Advances in the Preclinical Study of Some Flavonoids as ...downloads.hindawi.com/journals/scientifica/2018/2963565.pdf · ReviewArticle Advances in the Preclinical Study of Some Flavonoids

Review ArticleAdvances in the Preclinical Study of Some Flavonoids asPotential Antidepressant Agents

Leoacuten Jesuacutes German-Ponciano1 Gilberto Uriel Rosas-Saacutenchez1

Eduardo Rivadeneyra-Domiacutenguez2 and Juan Francisco Rodriacuteguez-Landa 23

1Programa de Doctorado en Neuroetologıa Instituto de Neuroetologıa Universidad Veracruzana Xalapa VER Mexico2Facultad de Quımica Farmaceutica Biologica Universidad Veracruzana Xalapa VER Mexico3Laboratorio de Neurofarmacologıa Instituto de Neuroetologıa Universidad Veracruzana Xalapa VER Mexico

Correspondence should be addressed to Juan Francisco Rodrıguez-Landa juarodriguezuvmx

Received 25 August 2017 Revised 11 December 2017 Accepted 24 December 2017 Published 1 February 2018

Academic Editor Marie-Aleth Lacaille-Dubois

Copyright copy 2018 Leon Jesus German-Ponciano et al 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

Flavonoids are phenolic compounds found commonly in plants that protect them against the negative effects of environmentalinsultsThese secondarymetabolites have been widely studied in preclinical research because of their biological effects particularlyas antioxidant agents Diverse flavonoids have been studied to explore their potential therapeutic effects in the treatment ofdisorders of the central nervous system including anxiety and depression The present review discusses advances in the studyof some flavonoids as potential antidepressant agents We describe their behavioral physiological and neurochemical effects andthe apparent mechanism of action of their preclinical antidepressant-like effects Natural flavonoids produce antidepressant-likeeffects in validated behavioralmodels of depressionThemechanismof action of these effects includes the activation of serotonergicdopaminergic noradrenergic and 120574-aminobutyric acid-ergic neurotransmitter systems and an increase in the production ofneural factors including brain-derived neurotrophic factor and nerve growth factor Additionally alterations in the function oftropomyosin receptor kinase B and activity of the enzyme monoamine oxidase A have been reported In conclusion preclinicalresearch supports the potential antidepressant effects of some natural flavonoids which opens new possibilities of evaluating thesesubstances to develop complementary therapeutic alternatives that could ameliorate symptoms of depressive disorders in humans

1 Introduction

Depression is one of the most frequently diagnosed psy-chiatric disorders in the general population the symptomsof which negatively impact health and are associated withhigh financial costs [1] According to the World HealthOrganization depression will become the primary cause ofdisability by 2030 [2]

A wide variety of antidepressant drugs are availableto treat the symptoms of depression Such antidepressantsproduce their therapeutic effects through actions on diverseneurotransmitter systems including the serotonergic nora-drenergic and dopaminergic systems [3] The principal anti-depressant drugs are tricyclic antidepressants (eg clomi-pramine and imipramine) monoamine oxidase inhibitors(eg phenelzine and selegiline) selective serotonin reuptake

inhibitors (eg fluoxetine andfluvoxamine) selective dopam-ine reuptake inhibitors (eg amineptine and methylpheni-date) selective norepinephrine reuptake inhibitors (egreboxetine and viloxazine) and dual antidepressant drugs(eg venlafaxine and duloxetine) [4 5]

Most antidepressant drugs have a delayed onset of ther-apeutic actions and many have side effects when taken inthe long termThis has led patients to search for alternativesbased on the use of plantswith reputed antidepressant activity[6] An increasing number of studies have investigated natu-ral chemical compounds with potential antidepressant activ-ity [7] including bioactive metabolites such as flavonoidsthat exert multiple effects on the central nervous system [8]

Substantial preclinical evidence indicates that some fla-vonoids reduce behavioral endophenotypes of depression inanimal models by increasing the concentrations of different

HindawiScientificaVolume 2018 Article ID 2963565 14 pageshttpsdoiorg10115520182963565

2 Scientifica

A C

BO

2

345

6

78 1

2

3

4

5

6

Figure 1 Basic structure of flavonoids and the system of numera-tion A and B are phenyls and C corresponds to pyrene Numbersindicate the numeration system of the basic structure of flavonoids

neurotransmitters and expression of neurotrophic factors inthe brain [9 10] The present review focuses on the results ofpreclinical research that indicate the potential antidepressanteffects of some flavonoids and describes the mechanismsof action that are involved in these effects We proposefuture scientific research in the area of pharmacotherapyto develop safe and effective antidepressant drugs based onnatural products to ameliorate the symptoms of depressionin humans

2 Background on Flavonoids

Flavonoids are phenolic compounds that are widely dis-tributed in vascular plants Many chemical compounds bothin their free form and in the form of glycosides have beenevaluated to determine their biological activity [11] Morethan 5000 types of flavonoids have been identified which arestructurally different and possess a wide range of biologicalactivities Flavonoids are chemical compounds with a lowmolecular weight whose base structure (Figure 1) comprisesa system of rings of diphenyl pyrene or phenyl benzopyreneaccompanied by two variable groups of hydroxyl phenolicradicals [12]

According to the chemical structure of flavonoids (Fig-ure 2) they can be classified as flavonoids flavones fla-vanones isoflavones and anthocyanidins [62] Studies inmammals and in vitro have shown that flavonoids exertantioxidant antiallergic hepatoprotective antiviral anticar-cinogenic neuroprotective antitoxic anxiolytic antiepilep-tic estrogenic and antidepressant-like effects by inhibitingsome enzymes [63ndash66] which is dependent on the dose andtype of flavonoid administered

3 Flavonoid Metabolism

The daily dietary intake of flavonoids in humans is approx-imately 1-2 g per day principally depending on individualalimentary habits [67] Most flavonoids are found in plants inthe120573-glycoside form After intake the processes of hydrolysisoccur but since the union-120573 in these sugars is resistantto the hydrolysis produced by pancreatic enzymes thismetabolic process occurs in the intestinal lumen throughactions of the lactase phlorizin hydrolase that is locatedin the membrane of enterocytes When phlorizin hydro-lase hydrolyzes flavonoids they become capable of crossingintestinal membranes through passive diffusion Another

O

OH

O

O

OOH

O

O

O

O

O

OOH

Flavones Flavonols

Flavanones Flavan-3-ols

Flavanonol Isoflavones

Figure 2 General classification and basic structure of flavonoids

enzyme that facilitates the hydrolysis of flavonoids is cytosolic120573-glycosidase which hydrolyzes a high number of glycosides[68 69] Cytosolic 120573-glycosidase is located intracellularlyin erythrocytes therefore active transport is required tocross cellular membranes It is produced by sodium-glucosetransport protein which depends on sodium (SGLT-1) [69]

Hydrolyzed flavonoids (aglycones) are conjugatedthrough methylation sulphatation and glucuronidationBecause of their high conjugation hydrolyzed flavonoids aredetected in low concentrations in plasma [70] For examplehesperetin aglycone (the active form of the flavonoidhesperidin) is metabolized by the cytochrome isoforms P450CYP1A and CYP1B1 This first-pass metabolism principallyoccurs through intestinal cells [71] The metabolites ofhesperidinhesperetin are eliminated by renal route Theirmetabolites are found in urine but not feces suggesting thatthe high bacterial degradation of phenolic acids occurs at thelevel of the colon allowing passage to the systemic circulation[71] Particularly the elimination of the flavonoid chrysindepends on the outflow in which conjugated structuresare hydrolyzed through sulphatases and glucuronidasesin the intestine suggesting that chrysin has low intestinalabsorption in which it is detected in high concentrations infeces [72]

