive processes such assynaptic plasticity notably pathways with CREB (cAMP-response element-binding protein) signalling CREB is atranscription factor linked with genes that express brain-derived neurotrophic factor (BDNF) The importance ofCREB in brain function is emphasized by studies thatdemonstrate impairments in memory formation induced bythe disruption of CREB activity and similarly accelerationsin memory formation stimulated by increased CREB activ-ity [37] Polyphenols can directly modulate these signalingpathways by induction of CREB and subsequently by BDNFactivation [23]

4 Major Depression

Major depression is a psychiatric disorder which representsthe fourth leading cause of disability worldwide and isexpected to become the second most prevalent disease afterischemic heart disease by 2020 Depression is also one of themost costly disorders in western countries and antidepres-sants account for 20 of total CNS drug sales [38]

Depression has a multifactorial aetiology arising fromgenetic environmental psychological and biological factorsThese factors are mainly applied jointly in aetiology ofdepression and their impact on the status and severity ofdisease are mutually intertwined (Figure 2)

Firstly the causal relation is assumed between distur-bance in monoamine (neurotransmitters) metabolism espe-cially serotonin abnormalities in its receptor and depres-sion [39] but also dopamine adrenaline and glutamateare involved [40 41] Metabolism of neurotransmitters is


Inflammatoryprocesses

Mitochondrialdysfunction

Imbalance inneurotransmitterrsquos

pathways

Mutual relationbetween aetiology

factors of depression

Oxidative andnitrosative

stress

Neurogenesisneuronal plasticity and

neurodegeneration

Dysfunction inHPA axis

Figure 2Mutual relations between aetiology factors of depression Explanation of individual factors is given in the text HPA hypothalamic-pituitary-adrenal

Presynaptic partof synapse

Substrates for NTsynthesis

NT degradation byenzymes (MAO)

Synapticcleft

Postsynaptic partof synapse

Synthesizing enzymes of NT

NT

Vesicle with NT

Exocytosis of NTAutoreceptor can linkNT via reuptake

Postsynaptic receptorwith linked NT

Figure 3 Neurotransmitters in synapseMolecules of NT are synthesized from their substrates by enzymes NT are stored in vesicles Vesiclesafter action potential fuse with presynapticmembrane andNT are released into synapse cleft ReleasedNT are linked to postsynaptic receptorsand signal is transferred (rarr ) to postsynapse NT can be reuptaken by autoreceptor and neurotransmission is inhibited ([) Reuptaken NTcan be enzymatically degraded (MAO) NT neurotransmitter MAO monoaminooxidase

influenced by enzymes involved in their degradation likemonoamine oxidase (MAO) and in synthesis of their aminoacid precursor tryptophan by enzyme tryptophan hydrox-ylase [42] The causal association between neurotransmit-ters and depression is also based on successful treatmentof depression with selective serotonin reuptake inhibitors(SSRIs) into the presynaptic cells increasing the level of

serotonin in the synaptic cleft available to bind to the postsy-naptic receptor (Figure 3) The process of neurotransmissionis explained in the text to the figure

Secondly increased inflammatory processes are alsoinvolved in the pathology of depression which was firstreported by Maes et al [43] Increased proinflammatorycytokines can induce various clinical characteristics such as


disturbed serotonin metabolic pathway and neurovegetativesymptoms [44] Increased level of proinflammatory cytokines(IL-6 tumor necrosis factor (TNF-alpha)) and C-reactiveprotein (CRP) in blood are recognized as good markers ofincreased inflammation in depressive patients These reliablemarkers of nonspecific inflammation showed positive corre-lation with the severity of depressive symptoms and somecomorbidities like impaired sleep cognitive dysfunction andfatigue [38 45 46]

Thirdly neurogenesis and synaptic plasticity in the con-text of adult hippocampal neurogenesis (AHN) are compro-mised in patients with depression with subsequent neurode-generation [47] This results in stress-induced alteration inthe number and shape of neurons and glial cells in brainregions of depressed patients and decreased proliferation ofneural stern cells [48] The most abundant neurotrophin inthe central nervous system involved in neuronal survivalgrowth and proliferation is the brain-derived neurotrophicfactor (BDNF) In patients with depression the levels ofBDNF are very low [49 50]

Fourthly dysfunction in hypothalamic-pituitary-adrenal(HPA) axis is characteristic for patients suffering fromdepression [51] This gives rise to the failure in the secre-tion of cortisol and glucocorticoids depending on the typeof depression and to the hypersecretion of corticotropin-releasing hormone (CRH) Treatment with antidepressantsregulates levels of these hormones [52ndash54]

Fifthly depression is associated with mitochondrial dys-function related to lower activities of respiratory chainenzymes ATP production and damage to mitochondrialDNA [55ndash58]

Sixthly it is assumed that redox imbalance (increasedoxidative and nitrosative stress) also plays a role in thepathology of depressionThe antioxidant defence systems aredecreased and the level of lowmolecular-weight antioxidantssuch as vitamin C vitamin E and coenzyme Q as well asthe activity of antioxidant enzyme glutathione peroxidase arereduced [59ndash62] Deficiencies in antioxidant defence systemsimpair protection of cells and organs against free radicals andreactive oxygen and nitrogen species leading to the damage toproteins DNA and lipids through oxidation of fatty acids inphospholipids of lipoproteins and membranes [8]

Increased oxidative stress is manifested by increasedmarkers of oxidative stress in depressed patients suchas increased level of malondialdehyde and isoprostanesproducts of lipoperoxidation [63 64] peroxides in plasma[65] xanthine oxidase activity [66] and oxidative damageto DNA represented by increased level of 8-hydroxy-2-deoxyguanosine [67 68]

41 Can Polyphenols Influence Aetiology Factors of DepressionSeveral in vitro and in vivo studies indicate that polyphenolscan affect neuronal system and processes [3] It should bekept in mind that the effects of polyphenols in vivo maybe different from the effects in vitro as in vivo rathermetabolites of polyphenols are active than original sub-stances For example curcumin a nonflavonoid phenoliccompound present in Curcuma longa known and used

in Indian traditional medicine after administration signifi-cantly decreased depression-like behaviour in rats probablythrough improvement of the BDNF level [69] Curcumincoadministered with alkaloid piperine inhibited MAO activ-ity and increased serotonin and dopamine level in mice[70] Sanmukhani et al [71] provides clinical evidence thatcurcumin (1000mgday) administered for 6 weeks to 60patients with major depression in randomized and placebocontrolled trial may be used as an effective and safe modalityfor treatment of depressive patients without concurrentsuicidal ideation On the contrary to results of Sanmukhaniet al Bergman et al [72] did not observe significant dif-ferences between the groups of patients with administeredcurcumin (500mg) and placebo for 5 weeks in randomizeddouble-blind and placebo controlled clinical study probablydue to low daily doses used However the patients in thecurcumin group demonstrated a trend to a more rapid reliefof depressive symptoms in comparison to those in the placebogroup

Curcumin is a lipophilic compound that can easily crossthe blood-brain barrier and directly induce neuroprotectionprobably through its antioxidant ability to inhibit lipidperoxidation and neutralize ROS and RNS [73] In addi-tion curcumin can affect number of cellular pathways onmolecular level and via anti-inflammatory properties it caninhibit cyclooxygenase 1 and cyclooxygenase 2 and influencemany other signalling pathways leading to cell protection andenhancement of cell survival [74]

Flavonoid derived from catechin epigallocatechin gallate(EGCG) present in green tea was used in traditional Chinesemedicine for at least 4000 years At present EGCG is knownfor its powerful antioxidant properties and for its abilityto attenuate stress and depression In experimental studyon mice increased level of BDNF was found after a long-term administration of green tea polyphenols [75] or reducedserum corticosterone and adrenocorticotropic hormone lev-els after forced swimming test [76] In vitro experimentswith cultured hippocampal neurons confirmed the specificmodulation of the GABA-A receptor benzodiazepine siteby application of EGCG [77] In a double-blind random-ized and placebo controlled human study with seventy-foursubjects who were administered green tea or placebo for 5weeks subjects with the long-term green tea extract supple-mentation increased the reward learning and prevented thedepressive symptoms [78] Also an extract of polyphenolsfrom Ginkgo biloba consisting namely of flavonol quercetinand kaemferol has been shown to have antidepressant-likeeffects in mice probably through increasing BDNF levelneuronal survival and plasticity and inhibition of MAOtowards serotonin [79] MAO is also inhibited in vitro byanthocyanins from berries flavone apigenin from celery andstilbene trans-resveratrol from red wine [80] The flavonoidsfrom cocoa showed also antidepressant-like effects in theanimal model using the forced swimming test in rats [81]and reduced symptoms of chronic fatigue in ten subjectsenrolled in double-blind randomized clinical pilot crossoverstudy [82] Polyphenolic extract from the wood of Quercusrobur (Robuvit Horphag Res Ltd) is a proprietary extractwith concentrated water-soluble components of the wood


(ellagitannins) also found in wine resting in oak barrelsRobuvit contains roburins (A B C D and E) and grandininThese components belong to the group of hydrolysabletannins (ellagitannins) Clinical investigation in healthy vol-unteers and patients with primary lymphedema has shownan increased antioxidant capacity of blood and a decreasein peripheral edema after supplementation with Robuvit [8384]

In the study of Natella et al [83] Robuvit actions werestudied on modulation of gene expression Robuvit affectsribosomes cell cycle and spliceosome pathway The effectsof Robuvit on stimulation of ribosomal activity and proteintranslation are suggested to be involved in relieving fatigue inhealthy volunteers and chronic fatigue syndrome in patients[85] In addition Robuvit was shown to accelerate healingin patients with temporary hepatic damage [86] In anotherstudy intake of 300mgday of Robuvit was associated withimproving effect on energy tiredness and tension subscalesevaluating fatigue in 20 volunteers with lower baseline offeelings scoring [87] In the same volunteers the decreaseof markers of oxidative stress and increase of activity ofantioxidant enzymes CuZn superoxide dismutase catalaseand total antioxidant capacity of plasma in vivowere observed[88]