Some studies have shown that hydrolyzed flavonoids andtheir conjugated derivatives may cross the hematoencephalicbarrier and exert actions on the central nervous system [73]This may at least partially explain their multiple pharma-cological actions at the neuronal level that affect cognitionand emotional and affective states Numerous preclinicalstudies have shown that some flavonoids reduce depressive-like behavior and these effects are related to the activation ofneurotransmitter systems and trophic factors in the brain

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Table 1 Plants with antidepressant-like effects associated with their total flavonoids content

Plant (family) Doses (animal) Duration oftreatment Behavioral test Reference

Alpinia oxyphyllaMiq(Zingiberaceae)

10mgkgpo (A) 14 days FST SPT [13]

Hemerocallis citrina L(Xanthorrhoeaceae)

400mgkgpo (B) Single dose TST [14]

10 20 and 40mgkgpo (C) 35 days SPT [15]

Apocynum venetum Linn(Apocynaceae)

035mMkgip (B) Single dose FST TST [16]

Hibiscus esculentus L(Malvaceae)

500 and 750mgkgip (D) Single dose FST TST [17]

Apocynum venetum L(Apocynaceae)

50 and 100mgkgpo (E) 10 days FST TST [18]

Glycyrrhiza uralensis Fisch(Fabaceae)

30 100 and 300mgkgpo (F) 28 days FST TST [19 20]

Byrsonima crassifolia (L) Kunth(Malpighiaceae)

500mgkgpo (E) Single dose FST [21]

Cecropia pachystachya Trecul(Urticaceae)

50mgkgpo (G) 8 days FST [22]

Chrysactinia mexicana A Gray(Asteraceae)

1 5 10 100 and 200mgkgpo (H) Single dose FST [23]

Opuntia ficus-indica (L) Mill(Cactaceae)

30mgkgpo (E) 14 days FST TST [24]

Hibiscus rosa-sinensis Linn(Malvaceae)

30 and 100mgkgpo (C) Single dose FST TST [25]

Actaea spicata L(Ranunculaceae)

200mgkgpo (I) Single dose FST [26]

Clerodendrum serratum Linn(Verbenaceae)

25 and 50mgkgpo 7 days FST TST [27]

(A) Male Kunming mice (B) male mice (C) male Sprague-Dawley rats (D) male Swiss albino mice (E) male ICR mice (F) rats (G) male Wistar rats (H)male Swiss Webster mice (I) male LACA mice FST forced swim test TST tail suspension test SPT sucrose preference test

4 Antidepressant-Like Effects of Flavonoids inPlant Extracts

The treatment of depressive disorders is principally basedon the use of synthetic antidepressant drugs (eg tricyclicantidepressants selective serotonin reuptake inhibitors anddual-action antidepressants) that are clinically effective butproduce side effects A principal limiting factor in the useof antidepressant drugs is their delayed onset of therapeu-tic antidepressant effects Generally therapeutic effects inhumans occur after 2-3 weeks of treatment through neuronalplastic changes and the modification of neurotransmitterreceptors This process requires a relatively long time toproduce antidepressant effects [74 75] In the first weeks ofantidepressant treatment patients may experience a worsemood state compared with their state before the initiation ofpharmacological treatment [76] Patients have sought ther-apeutic alternatives to ameliorate symptoms of depressionInfusions or standardized extracts of plants have been usedfor the alternative treatment of depression [77] Howeverin most cases these alternative therapies have not beeninvestigated in systematic studies to support or refute theirpurported medicinal properties Such a dearth of studies can

pose a health risk to patients Preclinical studies have evalu-ated the effects of plant extracts that contain a high percentageof total flavonoids (Table 1) that produce antidepressant-likeeffects in animal models of depression through actions onneurotransmitter receptors and production of neurotrophicfactors in the brain [40]

Behavioral models (eg tail suspension test forcedswim test and chronic unpredictable mild stress [CUMS]paradigm) allow identification of the potential antidepres-sant effects of diverse natural substances as flavonoids [7879] among others Naringenin (10 20 and 50mgkg) anisoflavone isolated from citrus peel reduced total immobilitytime in the tail suspension test in male mice similar to theeffects of 20mgkg fluoxetine a clinically effective antide-pressant drug These effects were interpreted as potentialantidepressant-like effects [52] Interestingly this effect wasblocked by pretreatment with p-chlorophenylalanine methylester (100mgkg) and 120572-methyl-p-tyrosine (100mgkg)inhibitors of the synthesis of serotonin and norepinephrinerespectively [52] This suggests that the mechanism ofaction of naringenin involves the activation of serotonergicand noradrenergic neurotransmitter systems in the brainAdditionally 10 and 20mgkg naringenin increased the

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expression of brain-derived neurotrophic factor (BDNF) inthe hippocampus after 21 days of treatment in mice thatwere subjected to CUMS [28] which was associated withan antidepressant-like effect These results indicate that theantidepressant-like effect of naringenin may be mediatedby the activation of both neurotransmitter systems andneurotrophic factors Such mechanisms of action have alsobeen identified for other clinically effective antidepressantdrugs such as fluoxetine [80]

Park et al (2006) [81] found that a standardized extractof Cirsium japonicum Fisch ex DC (Asteraceae) producedantidepressant-like effects in male miceThis effect was repli-cated in subsequent studies that evaluated the antidepressant-like effect of an ethanolic extract of this plant at dosesof 50 100 200 and 400mgkg and its principal chemicalconstituents (ie linarin pectolinarin chlorogenic acid andluteolin) at doses of 10mgkg in the forced swim and openfield tests [30] The authors showed that the antidepressant-like effects of this plant extract were produced by theflavonoid luteolin through actions on the GABAA receptorSuchGABAA receptor activationhas also been involved in theantidepressant-like activity of other plantmetabolites [82 83]and some neurosteroids such as allopregnanolone [84ndash86]

In male Sprague-Dawley rats CUMS and an acute injec-tion of corticosterone were used to produce depression-like behavior The antidepressant-like effects of the flavonoidicariin (60mgkg) isolated from Epimedium brevicornumMaxim (Berberidaceae) on depression-like behavior pro-duced by CUMS or corticosterone injection were evaluatedin the forced swim test Corticosterone and CUMS increasedtotal immobility time reflecting despair-like behavior andreduced BDNF concentrations in the hippocampus Theseeffects were prevented by the administration of icariinflavonoid which was associated with the antidepressant-likeeffect [32]

A preclinical study of themethanolic extract ofByrsonimacrassifolia (L) Kunth (Malpighiaceae) at a dose of 500mgkgreported an antidepressant-like effect that was similar to theclinically effective antidepressant imipramine in albino ICRmice in the forced swim test The authors indicated thatthis antidepressant-like effect was attributable to flavonoidsin the extract [21] corresponding to quercetin (14mgkg)rutin (44mgkg) and hesperidin (07mgkg) which pro-duce antidepressant-like effects when they are individuallyinjected [9 54 87 88] Additionally it has been reportedthat the administration for 7 days of flavonoid quercetin(10 50 and 200mgkg po) decreases the 5-hydroxyindoleacetaldehyde productionmodulating the serotonergic systemby attenuating mitochondrial MAO-A activity in the brain[89] which is involved in the therapeutic effect of someantidepressant drugs

Oral administration of 25 50 and 100mgkg of astandardized aqueous extract referred to as Xiaobuxin-Tang which contains four different natural products (ieHaematitum Flos Inulae Folium Phyllostachydis Henonisand Semen Sojae Preparatum) reduced immobility timein both the forced swim and the tail suspension tests inlipopolysaccharide-treated ICR mice thus demonstratingan antidepressant-like effect Xiaobuxin-Tang also reduced

the levels of proinflammatory cytokines in the brain [90]apparently by its high content of flavonoids A reduction ofimmobility time in the forced swim test was also producedby acute or chronic administration of 30 100 and 300mgkgof aqueous [91] or ethanolic [92] extracts of Melissa offic-inalis L (Lamiaceae) This same effect was produced byits active metabolite rosmarinic acid (36mgkg) in maleSprague-Dawley rats [91] and the authors suggested that theantidepressant-like effect of this extract could be associatedwith its high content of rosmarinic acid which is able tomod-ulate the serotonergic system [91] However it is not possibleto discard the participation of other chemical constituents ofthe M officinalis extracts in their antidepressant-like effectsconsidering the high content in essential oils and flavonoidssuch as quercitrin apigenin and luteolin derivatives thatmay inhibit monoamine oxidases A (MAO-A) activity andinteract with the GABAA receptors [93] which also occurswith the majority of the conventional antidepressant drugs[94]

Glycyrrhiza uralensis Fisch (Fabaceae) is another plantwith potential antidepressant-like effects that are associatedwith its content of at least five flavonoids (ie liquir-itin liquiritigenin isoliquiritigenin isoononin and 741015840-dihydroxyflavone) An extract of this plant inhibited theproduction of tumor necrosis factor-120572 (TNF-120572) in microglialcells inmice [95]These findings are important because TNF-120572 has been detected in high concentrations in patients withanxiety and depression symptoms Therefore a reduction ofTNF-120572 could be beneficial for ameliorating symptoms of anx-iety and depression as is the case with other antidepressantagents The flavonoid isoliquiritigenin also inhibits TNF-120572and increases the concentration of BDNF in the hippocampusand cerebral cortex [95] Administration of the flavonoid 57-dihydroxyflavone (chrysin) at doses of 1 and 10mgkg for60 days increased BDNF concentrations in the hippocampusand prefrontal cortex [96] and produced antidepressant-likeeffects in the forced swim test in mice [10] These data arerelevant because higher plasma and brain concentrations ofBDNF were detected when clinically effective antidepressantdrugswere administered in experimental animals (for reviewsee [97]) and depressed patients (for review see [80])suggesting that flavonoids have a similar pharmacologicalprofile as conventional antidepressant drugs

Su et al (2014) [98] evaluated the effects of the Chineseherbal formula Xiao Chai Hu Tang which contains partsfrom plants described as Radix Bupleuri Chinensis RadixScutellariae Baicalensis ginseng RhizomaPinelliae TernataeRadix Glycyrrhiza Uralensis Rhizoma Zingiberis Recensand Fructus Jujubae This herbal preparation contains ahigh percentage of flavonoids glycosylated flavonoids andsaponins The authors tested the effects of administration of06 17 and 5mgkg for 4weeksThe extractwas administeredin male Sprague-Dawley rats subjected to CUMS and theeffects were evaluated in the open field test glucose pref-erence and consumption and food consumption were alsoevaluated The results showed that CUMS reduced glucosepreference and food consumption reflecting anhedoniawhich is a principal symptom in depressed patients Interest-ingly these deleterious effects ofCUMSwere prevented by the

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herbal preparation Xiao Chai Hu Tang which was associatedwith higher levels of BDNF nerve growth factor (NGF)and tropomyosin receptor kinase A (TrkA) and tropomyosinreceptor kinase B (TrkB) in the hippocampus [98]

Another study explored the effects of a standardizedextract used in traditional Chinese medicine This herbalpreparation Xiaobuxin-Tang includes Flos Inulae FoliumPhyllostachydis Henonis and Semen Sojae Preparatum andcontains a high percentage of flavonoids A dose of 100mgkgof this extract produced antidepressant-like effects in maleICR mice which were blocked by pretreatment with l-arginine (750mgkg) a precursor of nitric oxide synthesisCoadministration of 7-nitroindazole (50mgkg) an inhibitorof nitric oxide synthesis potentiated the action of anineffective dose of Xiaobuxin-Tang (50mgkg) to produceantidepressant-like effects [41] These findings suggest thatthe antidepressant-like effect of this extract involves nitricoxide signaling A similar mechanism has been reported forlamotrigine which also has antidepressant-like activity [99]

Apocynum venetum L (Apocynaceae) extract producesantidepressant-like effects in male CD rats subjected tothe forced swim test apparently by their high content ofhyperoside and isoquercitrin which are major flavonoids inthe extract [100] Different doses (25 50 and 100mgkg) of anApocynum venetum L extract that contained a high percent-age of flavonoids were also evaluated in male ICR mice [18]The 50 and 100mgkg doses significantly reduced immobilitytime in both the forced swim test and the tail suspension testwithout producing nonspecific effects on motor activity inthe open field test a typical effect of substances with antide-pressant activity [101] These antidepressant-like effects wereassociated with higher concentrations of norepinephrine anddopamine and their metabolites 34-dihydroxyphenylaceticacid (DOPAC) and homovanillic acid (HVA) respectivelyin the hippocampus Furthermore these antidepressant-likeeffects were blocked by pretreatment with the dopamineD1 receptor antagonist SCH23390 (005mgkg) and D23receptor antagonist sulpiride (50mgkg) [18] confirmingthat the antidepressant-like effects of Apocynum venetum Loccur through actions on the dopaminergic system Thismechanism of action is important because clinically effec-tive antidepressant drugs such as clomipramine (tricyclicantidepressant) and fluoxetine (selective serotonin reup-take inhibitor) activate the serotonergic and noradrenergicsystems in the long term and parallelly also activate themesolimbic dopamine system producing their antidepressanteffects [102ndash104]

The aforementioned data show that flavonoids and likelyother active metabolites that are contained in plant extractsmay contribute to the antidepressant-like effects of plantsthat are used in traditional medicine to ameliorate symp-toms of depression These beneficial effects appear to occurthrough the activation of neurotransmitter systems and otherneuronal processes The activation of neurotrophic factorssuch as BDNF significantly impacts neuronal functionThe activation of neurotransmitter systems (ie principallyserotonergic noradrenergic and dopaminergic) in specificbrain areas (eg hippocampus and prefrontal cortex) reac-tivates chemical communication in the long term thus

allowing plastic changes and subsequently the therapeuticeffects of antidepressant drugs [105] Preclinical research hasalso investigated the effects of specific flavonoids that areextracted from medicinal plants These flavonoids have beenpurified chemically characterized and prepared for adminis-tration Such efforts have allowed the identification of specificflavonoids that have potential antidepressant-like effects

5 Antidepressant-Like Effects ofFlavonoids Isolated from Plants

Flavonoids produce pharmacological actions on the centralnervous system (Table 2) to regulate emotional and moodstates associated with plastic and neurochemical changes asis the case with conventional antidepressant drugs [9 10 38101]

Preclinical studies have also reported the potentialantidepressant-like effects of specific flavonoids (Table 3)Hesperidin is a flavonoid that has different pharmacologicalactions (eg antioxidant antineoplastic and neuroprotectiveeffects) in vitro and in vivoThis flavonoid has been studied asa potential antidepressant agent because of its actions on theserotonergic dopaminergic and noradrenergic systems Theadministration of 01 03 and 1mgkg hesperidin (ip) for21 days in Swiss mice significantly reduced total immobilitytime in the tail suspension test This antidepressant-likeeffect was associated with a significant increase in BDNFconcentrations in the hippocampus [9] and actions at the5-HT1A receptors [106] Also the administration of 10 20and 40mgkg astilbin (ip) for 21 days inmaleC57BL6Lmiceexerted antidepressant-like effects in the forced swim test tailsuspension test and CUMS paradigm and these effects wereassociated with an increase in BDNF concentrations in thecerebral cortex These effects were similar to those producedby 10mgkg of the tricyclic antidepressant imipramine [34]