5 Attention Deficit Hyperactivity Disorders(ADHD)

Attention deficit hyperactivity disorder is the most prevalentchildhood disorder estimated to affect 2ndash18 of childrendepending largely on diagnostic criteria [89] The economicconsequences of ADHD persisting into adulthood are signif-icant with one US analysis finding an average of 35 days ofannual lost work performance representing 120 million daysof annual lost work in the labor force equivalent to 195 billionUSD lost human capital [90]

ADHD is a complex polygenic disorder with high levelsof heterogeneity influenced by the interaction of multipleaetiological factors [91] Twin family and adoption studiesof ADHD have supported a strong genetic contributionto the disorder with heritability ranging from 60 to 90A plausible genetic hypothesis for ADHD is a mixture ofdominant and recessive major genes that act with complexpolygenic transmission patterns Molecular genetic studieshave implicated a number of possible genes (DRD4 DRD5DAT1 DRD1 and Taq1) However each of these genes onlyincreases relative risk of ADHD slightly Pre- peri- andpostnatal environmental factors play an important role in thepathogenesis of ADHD Prenatal factors are associated withmaternal lifestyle during pregnancy For example prenatalalcohol exposure is known to induce brain structural anoma-lies especially in the cerebellumMaternal smoking producesa 27-fold increased risk forADHD Perinatal factors have alsobeen implicated with a twofold increase in ADHD in verylow-birthweight children and an increased rate of pregnancywith birth complications Among postnatal factors a rolefor malnutrition and dietary deficiency in ADHD has beenproposed An imbalance of essential fatty acid (omega-3

and omega-6) intake has been suggested to be potentiallyinvolved in the development of ADHD Iron deficiency hasbeen implicated in some cases Early deprivation of socialenvironment during the postnatal period may also havesignificant effects [92]

Studies have identified various structural and func-tional abnormalities in frontostriatal network This networkinvolves the lateral prefrontal cortex the dorsal anteriorcingulate cortex and the caudate nucleus and putamen InADHD patients reductions in volume have been observed intotal cerebral the prefrontal cortex the basal ganglia (stria-tum) the dorsal anterior cingulate cortex the corpus callo-sum and the cerebellum A developmental trajectories studyin ADHDpatients showed a delay in cortical maturationThedelay was most prominent in prefrontal regions importantin the control of cognitive processes including attention andmotor planning Compensatory networks including basalganglia insula and cerebellum have been implicated forrelative lower cognitive load tasks in ADHD patients

Genetic influences predispose a child to catecholamin-ergic dysregulation (deficits in dopamine noradrenalineand serotonin transmission) and abnormalities in theirmetabolism [93 94]There is also persuasive relation betweenADHD and suboptimal level of catecholamines and thecomposition of consumed essential fatty acids [95] as well asconsumption of certain additives or food preservatives [96]

For diagnosis clear evidence of clinically significantimpairment in social academic or occupational functioningis required The essential feature of ADHD is a persis-tent pattern of inattention andor hyperactivity-impulsivitythat interferes with functioning or development Inattentionmanifests behaviorally in ADHD as wandering off tasklacking persistence having difficulty sustaining focus andbeing disorganized which is not due to defiance or lackof comprehension Hyperactivity refers to excessive motoractivity (such as a child running around) when it is notappropriate or excessive fidgeting tapping or talkativenessIn adults hyperactivity may manifest as extreme restlessnessor wearing others out with their activity Impulsivity refers tohasty actions that occur in the moment without forethoughtand that have high potential for harm to the individual (egdarting into the street without looking) (DSM V APA 2013)

Comorbidity is common in ADHD with strong linksto oppositional defiance disorder learning disorders in chil-dren major depressive disorder anxiety disorders socialdysfunction and substance abuse in adults Academic issuessurroundingADHD in childhood are linked to a higher drop-out rate from secondary (high) school with fewer than 5completing a university degree [97]

Conventional treatment options usually include eitherin isolation or in combination a pharmaceutical compo-nent a behavioural component and a psychosocial com-ponent Pharmacotherapies which inhibit the reuptake ofnoradrenaline and dopamine such as the psychostimulantsmethylphenidate and dextroamphetamine and nonstimu-lating prefrontal cortex noradrenaline reuptake inhibitoratomoxetine are the standardWestern treatments forADHDSelective serotonin reuptake inhibitors (SSRIs) and otherantidepressants are also used with varying degrees of success


A third of ADHD patients who take stimulants forADHD report significant adverse effects including anorexiaweight loss abdominal pain sleep disturbances headachesirritability depressed mood and appetite with some reportsof stimulant induced psychosis Increasing apprehensionregarding stimulant medication and the ramifications of itsuse in children has led to the investigation and acknowledg-ment of alternative therapeutic medications [94]

While more than 900 results can be found for the termldquodepressionrdquo in Pubmed only 47 studies including just onesystematic review can be found for the terms ldquooxidativestressrdquo and ADHD [98] When compared to oxidative stressresults from six studies with total 231 ADHD patients and207 controls indicate that the association between ADHDand antioxidant status was not significant However resultswith markers of oxidative stress are controversial Malondi-aldehyde (MDA) the marker of lipoperoxidation was foundincreased in 20 adult patients and correlated with the scoreof hyperactivity [99] but in 30 children with ADHD thisparameter was not different from healthy controls [100] Incontrast to results of Oztop et al [100] Essawy et al [101]found higher level ofMDA and decreased level of antioxidantelement zink in children with ADHD

Selek et al [102] found increased level of NO which atlow concentration exhibits important physiological functionsin neurotransmitters release memory and learning [103]but at high concentration NO with superoxide can formvery damaging oxidant peroxynitrite ONOOminus At low SODactivity which was found by Selek et al [102] a redoximbalance and oxidative stress can be observed in adults withADHD However in children decreased activity of SOD wasnot observed [104] Authors found altered activities also ofother antioxidant enzymes glutathione peroxidase and non-significantly changed catalase in comparison to the controlsOur results found in 61 children with ADHD investigatedin double-blind randomized and placebo controlled studysuggest increased level of the marker of oxidative damage toDNA 8-oxo-78-dihydroxyquanine (8-oxo-G) and decreasedtotal antioxidant status in comparison to the controls [24]We also investigated levels of neurotransmitters in urineIn ADHD children adrenaline and noradrenaline concen-trations positively correlated with plasma levels of oxidizedglutathione and noradrenaline positively correlated with thedegree of hyperactivity [105]

However the determination of only one or two markersof oxidative stress cannot reflect the real redox state in theorganism Therefore the evaluation of total oxidative status(TOS) and total antioxidant status (TAS) and their ratio asoxidative stress index (OSI) could be useful for identificationof redox imbalance [106ndash108]

However a small number of studies and their varietydo not allow drawing definitive conclusions concerninginvolvement of oxidative stress in pathophysiology of ADHD

51 Polyphenols in ADHDTreatment In experimental condi-tionsGinkgo biloba extract (EGb 761) was tested on synapto-somal fraction prepared from mice cerebral cortex EGb 761significantly increased uptake of serotonin Similar effect was

observed when synaptosomes were prepared from the cortexof mice treated orally with EGb 761 These observations werefound in an area of suspected deficit in people with ADHD[109] In ADHD patients several polyphenolic compoundswere tested for treatment [110] The extract from Ginkgobiloba at daily dose 80ndash120mg administered during 6 weeksto fifty children treated withmethylphenidate had no benefitsin double blind randomized and placebo controlled study[111] However in another study increased dosage with themaximum of 240mgday was administered to 20 childrenwith ADHD in an open clinical pilot study over 3 to 5 weeksImprovement of ADHD symptoms as well as brain-electricalactivity was observed [112]

St Johnrsquos wort from Hypericum perforatum (900mgday)was used for treatment of ADHD symptoms in a doubleblind randomized and placebo controlled study with 54children Positive results were observed after 8 weeks oftreatment [113] The effect of traditional Chinese medicinecompound (Ningdong NDG) at daily dose of 5mgkg wasstudied in 72 children with ADHD and compared with effectsof methylphenidate (1mgkg) in a randomized double-blindtrial After 8 weeks of treatment NDG significantly reducedADHD symptomsThe level of dopamin was not changed butserum level of homovanillic acid (a degrading product of cat-echolamine catabolism) increased [114] Oroxylin A is an O-methylated flavone a chemical compound that can be foundin the medicinal plant Scutellaria baicalensis and the Orox-ylum indicum tree It has demonstrated a dopamine but notnoradrenaline reuptake inhibitor activity Its analogue 57-dihydroxy-6-methoxy-41015840-phenoxyflavone showed the mostremarkable inhibition of dopamine reuptake comparable tomethylphenidate but not modulation of GABA pathway inspontaneously hypertensive rat model of attention-deficithyperactivity disorder [115 116]

Pycnogenol (Horphag Ltd) a standardized extract ofFrench maritime pine bark Pinus pinaster was also studiedin relation tomental health especially to ADHD Pycnogenolis a defined mixture of polyphenols mainly procyanidinscatechin taxifolin and a small amount of phenolic acids[117] It exhibits a number of biological activities espe-cially antioxidant properties in vitro and many differentbiomodulating activities in vivo [118] The exact mechanismby which Pycnogenol improves brain functions and mentalhealth is not entirely clear yet Several works on differentlevels (cell cultures experimental animal models and humanstudies) deal with effects of Pycnogenol on brain functionsor mental health The first condition for the positive effectof substances in the brain is the ability to cross the blood-brain barrier Pycnogenol is able to cross blood brain barrier[119] as well as other cell membranes Kurlbaum et al [120]analysed the binding of constituents and the metabolite M1(delta (34-dihydroxyphenyl)-gamma-valerolactone) of Pyc-nogenol that had been previously detected in plasma samplesof human Pycnogenol consumers to human erythrocytesAuthors found a transporter-mediated accumulation of theflavonoid metabolite probably via GLUT-1 transporter Itwas also found that Pycnogenol significantly increased themembrane fluidity predominantly at the membrane surfacePycnogenol efficacy to modify effectively some membrane


dependent processes is related not only to the chemicalaction of Pycnogenol but also to its ability to interact directlywith cell membranes andor penetrate the membrane thusinducing modification of the lipid bilayer and lipid-proteininteractions [121] The ability to modify membrane fluiditycan be related to the pathology of psychiatric disordersthrough modification of adrenergic receptors [122] Pyc-nogenol protected cultured SH-SY5Y neuroblastoma cellsagainst acrolein-induced oxidative stress toxicity probablythrough its antioxidant properties and increased level of GSH[123] The same cells were used in another experiment inwhich Pycnogenol and extract from Hypericum perforatum(St Johnrsquos wort) were used as alternatives to the classicalADHD drugs Pycnogenol exerted no significant effect onATP level but increased cell survival at the concentrations3225 and 250 ngmL [124]

Also results obtained from animal models support thepositive effects of Pycnogenol on mental health Increasedoxidative stress is implicated in the pathogenesis of Parkinsondisease in which dopaminergic neurons are intrinsically sus-ceptible to oxidative stress In Parkinson disease model micetreated with Pycnogenol (20mgkg) for 15 days decreasednumber of dopaminergic D2 receptors and increased levels ofdopamin and its metabolites were observed [125] Neuropro-tective effect of Pycnogenol was observed by Scheff et al [126]in a ratmodel after traumatic brain injury following increasedoxidative stress increased level of proinflammatory cytokinesin cortex and hippocampus In treated animals amelioratedlevel of protein carbonyls lipid peroxides protein nitrationsand proinflammatory cytokines were observed Inmentionedrat model the same group of authors also observed decreasedlevel of thiobarbituric acid reactive substances (TBARS) inbrain and injury-related declines in pre- and postsynapticproteins after Pycnogenol treatment (1ndash10mgkg) [127]

Influence of Pycnogenol on cognitive functions andenhancement of ldquonormalrdquomental performancewas studied in53 students in evaluation study After 8 weeks of supplemen-tation attention memory executive functions and moodrating were improved [128] Influence of Pycnogenol on cog-nitive functions attention mental performance and specificprofessional skills together with oxidative stress in healthyprofessionals was studied in 30 subjects and results werecompared with comparable control group After 12 weeksof Pycnogenol supplementation at the dose of 150mgdayimproved cognitive functions and oxidative stress parameterscompared to the control group [129]

First case reports about positive effects following sup-plementation of ADHD children with Pycnogenol werecollected by Passwater [130] Heimann [131] reported thatcoadministration of Pycnogenol and dextroamphetamineclearly improved symptoms of ADHD of a 10-year-oldboy Withdrawal of Pycnogenol while continuing dextroam-phetamine treatment caused a relapse reinstated Pycnogenolcaused again the significant improvement Positive experi-ence with Pycnogenol was also reported by Hanley in herbook ldquoAttention Deficit Disorderrdquo [132] Masao publishedin Japan a success rate of 70 when treating 40 childrenwith 1mgkg Pycnogenol [133] An attempt to demon-strate reduction of ADHD symptoms in adults failed in

a double-blind placebo controlled comparative study with24 adults [134]No significant differenceswere found betweenplacebo methylphenidate and Pycnogenol groups As thestudy could not show a difference between the active drugmethylphenidate and placebo the relevance of these resultsis questionable

One randomized double blind and placebo controlledstudy examined the role of Pycnogenol in alleviating ADHDsymptoms 61 childrenwith ICD-10 diagnoses of ADHDwereenrolled to either Pycnogenol or placebo groups Children inPycnogenol group were administered Pycnogenol at the doseof 1mgkgday for one month followed by 1 wash-out monthNo serious side effects were reported A significant reductionof symptoms was noted in the intervention group of theteacher-rated Child Attention Problems for hyperactivity andinattention with symptoms returning to pretreatment levelsafter the wash-out period Reduction of these symptomswas not observed in the placebo group When rated byparents and teachers on Connersrsquo rating scale symptomsdecreased slightly compared to the baseline and placebobut did not reach significance Also positive effects weredetected on visual-motor coordination and concentrationtasks in intervention but not in the placebo group Therelatively small number of 44 patients treated with Pyc-nogenol and the short duration of the study limits thegeneralization of our findings [17] In this study also levels ofcatecholamines in urine were investigated Patients sufferingfrom ADHD had significantly higher levels of adrenalineand noradrenaline at the baseline compared to healthy age-matched controls The concentration of noradrenaline inurine of patients with ADHD positively correlated with thescore for inattention Treatment with Pycnogenol resultedin significantly decreased dopamine levels while adrenalineand noradrenaline showed only a trend toward reducedlevels [105] Parallelly improvement of GSHGSSG ratio wasdetermined [135] as well as an increase of total antioxidantstatus and decrease of oxidative damage to DNA [24] Theseresults indicate that Pycnogenol can inhibit oxidative stressby normalizing catecholamine levels in children with ADHDwhich may in turn reduce hyperactivity and increase atten-tion [110] After completion of the study parents asked thattheir ADHD children continue the additional treatment withPycnogenol Mentioned studies indicate that Pycnogenolcould become a promising additive and complementarysupplement in ADHD treatment however more studies areneeded to confirm this conclusion [136]

6 Schizophrenia

Schizophrenia is a devastating mental disorder expressedin the form of abnormal mental functions and disturbedbehaviour It has a life-time prevalence of approximately 1 oftheworldrsquos population [137] Genetic and early environmentalfactors as well as psychological and social processes appearto be important contributory factors Many possible combi-nations of symptoms have triggered debate about whether thediagnosis represents a single disorder or a number of separatesyndromes


Symptoms begin typically in young adulthood and about03ndash07 of people are affected during their lifetime Thedisorder is thought to mainly affect the ability to thinkbut it also usually contributes to chronic problems withbehavior and emotions People with schizophrenia are likelyto have additional comorbidity including major depressionand anxiety disorders Social problems such as long-termunemployment poverty and homelessness are commonTheaverage life expectancy of people with the disorder is 12 to 15years less than those without schizophrenia This is the resultof increased physical health problems and a higher suiciderate (about 5) The mainstay of treatment is antipsychoticmedication which primarily suppresses dopamine receptoractivity Some recreational and prescription drugs appear tocause or worsen symptoms

It is assumed that increased oxidative stress may berelevant to the pathophysiology of schizophrenia [138]Molecular mechanisms contributing to oxidative stress arevery complex and not fully understood yet Although oxida-tive stress may not be the main cause oxidative damageto important biomolecules has been suggested to be acommon pathogenic process contributing to deterioratingcourse and poor outcome [139 140] Brain has a high rateof oxidative metabolic activity (see chapter Psychiatric dis-orders)Moreover neurotransmitters (dopamine adrenalineand noradrenaline) present in excess in the brain can beautooxidized to form relatively large amount of hydrogeneperoxide Additionally neuronal mitochondria can formexcess of superoxide anion radical Due to insufficient activityof Mn-superoxide dismutase (MnSOD) and low concentra-tion of major free radical scavenger in brain glutathione(GSH) mitochondria become damaged and dysfunctioned[141] Glutathione and redox regulation have a critical rolein myelination processes and white matter maturation inthe prefrontal cortex of rodent and human a mechanismpotentially disrupted in schizophrenia [142] However datafor the brain redox status are limited and contradictory inhuman The majority of information for oxidative stress inschizophrenia is received predominantly from determinationof markers in plasmaserum blood cells or urine respec-tively Reduced level of GSH was observed in plasma ofpatients with schizophrenia [143] The lower level of anotherendogenous low-molecular weight antioxidant uric acidwas found in plasma of schizophrenic patients [144] Thepresence of this antioxidant in the CNS is limited by theblood-brain-barrier and is about ten times lower than inblood [145] Concerning activities of antioxidant enzymessuch as superoxide dismutase glutathione peroxidase orcatalase controversial results in their activities (decreasedincreased and unchanged in comparison to healthy subjects)were observed in schizophrenic patients [146]

Similarly contrasting results were observed in markersof lipid peroxidation (malondialdehyde thiobarbituricacid reactive substances (TBARS) 4-hydroxynonenal andisoprostanes) in patients with schizophrenia [147] Meta-analysis of studies on MDA levels in schizophrenic patientsshowed very large heterogeneity of the results [148] Moreaccepted and more sensitive marker of nonenzymatic lipidperoxidation is F2-isoprostane the product of peroxidation

of arachidonic acid liberated from phospholipids [149]This marker was found to be increased in patients withschizophrenia [150] Also some other markers wereinvestigated in schizophrenic patientsThere were monitoredmarkers of oxidative damage to proteins (protein carbonylsor 3-nitrotyrosine) [150] DNA such as 8-oxo-78-dihydro-2-deoxyguanosine which was increased by 20 in 40schizophrenic patients when compared to the controls [151]or leukocyte telomere length in 53 schizophrenic patientswhich was found to be gender dependent but not differentfrom controls [152]

Oxidative stress is also related to apoptotic hypothesisof schizophrenia Apoptosis (a programmed cell death) isa mechanism of cell death that operates in normal neu-rodevelopment and is increasingly recognized for its role indiverse neuropathological conditions Activation of apoptosiscan lead to rapid and complete elimination of neurons andglial cells in the CNS In certain conditions proapoptotictriggers can lead to sublethal and localized apoptotic activitythat produces neuritic and synaptic loss without causing celldeath Neuropathology of schizophrenia includes reducedneuropil (especially synaptic elements) and limited and oftenlayer-specific reduction of neurons suggesting progressiveloss of cortical gray matter in first episode of psychosiswhen antioxidant activity is low [153 154] Apoptotic mecha-nism that can influence synaptic connectivity and neuronalcomplexity seems to support the apoptotic hypothesis ofschizophrenia connected also with oxidative stress [155]