The behavioral and molecular effects of the flavonoidbaicalein (40mgkg ip for 14 days) were evaluated in maleSprague-Dawley rats Baicalein significantly reduced totalimmobility time similar to the antidepressant fluoxetinein the forced swim test This antidepressant-like effect wasassociated with activation of the dopaminergic system andgreater expression of BDNF mRNA in the hippocampus aneffect also detected with the antidepressant fluoxetine [35]In support injections of baicalein (1 2 and 4mgkg ipfor 21 days) in male Kunming mice subjected to CUMSreduced immobility time in the forced swim and tail sus-pension tests which was accompanied by an increase inextracellular signal-regulated kinase and BDNF expression inthe hippocampus similar to 15mgkg of the antidepressantimipramine [36]

Another flavonoid baicalin isolated from the driedroot of Scutellaria baicalensis Georgi (Labiatae) producesan antidepressant-like effect in the forced swim and tailsuspension tests in mice treated with 25 and 50mgkg poThis effect was similar to that produced by 20mgkg of theantidepressant fluoxetine Apparently the baicalin effect wasassociated with inhibition of monoamine oxidase enzymestypes A and B [107] a mechanism of action involved in thetherapeutic effect of some antidepressant drugs

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Table 2 Neurobiological effects produced by some flavonoids

Flavonoid Doses Treatmentduration Effects Reference

Naringenin5 10 and 20mgkg 21 days Increase in BDNF concentrations in the

hippocampus in male mice [28]

5 10 and 20mgkg 14 days Increase in 5-HT DA and NE in thehippocampus in male ICR mice [29]

Luteolin10mgkg 30 min before

testIncreases in chloride ion flow at the GABAAreceptor in male rats [30]

50mgkg 23 daysAttenuation of the expression of endoplasmicreticulum stress-related proteins in thehippocampus in male ICR mice

[31]

Icariin 60mgkg 21 days Increases in BDNF concentrations in thehippocampus in male rats [32]

Hesperidin001 01 03 and 1mgkg 21 days Increase in BDNF concentrations in the


50mgkg 13 days Increase in BDNF and NGF concentrations in thehippocampus in male C57BL6 mice [33]

Astilbin 10 20 and 40mgkg 21 days Increase in BDNF concentrations in the cerebralcortex in male mice similar to imipramine [34]

Baicalein

10 20 and 40mgkg 14 days Increase in dopamine and BDNF concentrationsin the hippocampus in male rats [35]

1 and 4mgkg Single injectionor 21 days

Restoring of the reduction of extracellularsignal-regulated kinase phosphorylation andBDNF expression in the hippocampus of maleKunming mice subjected to CUMS

[36]

Chrysin

5 and 20mgkg 28 daysIncrease in BDNF concentrations in thehippocampus and prefrontal cortex in femalemice

[10]

5 and 20mgkg 14 days Increase in 5-HT and BDNF concentrations in thehippocampus in male C57B6J mice [37]

Fisetin

5 10 and 20mgkg 60min beforetest

Activation of the serotonergic system apparentlythrough inactivation of MAO-A enzyme in malemice

[38]

5mgkg 14 days Increases in phosphorylated TrkB (pTrkB) in thehippocampus in male ICR mice [39]

Orientin 20 and 40mgkg 21 daysIncrease in BDNF serotonin and norepinephrineconcentrations in the hippocampus and prefrontalcortex in male mice

[40]

78-Dihydroxyflavone 1 3 and 10mgkg 60min beforetest

Increase in BDNF concentrations in thehippocampus and prefrontal cortex in male mice [41]

Icariin 20 and 40mgkg 35 daysDecrease in oxidative stress andneuroinflammation in the hippocampus in malerats

[42]

Dihydromyricetin 10 and 20mgkg 7 days Increase inmRNA for BDNF in the hippocampusin male C57BL6 mice [43]

Silymarin 100 and 200mgkg 14 daysIncrease in 5-HT DA NE and BDNFconcentration in the hippocampus and cerebralcortex similar to fluoxetine in adult Wistar rats

[44]

Myricitrin 10mgkg 21 daysIncreases in cell proliferation in the subgranularzone of the hippocampal dentate gyrus in maleBALBc mice

[45]

Myricetin 50mgkg 21 days Increases in BDNF concentrations in thehippocampus in male C57BL6 mice [46]

356783101584041015840-Heptamethoxyflavone 50 and 100mgkg 15 days

Increase in BDNF concentration neurogenesisand neuroplasticity in the hippocampus in maleC57BL6 mice

[47 48]

Scientifica 7

Table 2 Continued


Apigenin 20 and 40mgkg 21 days Increase in BDNF concentrations in thehippocampus in male ICR mice [49]

Miquelianin 06mgkg 14 days

Modulation of thehypothalamic-pituitary-adrenal axis by reducingplasma concentration of ACTH andcorticosterone in male CD rats

[50]

Isoquercitrin 06mgkg 14ndash56 days


[50]

Liquiritin andisoliquiritin 20mgkg 30min before

sampleIncreases in 5-HT and NE concentrations in thehippocampus hypothalamus and cortex in mice [51]

BDNF brain-derived neurotrophic factor NGF nerve growth factor MAO-A monoamine oxidase type A TrkB tropomyosin receptor kinase B 5-HTserotonin DA dopamine NE norepinephrine ACTH adrenocorticotropic hormone

The administration of 10 20 30mgkg of the flavonoidvitexin (po) also significantly reduced total immobilitytime in both the forced swim and the tail suspensiontests Interestingly animals treated with vitexin exhibiteda significant increase in the time spent climbing in theforced swim test [53] suggesting that activation of thenoradrenergic systemmay be involved in the antidepressant-like effect of this flavonoid A selective increase in the timespent climbing is only produced by antidepressant drugsthat act on the noradrenergic system [108] Injections of theserotonin 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4-(4-[2-phthalimido]butyl)-piperazine (NAN-190) ordopamine receptor antagonist SCH23390 blocked theantidepressant-like effect of vitexin [53] indicating thatthe antidepressant-like effects involve the activation of atleast three neurotransmitter systems (ie serotonergicnoradrenergic and dopaminergic) Similarly the flavonoidnobiletin (25 50 and 100mgkg po) isolated fromcitrus peels produces antidepressant-like effects in theforced swim and tail suspension tests in male ICR miceInterestingly these effects are blocked by previous injectionof WAY 100635 (a serotonin 5-HT1A receptor antagonist)cyproheptadine (a serotonin 5-HT2A receptor antagonist)prazosin (an 1205721-adrenoceptor antagonist) SCH23390 (adopamine D1 receptor antagonist) or sulpiride (a dopamineD2 receptor antagonist) showing that the antidepressant-likeeffect of nobiletin involves participation of serotonergicnoradrenergic and dopaminergic systems [109] as is thecase as well with bioflavonoid apigenin in several brainstructures [59] This multiple mechanism of action isunsurprising The administration of standardized herbalproducts or phytomedicines prepared with Hypericumperforatum L (Hypericaceae) extracts activates multipleneurotransmitter systems and produces both preclinicaland clinical antidepressant effects [110ndash112] However thesemultiple actions have been associated with some severe sideeffects [113] Further studies are necessary to explore themultiple actions of flavonoids in the brain under differentexperimental conditions (eg acute or chronic treatment) toidentify potential side effects to ensure consumer safety