Oxidative stress markers could be used to indicate thedegree of severity of the disease in untreated schizophrenicpatients and may be associated with the subtype of disorder[156]

61 Polyphenols in Schizophrenia There are no studies yetreporting the direct interference of polyphenols with patho-physiology or pathobiochemistry of schizophrenia in humanUnderstanding of the molecular foundations of schizophre-nia pathophysiology would allow a targeted application ofpharmacotherapy However this cannot be studied in humantrials Therefore especially in chronic neurodegenerativeand psychiatric disorders the use of animal experiments isnecessary Conclusions of these experiments may then bemore or less used for application in human biomedical field

Preclinical studies suggest that the green tea extractwith the main polyphenol epigallocatechin-3-gallate (EGCG)may possibly benefit patients with schizophrenia Loftiset al [157] were interested in whether EGCG at doses of600mg per day is a useful adjunct for maintenance treatmentwith antipsychotic medication in 34 patients in the double-blind and placebo controlled study Authors have not foundtherapeutic effects of EGCG on psychotic symptoms incomparison to placebo In schizophrenic patients only fewworks investigated the influence of polyphenols on sideeffects following antipsychotic treatment Tardive dyskinesia(TD) is a serious adverse effect associated with the long-term administration of neuroleptics The pathophysiology ofantipsychotic treatment-induced TD is still unclear althoughseveral reports assumed that free radicals may be involved


[158] Involvement of oxidative stress in the development ofhaloperidol-induced orofacial TD was confirmed by Bish-noi et al [159] Authors found that chronic administra-tion of haloperidol increased vacuous chewing movementstongue protrusions facial jerking and also oxidative dam-age in all major regions of rat brain These changes weredose-dependently inhibited by curcumin Authors point tocurcumin as a possible therapeutic option to treat thishyperkinetic movement Similarly in experimental condi-tions flavonoid quercetin (3573101584041015840-pentahydroxyflavone)reverses haloperidol-induced extrapyramidal side effectscatalepsy usually associated with catatonic schizophreniaIt is a physical condition characterized by suspension ofsensationmuscular rigidity fixity of posture and often loss ofcontact with surroundings [160] Besides this quercetin andalso resveratrol (310158404101584051015840-trihydroxystilbene) reduced lipidperoxidation in human plasma caused by a first-generationantipsychotics haloperidol in ex vivo experiments Theamisulpride the second-generation of antipsychotic drugsdid not influence the level of lipid peroxidation biomarkerTBARS in comparison to the controls [161]

Flavonoid epicatechin present as a major component ingreen tea inhibits lipid peroxidation in human plasma causedby haloperidol in experiment ex vivo [162]

Plasma lipid peroxidation induced by atypical antipsy-chotic drug ziprasidone was also inhibited by polyphe-nols from berries isolated from Aronia melanocarpa in exvivo experiments [163] However results of experiment exvivo should be read and interpreted with caution becausepolyphenols passing through the GIT are metabolized toderivatives and therefore the effect on lipid peroxidation exvivomay not be identical to the effect of in vivo

Extract from Ginkgo biloba (EGb-761) which compo-nents are mostly lipophilic crosses the blood-brain barrierand protects the brain against damaging effect of oxidativestress In the study by Zhang et al [164] 157 patients sufferingfrom schizophrenia were included in the double-blind andplacebo controlled study Patients in EGb-761 group wereadministered daily dose of 240mg EGb-761 for 12 weeksSignificant improvement of TD symptoms in schizophrenicpatients was observed in EGb-761 group in comparison toplacebo The improvement may be mediated through thewell-known antioxidant activities of this extract

Genistein a polyphenol belonging to phytoestrogenstogether with amino acid leucine is able to potentiatethe haloperidol-induced catalepsy in rats compared withthe haloperidol treated group and reduced the number offights and increased latency to fights in foot shock-inducedaggression [165]

Since not all polyphenols are able to pass through theblood-brain barrier it is necessary to look for new thera-peutic approaches One of the new approaches is the useof exosomes Exosomes are small (30ndash150 nm) extracellularcell membrane-derived vesicles that are present in manyand perhaps all biological fluids including blood and urineExosomes are either released from the cells whenmultivesicalbodies fuse with the plasma membrane or released directlyfrom the plasmamembrane It is becoming increasingly clearthat exosomes have specialized functions and play a key

role in for example coagulation intercellular signaling andwaste management Exosomesrsquo simple structure and abilitiesto be incorporated into plasma membrane and to cross theblood-brain barrier allow them to be utilized as drug deliveryvehicles (in our case polyphenols) or genetic elements in thetreatment of immune psychiatric and neurologic disorders[166]

Several questions remain open for the role of oxida-tive stress in schizophrenia Antipsychotic drugs have beensuspected to generate increased ROS resulting in increasedoxidative stress What kind of antipsychotic drugs is involvedin oxidative stress What are the symptom domains asso-ciated with the oxidative stress Is the oxidative stress anattribute of early or chronic stages of the disease What isthe role of current treatment on oxidative stress The answerto these questions and explanation of the participation ofoxidative stress in pathology of schizophrenia need furthervalidation [167]

7 Conclusions

A large number of studies have focused on investigation ofeffects of natural polyphenols in mental disorders but theiruse in clinical practice is still a long way off [168]Theremightbe several reasons for such a slow and ineffective research

(1) There are no sufficient sophisticated analytical meth-ods for determination of levels of polyphenolic compoundsand their metabolites in brain (2) it is very difficult tofind a suitable animal model that would mimic the exactstatus of human mental disorder (3) isolated studies ofinterorgan actions and reactions between brain and periph-eral organs cannot give the complex view (4) application ofinformation obtained from in vitro or ex vivo experimentsinto in vivo conditions of the complex nervous system iscomplicated by the biotransformation of original polyphenolsto entirely different metabolites and (5) antipsychotic effectsof polyphenols have not been sufficiently validated in clinicalpractice yet

Due to the enormous complexity of the human brain theexact pathophysiology of psychiatric disorders is not knownyet and the understanding of these complex relations needsto collect huge amount of data on all levels of researchexperimental and human

Identification of the exact mechanism of pathologicalcomponents of mental disorders on molecular level canlead to the development of effective treatments Polyphenolsin the diet have the potential to become medicaments inthe field of mental health after a thorough study of theirmechanism of action Members of the International Societyfor Nutritional Psychiatry Research advocated recognition ofdiet and nutrition as central determinants of both physicaland mental health [169]

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper


Acknowledgments

Authors wish to thank Associate Professor Ingrid ZitnanovaPhD and Maria Stefıkova M D for their help withEnglish language and Mrs Lydia Mikova for completing theliterature This project was partly supported by the grantVEGA 01070313 Horphag Res Ltd Mind and Health civilassociation

References

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[2] R Meeusen ldquoExercise nutrition and the brainrdquo SportsMedicine vol 44 supplement 1 pp S47ndashS56 2014

[3] G P Dias N Cavegn A Nix et al ldquoThe role of dietarypolyphenols on adult hippocampal neurogenesis molecularmechanisms and behavioural effects on depression and anxietyrdquoOxidative Medicine and Cellular Longevity vol 2012 Article ID541971 18 pages 2012

[4] H Mo Y Chen L Huang H Zhang J Li and WZhou ldquoNeuroprotective effect of tea polyphenols on oxyhe-moglobin induced subarachnoid hemorrhage in micerdquo Oxida-tive Medicine and Cellular Longevity vol 2013 Article ID743938 7 pages 2013

[5] B Wright ldquoForging a modern generation of polyphenol-basedtherapeuticsrdquo British Journal of Pharmacology vol 169 no 4pp 844ndash847 2013

[6] U Gundimeda T HMcNeill J E Schiffman D R Hinton andR Gopalakrishna ldquoGreen tea polyphenols potentiate the actionof nerve growth factor to induce neuritogenesis possible role ofreactive oxygen speciesrdquo Journal of Neuroscience Research vol88 no 16 pp 3644ndash3655 2010

[7] M Ashafaq S S Raza M M Khan et al ldquoCatechin hydrateameliorates redox imbalance and limits inflammatory responsein focal cerebral ischemiardquo Neurochemical Research vol 37 no8 pp 1747ndash1760 2012

[8] Z Durackova ldquoFree radicals and antioxidants for non-expertsrdquoin Systems Biology of Free Radicals and Antioxidants I LaherEd Springer Berlin Germany 2014

[9] M Franco ldquoNew option for chronic fatigue syndromerdquo LifeExtension Magazine p 18 2014

[10] G Belcaro U Cornelli R Luzzi et al ldquoQR (Quercus RoburExtract Robuvit) supplementation in subjects with chronicfatigue syndrome (CFS) and increased oxidative stress A pilotregistry rdquo Journal of Neurosurgical Sciences In press

[11] J A Ross and CM Kasum ldquoDietary flavonoids bioavailabilitymetabolic effects and safetyrdquo Annual Review of Nutrition vol22 pp 19ndash34 2002

[12] C Manach and J L Donovan ldquoPharmacokinetics andmetabolism of dietary flavonoids in humansrdquo Free RadicalResearch vol 38 no 8 pp 771ndash785 2004

[13] T Grimm R Skrabala Z Chovanova et al ldquoSingle andmultiple dose pharmacokinetics of maritime pine bark extract(Pycnogenol) after oral administration to healthy volunteersrdquoBMC Clinical Pharmacology vol 6 article 4 2006

[14] Y Curin M F Ritz and R Andriantsitohaina ldquoCellularmechanisms of the protective effect of polyphenols on theneurovascular unit in strokesrdquo Cardiovascular amp HematologicalAgents in Medicinal Chemistry vol 4 no 4 pp 277ndash288 2006

[15] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006

[16] C Ramassamy ldquoEmerging role of polyphenolic compounds inthe treatment of neurodegenerative diseases a review of theirintracellular targetsrdquo European Journal of Pharmacology vol545 no 1 pp 51ndash64 2006

[17] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolrdquoEuropeanChild andAdolescent Psychiatry vol 15 no 6 pp 329ndash335 2006

[18] P Knekt J Kumpulainen R Jarvinen et al ldquoFlavonoid intakeand risk of chronic diseasesrdquo The American Journal of ClinicalNutrition vol 76 no 3 pp 560ndash568 2002

[19] R J Williams J P E Spencer and C Rice-Evans ldquoFlavonoidsantioxidants or signalling moleculesrdquo Free Radical Biology andMedicine vol 36 no 7 pp 838ndash849 2004

[20] S B Lotito and B Frei ldquoConsumption of flavonoid-rich foodsand increased plasma antioxidant capacity in humans causeconsequence or epiphenomenonrdquo Free Radical Biology andMedicine vol 41 no 12 pp 1727ndash1746 2006

[21] M Kolacek J Muchova S Vrankova et al ldquoEffect of naturalpolyphenols pycnogenol on superoxide dismutase and nitricoxide synthase in diabetic ratsrdquo Prague Medical Report vol 111no 4 pp 279ndash288 2010

[22] B Halliwell J Rafter and A Jenner ldquoHealth promotion byflavonoids tocopherols tocotrienols and other phenols director indirect effects Antioxidant or notrdquo The American Journalof Clinical Nutrition vol 81 supplement 1 pp 268Sndash276S 2005

[23] F Gomez-Pinilla and T T J Nguyen ldquoNatural mood foodsthe actions of polyphenols against psychiatric and cognitivedisordersrdquo Nutritional Neuroscience vol 15 no 3 pp 127ndash1332012

[24] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenol on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006

[25] Z Durackova ldquoSome current insights into oxidative stressrdquoPhysiological Research vol 59 no 4 pp 459ndash469 2010

[26] J P E Spencer ldquoInteractions of flavonoids and theirmetaboliteswith cell signaling cascadesrdquo in Nutrigenomics G Rimbach JFuchs and L Packer Eds Taylor amp Francis Boca Raton FlaUSA 2005

[27] L Krizkova Z Chovanova Z Durackova and J KrajcovicldquoAntimutagenic in vitro activity of plant polyphenolsPycnogenol and Ginkgo biloba extract (EGb 761)rdquo Phytother-apy Research vol 22 no 3 pp 384ndash388 2008

[28] Z Durackova B Trebaticky V Novotny I Zitnanova and JBreza ldquoLipidmetabolism and erectile function improvement byPycnogenol extract from the bark of Pinus pinaster in patientssuffering from erectile dysfunctionmdasha pilot studyrdquo NutritionResearch vol 23 no 9 pp 1189ndash1198 2003

[29] J Golanski J Muchova R Golanski Z Durackova LMarkuszewski and C Watała ldquoDoes pycnogenol intensifythe efficacy of acetylsalicylic acid in the inhibition of plateletfunction In vitro experiencerdquo Postepy Higieny I MedycynyDoswiadczalnej vol 60 pp 316ndash321 2006

[30] G Nie C Jin Y Cao S Shen and B Zhao ldquoDistinct effectsof tea catechins on 6-hydroxydopamine-induced apoptosis inPC12 cellsrdquoArchives of Biochemistry and Biophysics vol 397 no1 pp 84ndash90 2002


[31] A Schafer Z Chovanova JMuchova et al ldquoInhibition of COX-1 and COX-2 activity by plasma of human volunteers afteringestion of French maritime pine bark extract (Pycnogenol)rdquoBiomedicine and Pharmacotherapy vol 60 no 1 pp 5ndash9 2006

[32] D Nowak ldquoAntioxidant plant polyphenols and cognitivedisordersrdquo in Studies on Psychiatric Disorders A Dietrich-Muszalska V Chauhan and S Grignon Eds Humana PressNew York NY USA 2015

[33] S Schaffer andBHalliwell ldquoDopolyphenols enter the brain anddoes it matter Some theoretical and practical considerationsrdquoGenes and Nutrition vol 7 no 2 pp 99ndash109 2012

[34] J Labuda M Buckova L Heilerova S Silhar and I StepanekldquoEvaluation of the redox properties and antipro-oxidant effectsof selected flavonoids by means of a DNA-based electrochemi-cal biosensorrdquo Analytical and Bioanalytical Chemistry vol 376no 2 pp 168ndash173 2003

[35] D Prochazkova I Bousova and N Wilhelmova ldquoAntioxidantand prooxidant properties of flavonoidsrdquoFitoterapia vol 82 no4 pp 513ndash523 2011

[36] G P Kumar and F Khanum ldquoNeuroprotective potential ofphytochemicalsrdquo Pharmacognosy Reviews vol 6 no 12 pp 81ndash90 2012

[37] C Finsterwald H Fiumelli J-R Cardinaux and J-L Mar-tin ldquoRegulation of dendritic development by BDNF requiresactivation of CRTC1 by glutamaterdquo The Journal of BiologicalChemistry vol 285 no 37 pp 28587ndash28595 2010

[38] G Scapagnini S Davinelli F Drago A de Lorenzo and GOriani ldquoAntioxidants as antidepressants fact or fictionrdquo CNSDrugs vol 26 no 6 pp 477ndash490 2012

[39] G V Carr and I Lucki ldquoThe role of serotonin receptorsubtypes in treating depression a review of animal studiesrdquoPsychopharmacology (Berl) vol 213 no 2-3 pp 265ndash287 2011

[40] M J Owens ldquoSelectivity of antidepressants from themonoamine hypothesis of depression to the SSRI revolutionand beyondrdquo Journal of Clinical Psychiatry vol 65 no 4 pp5ndash10 2004

[41] V Maletic M Robinson T Oakes S Iyengar S G Ball and JRussell ldquoNeurobiology of depression an integrated view of keyfindingsrdquo International Journal of Clinical Practice vol 61 no12 pp 2030ndash2040 2007

[42] S Matthes V Mosienko S Bashammakh N Alenina andM Bader ldquoTryptophan hydroxylase as novel target for thetreatment of depressive disordersrdquo Pharmacology vol 85 no2 pp 95ndash109 2010

[43] MMaes E Bosmans E Suy C Vandervorst C De Jonckheereand J Raus ldquoImmune disturbances during major depressionupregulated expression of interleukin-2 receptorsrdquo Neuropsy-chobiology vol 24 no 3 pp 115ndash120 1990

[44] M Maes ldquoThe monocyte-T-lymphocyte hypothesis of majordepressionrdquo Psychoneuroendocrinology vol 20 no 2 pp 111ndash116 1995

[45] C A Meyers M Albitar and E Estey ldquoCognitive impairmentfatigue and cytokine levels in patients with acute myelogenousleukemia or myelodysplastic syndromerdquo Cancer vol 104 no 4pp 788ndash793 2005

[46] S J Motivala A Sarfatti L Olmos and M R Irwin ldquoInflam-matory markers and sleep disturbance in major depressionrdquoPsychosomatic Medicine vol 67 no 2 pp 187ndash194 2005

[47] B-H Lee and Y-K Kim ldquoThe roles of BDNF in the pathophys-iology of major depression and in antidepressant treatmentrdquoPsychiatry Investigation vol 7 no 4 pp 231ndash235 2010

[48] H Eyre and B T Baune ldquoNeuroplastic changes in depression arole for the immune systemrdquo Psychoneuroendocrinology vol 37no 9 pp 1397ndash1416 2012

[49] R S Duman ldquoNeuronal damage and protection in the patho-physiology and treatment of psychiatric illness stress anddepressionrdquoDialogues in Clinical Neuroscience vol 11 no 3 pp239ndash255 2009

[50] A L Lopresti S D Hood and P D Drummond ldquoA review oflifestyle factors that contribute to important pathways associ-ated with major depression diet sleep and exerciserdquo Journal ofAffective Disorders vol 148 no 1 pp 12ndash27 2013

[51] C M Pariante and S L Lightman ldquoThe HPA axis in majordepression classical theories and new developmentsrdquo Trends inNeurosciences vol 31 no 9 pp 464ndash468 2008

[52] P W Gold and G P Chrousos ldquoOrganization of the stresssystem and its dysregulation in melancholic and atypicaldepression high vs low CRHNE statesrdquo Molecular Psychiatryvol 7 no 3 pp 254ndash275 2002

[53] C Anacker P A Zunszain L A Carvalho and C M ParianteldquoThe glucocorticoid receptor pivot of depression and of antide-pressant treatmentrdquo Psychoneuroendocrinology vol 36 no 3pp 415ndash425 2011

[54] C Anacker P A Zunszain A Cattaneo et al ldquoAntidepressantsincrease human hippocampal neurogenesis by activating theglucocorticoid receptorrdquoMolecular Psychiatry vol 16 no 7 pp738ndash750 2011

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[56] A Gardner A Johansson R Wibom et al ldquoAlterations ofmitochondrial function and correlations with personality traitsin selected major depressive disorder patientsrdquo Journal ofAffective Disorders vol 76 no 1ndash3 pp 55ndash68 2003

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[58] A Gardner and R G Boles ldquoBeyond the serotonin hypothesismitochondria inflammation and neurodegeneration in majordepression and affective spectrumdisordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychiatry vol 35 no 3 pp730ndash743 2011

[59] S D Khanzode G N Dakhale S S Khanzode A Saoji andR Palasodkar ldquoOxidative damage and major depression thepotential antioxidant action of selective serotonin-re-uptakeinhibitorsrdquo Redox Report vol 8 no 6 pp 365ndash370 2003