Other flavonoids with antioxidant anti-inflammatoryand neuroprotective effects have also been evaluated aspotential antidepressant agents one example of which isthe flavonoid fisetin The administration of 10 and 20mgkgfisetin (ip) significantly reduced total immobility timein the forced swim and tail suspension tests [38] Thisantidepressant-like effect was apparently produced by acti-vation of the serotonergic system The blockade of sero-tonin synthesis by pretreatment with p-chlorophenylalanineblocked the antidepressant-like effect of fisetin This studyalso found that fisetin inhibited the activity of MAO-Awhich is involved in the metabolism of serotonin andnorepinephrine [38] Similarly to other flavonoids fisetinseems to exert its antidepressant-like effects through atleast two different mechanisms of action activating theserotonergic system and inhibiting monoamine metabolismHowever other neurotransmitter systems could be involvedin the antidepressant-like effect produced by flavonoidsTwo synthetic flavones 31015840-methoxy-6-methylflavone and 31015840-hydroxy-6-methylflavone in doses of 100mgkg ip pro-duce antidepressant-like effects in the forced swim andtail suspension tests similar to antidepressant imipramine[114] Interestingly the effect produced by both syntheticflavonoids was partially ameliorated by coadministration ofbicuculline (a competitive 120574-aminobutyric acid binding siteantagonist) suggesting the modulationdirect activation ofthe GABAA receptors as is the case with neurosteroids withantidepressant-like activity [85 86]

Depressive disorders are highly prevalent in diabeticpatients Using a preclinical model of diabetes that wasinduced by streptozotocin in mice the effects of the biofla-vonoid quercetin (50 and 100mgkg ip) were comparedwith fluoxetine (5mgkg ip) and imipramine (15mgkgip) in the forced swim test [115] Results showed thatquercetin significantly reduced depressive-like behavior indiabeticmice similar to the conventional antidepressants flu-oxetine and imipramine Interestingly the quercetin-inducedreduction of depressive-like behavior was only detected indiabetic mice and not in healthy mice while fluoxetineand imipramine produced antidepressant-like effects in both

8 ScientificaTa

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Mod

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depressio

nFlavon

oid(animal)

Doses

Treatm

entd

uration

Effect

Reference

Forced

swim

test1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Noeffect

[52]

Luteolin

(A)

10mgkgpo

30min

before

test

Antidepressant

[30]

50mgkgpo

23days

Antidepressant

[31]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Baicalein(B)

1020and40

mgkgip

14days

Antidepressant

[35]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Quercetin

(E)

50and100m

gkgip

21days

Antidepressant

[54]

40and80

mgkgpo

14days

Antidepressant

[55]

Quercetin

(I)

50mgkgip

21days

Antidepressant

[54]

Quercetin

(L)

25and50

mgkgpo

14days

Antidepressant

[56]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

13and10mgkgip

60min

before

test

Antidepressant

[41]

Isosakuranetin-5-O

-rutinoside(A)

15and30

mgkgpo

2118and1h

before

test

Antidepressant

[57]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Naringin(E)

50and100m

gkgip

14days

Antidepressant

[58]

Tailsuspensio

ntest1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Antidepressant

[52]

510and

20mgkgpo

14days

Antidepressant

[29]

Hesperid

in(H

)0103and1m

gkgip

21days

Antidepressant

[9]

Astilbin(G

)1020and40

mgkgip

21days

Antidepressant

[34]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

3and10mgkgip

60min

before

test

Antidepressant

[41]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

CUMS-sucroseintake2

Naringenin(A

)10

and20

mgkgpo

21days

Antidepressant

[28]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

Apigenin

(A)

7and14mgkgpo

49days

Antidepressant

[59]

78-D

ihydroxyflavone

(G)

10and20

mgkgip

28days

Antidepressant

[60]

Icariin

(B)

20and40

mgkgpo

35days

Antidepressant

[61]

1Th

eantidepressant-likee

ffectissuggestedby

ther

eductio

nin

immob

ilitytim

ewith

outsignificantchanges

intheg

enerallocomotor

activ

ity2Th


ffectissuggestedby

theincreaseinsucrose

intakeC

UMSchronicun

predictablemild

stress(A

)Adu

ltmaleICRmice(B)M

aleSprague-Daw

leyrats

(C)M

aleC5

7BL6J

mice(D

)Adu

ltmaleBA

LBc

mice(E)A

dultmaleWistar

rats

(F)A

dultmale

Kunm

ingmice(G

)Adu

ltmaleC

57BL

6mice(H

)Adu

ltmaleS

wiss

mice(I)M

ale2

1-day

streptozotocin-indu

ceddiabeticWistar

rats

(J)F

emaleC

57BL

6Jm

ice(K

)Mices

exandstr

ainweren

otidentifi

ed(L)

FemaleS

wiss

mice

Scientifica 9

diabetic and healthy mice In another study quercetin(50mgkg ip for 21 days) also exerted antidepressant-likeeffects in diabetic rats in the forced swim test These effectsdid not involve regulation of the hypothalamic-pituitary-adrenal axis in which this flavonoid did not produce sig-nificant changes in plasma adrenocorticotropic hormone orcorticosterone concentrations [54] These data suggest thatquercetin may have a mechanism of action that is differentfrom conventional antidepressants The antidepressant-likeeffects of quercetin have been suggested to primarily occurthrough antioxidative actions and a reduction of proinflam-matory cytokine concentrations in the brain [54] that in thelong term restore neurochemical function as is the case withconventional antidepressant drugs Future studies shouldexplore the ability of quercetin to ameliorate symptoms ofdepression particularly in diabetic patients

Finally studies of the neurobiological bases of depressivedisorders and mechanisms of action of antidepressant drugshave shown that reductions of neurotransmitter system activ-ity and BDNF concentrations are associated with depressivesymptoms in humans [116] and depression-like behavior instressor-exposed rats [42] A reduction of BDNF synthesishas been observed in the hippocampus and cerebral cortexamong other brain structures in experimental animalsAntidepressant drugs increase BDNFproduction in both ani-mals and depressed patients [97 117] suggesting a negativecorrelation between BDNF concentrations and the severityof depressive symptoms

Mice that are subjected to CUMS develop symptomsof anhedonia (eg a reduction of sucrose preference andconsumption) and depressive-like behavior (eg increase inimmobility time in the forced swim test) and these effectswere prevented by oral administration of 5 and 20mgkgof the flavonoid chrysin after 28 days of treatment Thisantidepressant-like effect of chrysin was accompanied byan increase in BDNF concentrations in the hippocampusand prefrontal cortex and the activation of NGF in mice[10] Additionally flavonoid chrysin (5 and 20mgkg po28 days) similar to antidepressant fluoxetine (10mgkg po28 days) increases serotonin concentration and reduces theindoleamine-23-dioxygenase and caspases 3 and 9 activi-ties in the prefrontal cortex and hippocampus in C57B6Jmice subjected to CUMS which was associated with theantidepressant-like effect detected in the tail suspensiontest [118] with the participation of BDNF Similarly theadministration of 20 and 40mgkg of the flavonoid orientinfor 21 days also produced antidepressant-like effects in micethat were subjected to CUMS and this effect was associatedwith the activation of BDNF and an increase in serotonin andnorepinephrine concentration in the hippocampus and cere-bral cortex [40]The administration of 20 and 40mgkg of theflavonoid icariin for 35 days also produced antidepressant-like effects in rats that were subjected to CUMS In that studycontrol animals presented significant neuronal damage andneuroinflammation in the hippocampus which were asso-ciated with higher oxidative stress These deleterious effectswere reversed by the administration of icariin at doses thatreduced depressive-like behavior [42] These studies suggest

that the antioxidant activity and the activation of monoamin-ergic systems are associated with the production of BDNFby flavonoids [119] ultimately producing antidepressant-likeeffects in animals However this hypothesis requires furtherexploration