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[61] M Maes I Mihaylova M Kubera M Uytterhoeven NVrydags and E Bosmans ldquoLower plasma Coenzyme Q10 indepression a marker for treatment resistance and chronicfatigue in depression and a risk factor to cardiovascular disorderin that illnessrdquo Neuroendocrinology Letters vol 30 no 4 pp462ndash469 2009

[62] M Maes I Mihaylova M Kubera M Uytterhoeven NVrydags and E Bosmans ldquoLower whole blood glutathioneperoxidase (GPX) activity in depression but not in myalgicencephalomyelitischronic fatigue syndrome another pathwaythat may be associated with coronary artery disease and


neuroprogression in depressionrdquo Neuroendocrinology Lettersvol 32 no 2 pp 133ndash140 2011

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[64] Y-C Wei F-L Zhou D-L He et al ldquoThe level of oxidativestress and the expression of genes involved in DNA-damagesignaling pathways in depressive patients with colorectal car-cinomardquo Journal of Psychosomatic Research vol 66 no 3 pp259ndash266 2009

[65] HHerkenAGurel S Selek et al ldquoAdenosine deaminase nitricoxide superoxide dismutase and xanthine oxidase in patientswith major depression impact of antidepressant treatmentrdquoArchives of Medical Research vol 38 no 2 pp 247ndash252 2007

[66] M Maes I Mihaylova M Kubera M Uytterhoeven NVrydags and E Bosmans ldquoIncreased plasma peroxides andserum oxidized low density lipoprotein antibodies in majordepression markers that further explain the higher incidenceof neurodegeneration and coronary artery diseaserdquo Journal ofAffective Disorders vol 125 no 1ndash3 pp 287ndash294 2010

[67] M J Forlenza and G E Miller ldquoIncreased serum levels of 8-hydroxy-21015840-deoxyguanosine in clinical depressionrdquo Psychoso-matic Medicine vol 68 no 1 pp 1ndash7 2006

[68] M Maes I Mihaylova M Kubera M Uytterhoeven NVrydags and E Bosmans ldquoIncreased 8-hydroxy-deoxyguano-sine a marker of oxidative damage to DNA in major depres-sion andmyalgic encephalomyelitischronic fatigue syndromerdquoNeuroendocrinology Letters vol 30 no 6 pp 715ndash722 2009

[69] Z Huang X-M Zhong Z-Y Li C-R Feng A-J Panand Q-Q Mao ldquoCurcumin reverses corticosterone-induceddepressive-like behavior and decrease in brain BDNF levels inratsrdquo Neuroscience Letters vol 493 no 3 pp 145ndash148 2011

[70] S K Kulkarni M K Bhutani and M Bishnoi ldquoAntidepressantactivity of curcumin Involvement of serotonin and dopaminesystemrdquo Psychopharmacology vol 201 no 3 pp 435ndash442 2008

[71] J Sanmukhani V Satodia J Trivedi et al ldquoEfficacy andsafety of curcumin in major depressive disorder a randomizedcontrolled trialrdquo Phytotherapy Research vol 28 no 4 pp 579ndash585 2014

[72] J Bergman C Miodownik Y Bersudsky et al ldquoCurcumin asan add-on to antidepressive treatment a randomized double-blind placebo-controlled pilot clinical studyrdquo Clinical Neu-ropharmacology vol 36 no 3 pp 73ndash77 2013

[73] Sreejayan and M N A Rao ldquoNitric oxide scavenging bycurcuminoidsrdquo Journal of Pharmacy and Pharmacology vol 49no 1 pp 105ndash107 1997

[74] G Scapagnini S Vasto NG AbrahamC Caruso D Zella andG Fabio ldquoModulation of Nrf2ARE pathway by food polyphe-nols a nutritional neuroprotective strategy for cognitive andneurodegenerative disordersrdquo Molecular Neurobiology vol 44no 2 pp 192ndash201 2011

[75] W-Q Chen X-L Zhao Y Hou et al ldquoProtective effects ofgreen tea polyphenols on cognitive impairments induced bypsychological stress in ratsrdquo Behavioural Brain Research vol202 no 1 pp 71ndash76 2009

[76] W L ZhuH S Shi YMWei et al ldquoGreen tea polyphenols pro-duce antidepressant-like effects in adult micerdquo PharmacologicalResearch vol 65 no 1 pp 74ndash80 2012

[77] M Vignes T Maurice F Lante et al ldquoAnxiolytic propertiesof green tea polyphenol (-)-epigallocatechin gallate (EGCG)rdquoBrain Research vol 1110 no 1 pp 102ndash115 2006

[78] Q Zhang H Yang J Wang et al ldquoEffect of green tea on rewardlearning in healthy individuals a randomized double-blindplacebo-controlled pilot studyrdquo Nutrition Journal vol 12 no 1article 84 7 pages 2013

[79] Y Hou M A Aboukhatwa D-L Lei K Manaye I Khan andY Luo ldquoAnti-depressant natural flavonols modulate BDNF andbeta amyloid in neurons and hippocampus of double TgADmicerdquo Neuropharmacology vol 58 no 6 pp 911ndash920 2010

[80] A Dreiseitel G Korte P Schreier et al ldquoBerry anthocyaninsand their aglycons inhibit monoamine oxidases A and BrdquoPharmacological Research vol 59 no 5 pp 306ndash311 2009

[81] M Messaoudi J-F Bisson A Nejdi P Rozan and H JavelotldquoAntidepressant-like effects of a cocoa polyphenolic extract inWistar-Unilever ratsrdquoNutritional Neuroscience vol 11 no 6 pp269ndash276 2008

[82] T Sathyapalan S Beckett A S Rigby D D Mellor and SL Atkin ldquoHigh cocoa polyphenol rich chocolate may reducethe burden of the symptoms in chronic fatigue syndromerdquoNutrition Journal vol 9 no 1 article 55 2010

[83] F Natella G Leoni MMaldini et al ldquoAbsorption metabolismand effects at transcriptome level of a standardized frenchoak wood extract Robuvit in healthy volunteers Pilot StudyrdquoJournal of Agricultural and Food Chemistry vol 62 no 2 pp443ndash453 2014

[84] G Belcaro M Dugall S Hu A Ledda and E IppolitoldquoFrench oakwood (Quercus robur) extract (Robuvit) in primarylymphedema a supplement pilot registry evaluationrdquo Interna-tional Journal of Angiology 2014

[85] G Belcaro U Cornelli R Luzzi et al ldquoImproved managementof primary chronic fatigue syndrome with the supplementFrench oak wood extract (Robuvit) a pilot registry evaluationrdquoPanminerva Medica vol 56 no 1 pp 63ndash72 2014

[86] G Belcaro G Gizzi S Hu et al ldquoRobuvit (French oak woodextract) in the management of functional temporary hepaticdamage A registry pilot studyrdquoMinerva Medica vol 105 no 1pp 41ndash50 2014

[87] Z Orszaghova I Waczulıkova C Burki P Rohdewald andZ Durackova ldquoAn effect of oak-wood extract (Robuvit) onenergy levels in healthy adultsmdasha pilot studyrdquo Submitted toPhytotherapy Research

[88] M Horvathova Z Orszaghova L Laubertova et al ldquoEffect ofthe French oak wood extract Robuvit on markers of oxidativestress and activity of antioxidant enzymes in healthy volunteersa pilot studyrdquo Oxidative Medicine and Cellular Longevity vol2014 Article ID 639868 6 pages 2014

[89] N Sinn ldquoNutritional and dietary influences on attention deficithyperactivity disorderrdquo Nutrition Reviews vol 66 no 10 pp558ndash568 2008

[90] R C Kessler L Adler M Ames et al ldquoThe prevalence andeffects of adult attention deficithyperactivity disorder on workperformance in a nationally representative sample of workersrdquoJournal of Occupational and EnvironmentalMedicine vol 47 no6 pp 565ndash572 2005

[91] D Coghill S Bonnar S Duke J Graham and S SethChild andAdolescent Psychiatry Oxford University Press New York NYUSA 2009

[92] P Curatolo E DrsquoAgati and R Moavero ldquoThe neurobiologicalbasis of ADHDrdquo Italian Journal of Pediatrics vol 36 article 792010

[93] L T Curtis and K Patel ldquoNutritional and environmentalapproaches to preventing and treating autism and attention


deficit hyperactivity disorder (ADHD) a reviewrdquo Journal ofAlternative and Complementary Medicine vol 14 no 1 pp 79ndash85 2008

[94] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofAttentionDeficit Hyperactivity Disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011

[95] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007

[96] D McCann A Barrett A Cooper et al ldquoFood additives andhyperactive behaviour in 3-year-old and 89-year-old childrenin the community a randomised double-blinded placebo-controlled trialrdquo The Lancet vol 370 no 9598 pp 1560ndash15672007

[97] R E CimeraMaking ADHD a Gift Teaching Superman How toFly Scarecrow Education Rowman amp Littlefield Lanham MdUSA 2002

[98] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders 2013

[99] M Bulut S Selek H S Gergerlioglu et al ldquoMalondialdehydelevels in adult attention-deficit hyperactivity disorderrdquo Journalof Psychiatry and Neuroscience vol 32 no 6 pp 435ndash438 2007

[100] D Oztop H Altun G Baskol and S Ozsoy ldquoOxidative stress inchildren with attention deficit hyperactivity disorderrdquo ClinicalBiochemistry vol 45 no 10-11 pp 745ndash748 2012

[101] H Essawy I El-Ghohary A El-Missiry O Kahla A Solimanand O El-Rashidi ldquoOxidative stress in attention deficit hyper-activity disorder patientsrdquo Current Psychiatry vol 16 no 1 p5669 2009

[102] S Selek H A Savas H S Gergerlioglu M Bulut andH R Yilmaz ldquoOxidative imbalance in adult attentiondeficithyperactivity disorderrdquo Biological Psychology vol 79no 2 pp 256ndash259 2008

[103] O Akyol S Zoroglu F Armutcu S Sahin and A GurelldquoNitric oxide as a physiopathological factor in neuropsychiatricdisordersrdquo In Vivo vol 18 no 3 pp 377ndash390 2004

[104] M Ceylan S Sener A C Bayraktar and M KavutculdquoOxidative imbalance in child and adolescent patients withattention-deficithyperactivity disorderrdquo Progress in Neuro-Psychopharmacology and Biological Psychiatry vol 34 no 8 pp1491ndash1494 2010

[105] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenol)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007

[106] O Erel ldquoA novel automated method to measure total antiox-idant response against potent free radical reactionsrdquo ClinicalBiochemistry vol 37 no 2 pp 112ndash119 2004

[107] O Erel ldquoA new automated colorimetric method for measuringtotal oxidant statusrdquo Clinical Biochemistry vol 38 no 12 pp1103ndash1111 2005

[108] S Selek and M F Ceylan ldquoA relationship between oxidativestatus and attention deficit hyperactivity disorderrdquo in Studies onPsychiatric Disorders A Dietrich-Muszalska V Chauhan andS Grignon Eds Humana Press New York NY USA 2015

[109] C Ramassamy Y Christen F Clostre and J Costentin ldquoTheGinkgo biloba extract EGb761 increases synaptosomal uptakeof 5-hydroxytryptamine in-vitro and ex-vivo studiesrdquo Journalof Pharmacy and Pharmacology vol 44 no 11 pp 943ndash9451992

[110] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009

[111] B Salehi R Imani M R Mohammadi et al ldquoGinkgo bilobafor attention-deficithyperactivity disorder in children and ado-lescents a double blind randomized controlled trialrdquo Progressin Neuro-Psychopharmacology and Biological Psychiatry vol 34no 1 pp 76ndash80 2010

[112] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761 in children with ADHDrdquo Zeitschrift fur Kinder- undJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014

[113] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008

[114] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011

[115] I C Dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013

[116] S Y Yoon I D Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013

[117] P Rohdewald ldquoA review of the French maritime pine barkextract (Pycnogenol) a herbalmedicationwith a diverse clinicalpharmacologyrdquo International Journal of Clinical PharmacologyandTherapeutics vol 40 no 4 pp 158ndash168 2002

[118] P Rohdewald ldquoLetter to the editor pycnogenol protects DNAagainst oxidative damage in vivordquo Phytotherapy Research vol19 no 3 p 262 2005

[119] S A Baldwin I Fugaccia D R Brown L V Brown and S WScheff ldquoBlood-brain barrier breach following cortical contusionin the ratrdquo Journal of Neurosurgery vol 85 no 3 pp 476ndash4811996

[120] M Kurlbaum M Mulek and P Hogger ldquoFacilitated uptakeof a bioactive metabolite of maritime pine bark extract (pyc-nogenol) into human erythrocytesrdquo PLoS ONE vol 8 no 4Article ID e63197 2013

[121] M Sivonova I Waczulıkova E Kilanczyk et al ldquoThe effectof Pycnogenol on the erythrocyte membrane fluidityrdquo GeneralPhysiology and Biophysics vol 23 no 1 pp 39ndash51 2004

[122] J E Piletz M Sarasua M Chotani A Saran and A HalarisldquoRelationship between membrane fluidity and adrenoceptorbinding in depressionrdquo Psychiatry Research vol 38 no 1 pp1ndash12 1991

[123] M A Ansari J N Keller and S W Scheff ldquoProtectiveeffect of Pycnogenol in human neuroblastoma SH-SY5Y cells


following acrolein-induced cytotoxicityrdquo Free Radical Biologyand Medicine vol 45 no 11 pp 1510ndash1519 2008

[124] A J Schmidt J-C Krieg U M Hemmeter et al ldquoImpact ofplant extracts tested in attention-deficithyperactivity disordertreatment on cell survival and energy metabolism in humanneuroblastoma SH-SY5Y cellsrdquo Phytotherapy Research vol 24no 10 pp 1549ndash1553 2010

[125] M M Khan M N Hoda T Ishrat et al ldquoAmeliora-tion of 1-methyl-4-phenyl-1236-tetrahydropyridine-inducedbehavioural dysfunction and oxidative stress by Pycnogenol inmouse model of Parkinsonrsquos diseaserdquo Behavioural Pharmacol-ogy vol 21 no 5-6 pp 563ndash571 2010

[126] S W Scheff M A Ansari and K N Roberts ldquoNeuroprotectiveeffect of Pycnogenol following traumatic brain injuryrdquo Experi-mental Neurology vol 239 no 1 pp 183ndash191 2013

[127] M A Ansari K N Roberts and S W Scheff ldquoDose- and time-dependent neuroprotective effects of Pycnogenol followingtraumatic brain injuryrdquo Journal of Neurotrauma vol 30 no 17pp 1542ndash1549 2013

[128] R Luzzi G Belcaro C Zulli et al ldquoPycnogenol supplementa-tion improves cognitive function attention and mental perfor-mance in studentsrdquo Panminerva Medica vol 53 supplement 1no 3 pp 75ndash82 2011

[129] G Belcaro R Luzzi M Dugall E Ippolito and A SagginoldquoPycnogenol improves cognitive function attention mentalperformance and specific professional skills in healthy profes-sionals age 35ndash55rdquo Journal of Neurosurgical Sciences vol 58 no4 pp 239ndash248 2014

[130] R A Passwater All about Pycnogenol Avery Publishing GroupNew York NY USA 1998

[131] S W Heimann ldquoPycnogenol for ADHDrdquo Journal of theAmerican Academy of Child ampAdolescent Psychiatry vol 38 no4 pp 357ndash358 1999

[132] J L Hanley Attention Deficit Disorder Impact Communica-tions Green Bay Wis USA 1999

[133] H Masao ldquoPycnogenolrsquos therapeutic effect in improvingADHD symptoms in children confirmedrdquo Mainichi Shimbunvol 10 2000

[134] S Tenenbaum J C Paull E P Sparrow D K Dodd andL Green ldquoAn experimental comparison of Pycnogenol andmethylphenidate in adultswithAttention-DeficitHyperactivityDisorder (ADHD)rdquo Journal of Attention Disorders vol 6 no 2pp 49ndash60 2002

[135] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenol on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006

[136] A Schoonees J Visser A Musekiwa and J Volmink ldquoPyc-nogenol (extract of French maritime pine bark) for the treat-ment of chronic disordersrdquo Cochrane Database of SystematicReviews vol 4 Article ID CD008294 2012

[137] M Boskovic T Vovk B K Plesnicar and I Grabnar ldquoOxidativestress in schizophreniardquo Current Neuropharmacology vol 9 no2 pp 301ndash312 2011

[138] K Q Do ldquoSchizophrenia genes environment and neurodevel-opmentrdquo Revue Medicale de la Suisse Romande vol 9 no 398pp 1672ndash1677 2013 (French)

[139] S P Mahadik and S Mukherjee ldquoFree radical pathology andantioxidant defense in schizophrenia a reviewrdquo SchizophreniaResearch vol 19 no 1 pp 1ndash17 1996

[140] I Perez-Neri J Ramırez-Bermudez S Montes and C RıosldquoPossible mechanisms of neurodegeneration in schizophreniardquoNeurochemical Research vol 31 no 10 pp 1279ndash1294 2006

[141] V Tang and J-F Wang ldquoMitochondrial dysfunction and oxida-tive stress in bipolar disorderrdquo in SystemsBiology of Free Radicalsand Antioxidants I Laher Ed Springer Berlin Germany 2014

[142] A Monin P S Baumann A Griffa et al ldquoGlutathione deficitimpairs myelin maturation relevance for white matter integrityin schizophrenia patientsrdquoMolecular Psychiatry 2014

[143] A Dietrich-Muszalska and B Olas ldquoIsoprostenes as indicatorsof oxidative stress in schizophreniardquo The World Journal ofBiological Psychiatry vol 10 no 1 pp 27ndash33 2009

[144] R Reddy M Keshavan and J K Yao ldquoReduced plasma antiox-idants in first-episode patients with schizophreniardquo Schizophre-nia Research vol 62 no 3 pp 205ndash212 2003

[145] G L Bowman J Shannon B Frei J A Kaye and J F QuinnldquoUric acid as a CNS antioxidantrdquo Journal of Alzheimerrsquos Diseasevol 19 no 4 pp 1331ndash1336 2010

[146] T M Michel J Thome D Martin et al ldquoCu Zn- andMn-superoxide dismutase levels in brains of patients withschizophrenic psychosisrdquo Journal of Neural Transmission vol111 no 9 pp 1191ndash1201 2004

[147] A Ciobica M Padurariu I Dobrin C Stefanescu and RDobrin ldquoOxidative stress in schizophreniamdashfocusing on themainmarkersrdquoPsychiatriaDanubina vol 23 no 3 pp 237ndash2452011

[148] S Grignon and J M Chianetta ldquoAssessment of malondialde-hyde levels in schizophrenia ameta-analysis and somemethod-ological considerationsrdquoProgress inNeuro-Psychopharmacologyand Biological Psychiatry vol 31 no 2 pp 365ndash369 2007

[149] J D Morrow ldquoThe isoprostanesmdashunique products of arachi-donate peroxidation their role as mediators of oxidant stressrdquoCurrent Pharmaceutical Design vol 12 no 8 pp 895ndash902 2006

[150] A Dietrich-Muszalska B Olas R Głowacki and E BaldldquoOxidativenitrativemodifications of plasma proteins and thiolsfrom patients with schizophreniardquo Neuropsychobiology vol 59no 1 pp 1ndash7 2009

[151] A Jorgensen K Broedbaek A Fink-Jensen et al ldquoIncreasedsystemic oxidatively generated DNA and RNA damage inschizophreniardquo Psychiatry Research vol 209 no 3 pp 417ndash4232013