6 Concluding Remarks

Preclinical data on the antidepressant-like effects of someflavonoids have consistently reported behavioral effects andneurochemical actions in the brain thus supporting thepotential therapeutic application of these natural compoundsfor the amelioration of depressive symptoms in humansThe data that were reviewed herein implicate BDNF in theantidepressant-like effects of flavonoids This mechanism ofaction is relevant because it has been associated with theactions of clinically effective antidepressant drugs [80 120]BDNFmodulates neurotransmitters and receptor activity andis involved in the activation of serotonergic noradrenergicand dopaminergic pathways and neurogenesis in the hip-pocampus and cerebral cortex which are implicated in theneurobiology of psychiatric disorders including depression

Activation of BDNF and TrkB is produced after admin-istration of conventional antidepressant drugs such as flu-oxetine and citalopram [28 101 121] which is associatedwith the reduction of most of the symptoms of depression[97 122ndash124] Some flavonoids (eg 78-dihydroxyflavone)also act as TrkB receptor agonists and stimulate neurogenesisin the hippocampus [41] Such findings may reveal newpossibilities for the development of therapeutic alternativesfor the treatment of depression including the administrationof subthreshold doses of flavonoids combined with con-ventional antidepressant drugs Combined administrationof both substances could likely produce antidepressant-likeeffects with a shorter onset of action through the earlystimulation of BDNF production and parallelly modify theneurotransmitter receptor function which requires furtherexploration

Finally despite the positive findings regarding theantidepressant-like effects of some flavonoids at the preclin-ical level potential side effects of long-term consumptionneed to be investigated including studies of toxicology andpossible pharmacological interactions with other substancesto determine the tolerability and safety of flavonoids inhumans Such studies may eventually demonstrate that someflavonoids are safe alternatives for the treatment of depressivedisorders in clinical practice

Conflicts of Interest

The authors declare that there are no conflicts of interest

Acknowledgments

The authors would like to thank Michel Arends for revis-ing and editing the English of this manuscript LeonJesus German-Ponciano and Gilberto Uriel Rosas-Sanchezreceived fellowships from Consejo Nacional de Ciencia yTecnologıa (CONACyT) for postgraduate studies in neu-roethology (Reg nos 297560 and 592165 resp)

10 Scientifica

References

[1] R C Kessler ldquoThe costs of depressionrdquo Psychiatric Clinics ofNorth America vol 35 no 1 pp 1ndash14 2014

[2] WorldHealthOrganization ldquoGlobal burden ofmental disordersand the need for a comprehensive coordinated responsefrom health and social sectors at the country level report bythe SecretariatrdquoWorldHealthOrganizationGeneva Switzerland2011 httpappswhointgbebwhapdf filesEB130B130 R8-enpdf

[3] C J Harmer R S Duman and P J Cowen ldquoHow do antide-pressants work New perspectives for refining future treatmentapproachesrdquo The Lancet Psychiatry vol 4 no 5 pp 409ndash4182017

[4] Y Xing J He J Hou F Lin J Tian and H Kurihara ldquoGenderdifferences in CMS and the effects of antidepressant venlafaxinein ratsrdquo Neurochemistry International vol 63 no 6 pp 570ndash575 2013

[5] M Olivares-Nazario A Fernandez-Guasti and L Martınez-Mota ldquoAge-related changes in the antidepressant-like effectof desipramine and fluoxetine in the rat forced-swim testrdquoBehavioural Pharmacology vol 27 no 1 pp 22ndash28 2016

[6] C Lopez-Rubalcava and E Estrada-Camarena ldquoMexicanmedicinal plants with anxiolytic or antidepressant activityFocus on preclinical researchrdquo Journal of Ethnopharmacologyvol 186 pp 377ndash391 2016

[7] F Ferre Navarrete and D Gimeno Alvarez ldquoProtocolo diag-nostico y tratamiento de la ansiedad generalizadardquo Medicine -Programa de Formacion Medica Continuada Acreditado vol 10no 86 pp 5846ndash5850 2011

[8] I Matias A S Buosi and F C A Gomes ldquoFunctions offlavonoids in the central nervous system Astrocytes as targetsfor natural compoundsrdquo Neurochemistry International vol 95pp 85ndash91 2016

[9] F Donato M G de Gomes A T R Goes et al ldquoHesperidinexerts antidepressant-like effects in acute and chronic treat-ments in mice Possible role of l-arginine-NO-cGMP pathwayand BDNF levelsrdquo Brain Research Bulletin vol 104 pp 19ndash262014

[10] C B Filho C R Jesse F Donato et al ldquoChronic unpredictablemild stress decreases BDNF and NGF levels and Na+K+-ATPase activity in the hippocampus and prefrontal cortex ofmice antidepressant effect of chrysinrdquo Neuroscience vol 289pp 367ndash380 2015

[11] J B Harborne and C A Williams ldquoAdvances in flavonoidresearch since 1992rdquo Phytochemistry vol 55 no 6 pp 481ndash5042000

[12] S Martınez-Florez J Gonzalez-Gallego J M Culebras andM J Tunon ldquoLos flavonoides propiedades y acciones antiox-idantesrdquoNutricion Hospitalaria vol 17 no 6 pp 271ndash278 2002

[13] T Yan B Wu Z-Z Liao et al ldquoBrain-derived neurotrophicfactor signaling mediates the antidepressant-like effect of thetotal flavonoids of Alpiniae oxyphyllae fructus in chronicunpredictable mild stress micerdquo Phytotherapy Research vol 30no 9 pp 1493ndash1502 2016

[14] B Du C Zhang F Ren et al ldquoAntidepressant-like effectsof the hydroalcoholic extracts of Hemerocallis Citrina andits potential active componentsrdquo BMC Complementary andAlternative Medicine vol 14 no 1 p 326 2014

[15] P Xu K Z Wang C Lu et al ldquoAntidepressant-like effects andcognitive enhancement of the total phenols extract of Heme-rocallis citrina Baroni in chronic unpredictable mild stress rats

and its related mechanismrdquo Journal of Ethnopharmacology vol194 pp 819ndash826 2016

[16] S-X Yan J-L Lang Y-Y Song et al ldquoStudies on anti-depressant activity of four flavonoids isolated from Apocynumvenetum linn (Apocynaceae) leaf in micerdquo Tropical Journal ofPharmaceutical Research vol 14 no 12 pp 2269ndash2277 2015

[17] M A Ebrahimzadeh S M Nabavi and S F Nabavi ldquoAntide-pressant activity of Hibiscus esculentus Lrdquo European Review forMedical and Pharmacological Sciences vol 17 no 19 pp 2609ndash2612 2013

[18] M Zheng Y Fan D Shi and C Liu ldquoAntidepressant-like effectof flavonoids extracted from Apocynum venetum leaves onbrain monoamine levels and dopaminergic systemrdquo Journal ofEthnopharmacology vol 147 no 1 pp 108ndash113 2013

[19] Z Z Fan W H Zhao J Guo et al ldquoAntidepressant activitiesof flavonoids from Glycyrrhiza uralensis and its neurogenesisprotective effect in ratsrdquo Acta Pharmaceutica Sciencia vol 47no 12 pp 1612ndash1617 2012

[20] G Jia Z Weihong F Zizhou et al ldquoEffects of the flavonoidsextracted parts on antidepressant activities from Glycyrrhizauralensisrdquo Pharmacology andClinics of ChineseMateriaMedicavol 6 p 20 2012

[21] M Herrera-Ruiz A Zamilpa M Gonzalez-Cortazar et alldquoAntidepressant effect and pharmacological evaluation of stan-dardized extract of flavonoids from Byrsonima crassifoliardquoPhytomedicine vol 18 no 14 pp 1255ndash1261 2011

[22] C F Ortmann G Z Reus Z M Ignacio et al ldquoEnrichedflavonoid fraction from cecropia pachystachya trecul leavesexerts antidepressant-like behavior and protects brain againstoxidative stress in rats subjected to chronic mild stressrdquo Neuro-toxicity Research vol 29 no 4 pp 469ndash483 2016