[152] D Malaspina R Dracxler J Walsh-Messinger et al ldquoTelomerelength family history and paternal age in schizophreniardquoMolecular Genetics amp Genomic Medicine vol 2 no 4 pp 326ndash331 2014

[153] L F Jarskog L A Glantz J H Gilmore and J A LiebermanldquoApoptotic mechanisms in the pathophysiology of schizophre-niardquo Progress in Neuro-Psychopharmacology and Biological Psy-chiatry vol 29 no 5 pp 846ndash858 2005

[154] L A Glantz J H Gilmore J A Lieberman and L FJarskog ldquoApoptotic mechanisms and the synaptic pathology ofschizophreniardquo Schizophrenia Research vol 81 no 1 pp 47ndash632006

[155] A Dietrich-Muszalska ldquoOxidative stress in schizophreniardquoin Studies on Psychiatric Disorders A Dietrich-Muszalska VChauhan and S Grignon Eds Humana Press NewYork NYUSA 2015

[156] O Pazvantoglu S Selek I T Okay et al ldquoOxidative mech-anisms in schizophrenia and their relationship with illnesssubtype and symptom profilerdquo Psychiatry and Clinical Neuro-sciences vol 63 no 5 pp 693ndash700 2009


[157] J M Loftis C J Wilhelm and M Huckans ldquoEffect of epigal-locatechin gallate supplementation in schizophrenia and bipo-lar disorder an 8-week randomized double-blind placebo-controlled studyrdquoTherapeutic Advances in Psychopharmacologyvol 3 no 1 pp 21ndash27 2013

[158] G Tsai D C Goff RWChang J Flood L Baer and J T CoyleldquoMarkers of glutamatergic neurotransmission and oxidativestress associated with tardive dyskinesiardquoTheAmerican Journalof Psychiatry vol 155 no 9 pp 1207ndash1213 1998

[159] M Bishnoi K Chopra and S K Kulkarni ldquoProtective effectof Curcumin the active principle of turmeric (Curcuma longa)in haloperidol-induced orofacial dyskinesia and associatedbehavioural biochemical and neurochemical changes in ratbrainrdquo Pharmacology Biochemistry and Behavior vol 88 no 4pp 511ndash522 2008

[160] P S Naidu and S K Kulkarni ldquoQuercefin a bioflavonoidreverses haloperidol-induced catalepsyrdquo Methods and Findingsin Experimental and Clinical Pharmacology vol 26 no 5 pp323ndash326 2004

[161] A Dietrich-Muszalska B Olas B Kontek and J Rabe-Jabłonska ldquoBeta-glucan fromSaccharomyces cerevisiae reducesplasma lipid peroxidation induced by haloperidolrdquo Interna-tional Journal of Biological Macromolecules vol 49 no 1 pp113ndash116 2011

[162] A Dietrich-Muszalska B Kontek B Olas and J Rabe-Jablonska ldquoEpicatechin inhibits human plasma lipid peroxida-tion caused by haloperidol in vitrordquo Neurochemical Researchvol 37 no 3 pp 557ndash562 2012

[163] A Dietrich-Muszalska J Kopka and B Kontek ldquoPolyphenolsfrom berries of Aronia melanocarpa reduce the plasma lipidperoxidation induced by Ziprasidonerdquo Schizophrenia Researchand Treatment vol 2014 Article ID 602390 7 pages 2014

[164] W-F Zhang Y-L Tan X-Y Zhang R C K Chan H-RWu and D-F Zhou ldquoExtract of Ginkgo biloba treatment fortardive dyskinesia in schizophrenia a randomized double-blind placebo-controlled trialrdquo Journal of Clinical Psychiatryvol 72 no 5 pp 615ndash621 2011

[165] P Suresh and A B Raju ldquoAntidopaminergic effects of leucineand genistein on shizophrenic rat modelsrdquo Neurosciences vol18 no 3 pp 235ndash241 2013

[166] I Tsilioni S Panagiotidou and T C Theoharides ldquoExosomesin Neurologic and Psychiatric Disordersrdquo Clinical Therapeutics2014

[167] P OrsquoDonnell K Q Do and C Arango ldquoOxidativenitrosativestress in psychiatric disorders are we there yetrdquo SchizophreniaBulletin vol 40 no 5 pp 960ndash962 2014

[168] L Pathak Y Agrawal and A Dhir ldquoNatural polyphenolsin the management of major depressionrdquo Expert Opinion onInvestigational Drugs vol 22 no 7 pp 863ndash880 2013

[169] J Sarris A C Logan T N Akbaraly et al ldquoNutritionalmedicine as mainstream in psychiatryrdquo The Lancet Psychiatry2015

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


O

A

B

345

6

78

Flavonoid basic structure

O

OH

Flavane-3-ol

O

OFlavanone

OHAnthocyanidin

O

O

OH

Flavone-3-ol

O

OFlavone

2998400

3998400

4998400

5998400

6998400

O+

Figure 1 Basic flavonoid structures

structural class of organic compounds characterized by thepresence of large multiples of phenol structural units Thesephenol structures underlie the unique physical chemical andbiological (metabolic toxic therapeutic etc) properties ofparticular members of the class The name derives from theancient Greek word 120587o120582 120592120589 (polus meaning ldquomany muchrdquo)and the word phenol which refers to a chemical structureformed by attaching a hydroxyl (ndashOH) group to an aromaticphenyl ring They are divided into three groups accordingto their hydrolytic cleavage products (i) tannins derivativesof catechin or gallic acid with mostly antioxidant properties[8] (ii) phenylpropane derivatives (lignans ellagitanninscinnamic acid derivatives and others) for example higherdietary intake of lignans is associated with better cognitivefunctions in postmenopausal women [9] or extract of ellag-itannins from oak wood reduced many of key symptomsof chronic fatigue [10] and (iii) flavonoids phenolic com-pounds spread in the plant kingdomThey includemore than4000 different derivatives and their list constantly increasesFormation of so many derivatives is possible due to thesubstitution of hydrogen atoms by hydroxyl methoxyl andother groups at different sites of the basic structures Thebasic flavonoid structures include the following flavan-3-ols (epicatechin and gallocatechin) flavanones (naringeninand hesperidin) flavones (apigenin and luteolin) flavone-3-ol (quercetin and myricetin) anthocyanidins (cyanidin andpelargonidin) and isoflavones (genistein and daidzein) [11](Figure 1)

Polyphenols occur in food (vegetables and fruits) eitheras free monomers (quercetin and catechin) or oligomers(procyanidins) They are bound to saccharides as glycosidesor occasionally they are found as free aglycones Afteringestion flavonoids can undergo biotransformation to theirmetabolites which can be detected in plasma reaching con-centration of about 1120583molsdotLminus1 [12 13]

Consumption of polyphenol-rich foods is associated witha lower incidence of coronary heart disease myocardialinfarction [14] cancer [15] neurodegenerative diseases [16]

psychiatric disorders (like ADHD) [17] and other chronicdiseases [18] Since in the pathology of these diseases inaddition to other factors oxidative stress has been assumedto play a role dietary flavonoids have been suggested toexert health benefits through antioxidant mechanisms Inexperiments in vitro flavonoids exert a significant antioxi-dant [8 19] and redox modulating [20] ability Polyphenolsact as strong antioxidants in vitro through the numerousmechanisms such as radical scavenging metal ions (Fe Cuand others) chelation and the modulation of antioxidantenzyme activities [8 21] In the scavenging ability the positionand the number of phenolic ndashOH groups play a role throughdonation of a hydrogen atom from their hydroxyl groupsto radicals resulting in radical moiety elimination Duringthis reaction phenoxyl radical is formed that can form stablecompound and terminates radical reaction via reaction withanother radical [20]

Upon consumption of food polyphenols are available inthe form of esters glycosides or polymers that cannot beabsorbed in the intestine The original molecules of polyphe-nolic compounds are hydrolyzed by microbial enzymes incolon and transformed via methylation sulfation and glu-curonidation to derivatives of original molecules followed bytheir absorption in the colon and travelling through bloodto various tissues and organs such as the brain Howeverdue to the diverse susceptibilities of phenolic compounds tocolon enzymemetabolism their bioavailability can vary fromvery low to very high [22 23] The low bioavailability andtransformation of polyphenolic compounds in vivo to differ-ent derivatives lead to their low direct antioxidant activity incomparison to other low-molecularweight antioxidants suchas vitamins C and E and uric acid [24]

However in addition to antioxidant activities polyphe-nols at low concentration can exert also other biologicaleffects in vivo Polyphenols can participate in modulationof different signaling pathways thus influencing the fateof cells [25] including nerve cells via influencing theneuronal survival regeneration development or death [26]












4 Major Depression








pathways




stress


neurodegeneration






Synapticcleft



NT

Vesicle with NT















































6 Schizophrenia




















7 Conclusions








Acknowledgments


References























































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























4 Major Depression








pathways




stress


neurodegeneration






Synapticcleft



NT

Vesicle with NT















































6 Schizophrenia




















7 Conclusions








Acknowledgments


References























































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















pathways




stress


neurodegeneration






Synapticcleft



NT

Vesicle with NT















































6 Schizophrenia




















7 Conclusions








Acknowledgments


References























































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























































6 Schizophrenia




















7 Conclusions








Acknowledgments


References























































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of













































6 Schizophrenia




















7 Conclusions








Acknowledgments


References























































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































6 Schizophrenia




















7 Conclusions








Acknowledgments


References























































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























6 Schizophrenia




















7 Conclusions








Acknowledgments


References























































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































7 Conclusions








Acknowledgments


References























































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























7 Conclusions








Acknowledgments


References























































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Acknowledgments


References























































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of








































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of







































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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Category:	Documents
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Review Article Psychiatric Disorders and Polyphenols: Can...

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