[23] J Cassani O A Ferreyra-Cruz A M Dorantes-Barron RM Vigueras Villasenor D Arrieta-Baez and R Estrada-ReyesldquoAntidepressant-like and toxicological effects of a standardizedaqueous extract of Chrysactinia mexicana A Gray (Asteraceae)in micerdquo Journal of Ethnopharmacology vol 171 pp 295ndash3062015

[24] S Park Y Sim P Han J Lee and H Suh ldquoAntidepressant-like effect of kaempferol and quercitirin isolated from Opuntiaficus-indica varSabotenrdquoExperimentalNeurobiology vol 19 no1 p 30 2010

[25] P B Shewale R A Patil and Y A Hiray ldquoAntidepressant-likeactivity of anthocyanidins from Hibiscus rosa-sinensis flowersin tail suspension test and forced swim testrdquo Indian Journal ofPharmacology vol 44 no 4 pp 454ndash457 2012

[26] S Batra and S Kumar ldquoAntidepressant activity evaluation ofActaea spicata L Rootsrdquo Journal of Fundamental Pharmaceu-tical Research vol 2 no 1 pp 1ndash6 2014

[27] B K Vazhayil S S Rajagopal T Thangavelu G Swaminathanand E Rajagounder ldquoNeuroprotective effect of Clerodendrumserratum Linn leaves extract against acute restraint stress-induced depressive-like behavioral symptoms in adult micerdquoIndian Journal of Pharmacology vol 49 no 1 pp 34ndash41 2017

[28] L-T Yi B-B Liu J Li et al ldquoBDNF signaling is necessary forthe antidepressant-like effect of naringeninrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 48 pp 135ndash141 2014

[29] L-T Yi J Li H-C Li et al ldquoAntidepressant-like behavioralneurochemical and neuroendocrine effects of naringenin inthe mouse repeated tail suspension testrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 39 no 1 pp175ndash181 2012

Scientifica 11

[30] J B I De La Pena C A Kim H L Lee et al ldquoLuteolinmediatesthe antidepressant-like effects of Cirsium japonicum in micepossibly through modulation of the GABAA receptorrdquo Archivesof Pharmacal Research vol 37 no 2 pp 263ndash269 2014

[31] M Ishisaka K Kakefuda M Yamauchi et al ldquoLuteolin showsan antidepressant-like effect via suppressing endoplasmic retic-ulum stressrdquo Biological amp Pharmaceutical Bulletin vol 34 no 9pp 1481ndash1486 2011

[32] M-J Gong B Han S-M Wang S-W Liang and Z-J ZouldquoIcariin reverses corticosterone-induced depression-like behav-ior decrease in hippocampal brain-derived neurotrophic factor(BDNF) andmetabolic network disturbances revealed byNMR-based metabonomics in ratsrdquo Journal of Pharmaceutical andBiomedical Analysis vol 123 pp 63ndash73 2016

[33] M S Antunes C R Jesse J R Ruff et al ldquoHesperidin reversescognitive and depressive disturbances induced by olfactorybulbectomy inmice bymodulating hippocampal neurotrophinsand cytokine levels and acetylcholinesterase activityrdquo EuropeanJournal of Pharmacology vol 789 pp 411ndash420 2016

[34] Q-Q Lv W-J Wu X-L Guo et al ldquoAntidepressant activity ofastilbin Involvement of monoaminergic neurotransmitters andBDNF signal pathwayrdquo Biological amp Pharmaceutical Bulletinvol 37 no 6 pp 987ndash995 2014

[35] B Lee B Sur J Park et al ldquoChronic administrationof baicalein decreases depression-like behavior induced byrepeated restraint stress in ratsrdquo Korean Journal of Physiologyamp Pharmacology vol 17 no 5 pp 393ndash403 2013

[36] Z Xiong B Jiang P-F Wu et al ldquoAntidepressant effectsof a plant-derived flavonoid baicalein involving extracellularsignal-regulated kinases cascaderdquo Biological amp PharmaceuticalBulletin vol 34 no 2 pp 253ndash259 2011

[37] C B Filho C R Jesse FDonato et al ldquoChrysin promotes atten-uation of depressive-like behavior and hippocampal dysfunc-tion resulting from olfactory bulbectomy in micerdquo Chemico-Biological Interactions vol 260 pp 154ndash162 2016

[38] L Zhen J Zhu X Zhao et al ldquoThe antidepressant-like effectof fisetin involves the serotonergic and noradrenergic systemrdquoBehavioural Brain Research vol 228 no 2 pp 359ndash366 2012

[39] Y Wang B Wang J Lu et al ldquoFisetin provides antidepressanteffects by activating the tropomyosin receptor kinase B signalpathway in micerdquo Journal of Neurochemistry vol 143 no 5 pp561ndash568 2017

[40] Y Liu N Lan J Ren et al ldquoOrientin improves depression-like behavior and BDNF in chronic stressed micerdquo MolecularNutrition amp Food Research vol 59 no 6 pp 1130ndash1142 2015

[41] L-M Zhang H-LWang N Zhao H-X Chen Y-F Li and Y-Z Zhang ldquoInvolvement of nitric oxide (NO) signaling pathwayin the antidepressant action of the total flavonoids extractedfrom Xiaobuxin-TangrdquoNeuroscience Letters vol 575 pp 31ndash362014

[42] B Liu C Xu XWu et al ldquoIcariin exerts an antidepressant effectin an unpredictable chronic mild stress model of depressionin rats and is associated with the regulation of hippocampalneuroinflammationrdquo Neuroscience vol 294 pp 193ndash205 2015

[43] Z Ren P Yan L Zhu et al ldquoDihydromyricetin exerts a rapidantidepressant-like effect in association with enhancementof BDNF expression and inhibition of neuroinflammationrdquoPsychopharmacology vol 235 no 1 pp 233ndash244 2018

[44] V N Thakare M K Aswar Y P Kulkani R R Patil andB M Patel ldquoSilymarin ameliorates experimentally induceddepressive like behavior in rats Involvement of hippocampal

BDNF signaling inflammatory cytokines and oxidative stressresponserdquo Physiology Behavior vol 179 pp 401ndash410 2017

[45] E Meyer M A Mori A C Campos et al ldquoMyricitrin inducesantidepressant-like effects and facilitates adult neurogenesis inmicerdquo Behavioural Brain Research vol 316 pp 59ndash65 2017

[46] Z Ma G Wang L Cui and Q Wang ldquoMyricetin attenuatesdepressant-like behavior in mice subjected to repeated restraintstressrdquo International Journal of Molecular Sciences vol 16 no12 pp 28377ndash28385 2015

[47] A Sawamoto S Okuyama K Yamamoto et al ldquo356783141-Heptamethoxyflavone a citrus flavonoid Ameliorates corti-costerone-induced depression-like behavior and restores brain-derived neurotrophic factor expression neurogenesis and neu-roplasticity in the hippocampusrdquoMolecules vol 21 no 4 articleno 541 2016

[48] A Sawamoto S Okuyama Y Amakura et al ldquo356783101584041015840-Heptamethoxyflavone ameliorates depressive-like behavior andhippocampal neurochemical changes in chronic unpredictablemild stressed mice by regulating the brain-derived neu-rotrophic factor requirement for erk activationrdquo InternationalJournal of Molecular Sciences vol 18 no 10 p 2133 2017

[49] L Weng X Guo Y Li X Yang and Y Han ldquoApigenin reversesdepression-like behavior induced by chronic corticosteronetreatment in micerdquo European Journal of Pharmacology vol 774pp 50ndash54 2016

[50] V ButterweckMHegger andHWinterhoff ldquoFlavonoids of StJohnrsquosWort reduceHPA axis function in the ratrdquo PlantaMedicavol 70 no 10 pp 1008ndash1011 2004

[51] W Wang X Hu Z Zhao et al ldquoAntidepressant-like effectsof liquiritin and isoliquiritin from Glycyrrhiza uralensis in theforced swimming test and tail suspension test in micerdquo Progressin Neuro-Psychopharmacology amp Biological Psychiatry vol 32no 5 pp 1179ndash1184 2008

[52] L-T Yi C-F Li X Zhan et al ldquoInvolvement of monoamin-ergic system in the antidepressant-like effect of the flavonoidnaringenin in micerdquo Progress in Neuro-Psychopharmacology ampBiological Psychiatry vol 34 no 7 pp 1223ndash1228 2010

[53] O D Can U Demir Ozkay and U I Ucel ldquoAnti-depressant-like effect of vitexin in BALBc mice and evidence for theinvolvement of monoaminergic mechanismsrdquo European Jour-nal of Pharmacology vol 699 no 1-3 pp 250ndash257 2013

[54] E A Demir H S Gergerlioglu and M Oz ldquoAntidepressant-like effects of quercetin in diabetic rats are independent ofhypothalamic-pituitary-adrenal axisrdquo Acta Neuropsychiatricavol 28 no 1 pp 23ndash30 2016

[55] P Rinwa and A Kumar ldquoQuercetin suppress microglial neu-roinflammatory response and induce antidepressent-like effectin olfactory bulbectomized ratsrdquoNeuroscience vol 255 pp 86ndash98 2013

[56] I Holzmann L M Da Silva J A Correa Da Silva V M BSteimbach and M M De Souza ldquoAntidepressant-like effectof quercetin in bulbectomized mice and involvement of theantioxidant defenses and the glutamatergic and oxidonitrergicpathwaysrdquo Pharmacology Biochemistry amp Behavior vol 136 pp55ndash63 2015

[57] M Gonzalez-Cortazar A M Maldonado-Abarca E Jimenez-Ferrer et al ldquoIsosakuranetin-5-O-rutinoside ANew Flavanonewith Antidepressant Activity Isolated from Salvia elegans VahlrdquoMolecules vol 18 no 11 pp 13260ndash13270 2013

[58] M Kwatra A Jangra M Mishra et al ldquoNaringin andsertraline ameliorate doxorubicin-induced behavioral deficits

12 Scientifica

throughmodulation of serotonin level andmitochondrial com-plexes protection pathway in rat hippocampusrdquo NeurochemicalResearch vol 41 no 9 pp 2352ndash2366 2016

[59] L-T Yi J-M Li Y-C Li Y Pan Q Xu and L-D KongldquoAntidepressant-like behavioral and neurochemical effects ofthe citrus-associated chemical apigeninrdquo Life Sciences vol 82no 13-14 pp 741ndash751 2008

[60] M-W Zhang S-F Zhang Z-H Li and F Han ldquo78-Dihydroxyflavone reverses the depressive symptoms in mousechronic mild stressrdquo Neuroscience Letters vol 635 pp 33ndash382016

[61] K Wei Y Xu Z Zhao et al ldquoIcariin alters the expressionof glucocorticoid receptor FKBP5 and SGK1 in rat brainsfollowing exposure to chronicmild stressrdquo International Journalof Molecular Medicine vol 38 no 1 pp 337ndash344 2016

[62] S P Fernandez C Wasowski L M Loscalzo et al ldquoCentralnervous system depressant action of flavonoid glycosidesrdquoEuropean Journal of Pharmacology vol 539 no 3 pp 168ndash1762006

[63] A C Paladini M Marder H Viola C Wolfman C Wasowskiand J H Medina ldquoFlavonoids and the central nervous systemFrom forgotten factors to potent anxiolytic compoundsrdquo Jour-nal of Pharmacy and Pharmacology vol 51 no 5 pp 519ndash5261999

[64] E Middleton Jr C Kandaswami and T C Theoharides ldquoTheeffects of plant flavonoids on mammalian cells implicationsfor inflammation heart disease and cancerrdquo PharmacologicalReviews vol 52 no 4 pp 673ndash751 2000

[65] S F Nabavi N Braidy S Habtemariam et al ldquoNeuroprotectiveeffects of chrysin from chemistry to medicinerdquoNeurochemistryInternational vol 90 pp 224ndash231 2015

[66] M Bakhtiari Y Panahi J Ameli and B Darvishi ldquoProtectiveeffects of flavonoids against Alzheimerrsquos disease-related neuraldysfunctionsrdquo Biomedicine amp Pharmacotherapy vol 93 pp218ndash229 2017

[67] M Ebadi Pharmacodynamic Basis of Herbal Medicine CRCPress Florida FLa USA 2001

[68] J-G Berrin W R McLauchlan P Needs et al ldquoFunctionalexpression of human liver cytosolic 120573-glucosidase in Pichiapastoris Insights into its role in the metabolism of dietaryglucosidesrdquo European Journal of Biochemistry vol 269 no 1 pp249ndash258 2002

[69] K Nemeth GW Plumb J-G Berrin et al ldquoDeglycosylation bysmall intestinal epithelial cell 120573-glucosidases is a critical step inthe absorption and metabolism of dietary flavonoid glycosidesin humansrdquo European Journal of Nutrition vol 42 no 1 pp 29ndash42 2003

[70] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo American Jour-nal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004

[71] A Roohbakhsh H Parhiz F Soltani R Rezaee and MIranshahi ldquoNeuropharmacological properties and pharmacoki-netics of the citrus flavonoids hesperidin and hesperetin - Amini-reviewrdquo Life Sciences vol 113 no 1-2 pp 1ndash6 2014

[72] U K Walle A Galijatovic and T Walle ldquoTransport of theflavonoid chrysin and its conjugated metabolites by the humanintestinal cell line Caco-2rdquo Biochemical Pharmacology vol 58no 3 pp 431ndash438 1999

[73] A G de Boer and P J Gaillard ldquoDrug targeting to the brainrdquoAnnual Review of Pharmacology and Toxicology vol 47 no 1pp 323ndash355 2007

[74] I Mendez-David L Tritschler Z El Ali et al ldquoNrf2-signalingand BDNF A new target for the antidepressant-like activityof chronic fluoxetine treatment in a mouse model of anxi-etydepressionrdquoNeuroscience Letters vol 597 pp 121ndash126 2015

[75] R Ghosh R Gupta M S Bhatia A K Tripathi and L KGupta ldquoComparison of efficacy safety and brain derived neu-rotrophic factor (BDNF) levels in patients of major depressivedisorder treated with fluoxetine and desvenlafaxinerdquo AsianJournal of Psychiatry vol 18 pp 37ndash41 2015

[76] H H Stassen J Angst and A Delini-Stula ldquoDelayed onsetof action of antidepressant drugs Survey of recent resultsrdquoEuropean Psychiatry vol 12 no 4 pp 166ndash176 1997

[77] J Sarris and D J Kavanagh ldquoKava and St Johnrsquos wort Currentevidence for use in mood and anxiety disordersrdquo The Journalof Alternative and Complementary Medicine vol 15 no 8 pp827ndash836 2009

[78] Q Wang M A Timberlake K Prall and Y Dwivedi ldquoTherecent progress in animal models of depressionrdquo Progress inNeuro-Psychopharmacology amp Biological Psychiatry vol 77 pp99ndash109 2017

[79] H M Abelaira G Z Reus and J Quevedo ldquoAnimal modelsas tools to study the pathophysiology of depressionrdquo RevistaBrasileira de Psiquiatria vol 35 no 2 pp S112ndashS120 2013

[80] C Zhou J Zhong B Zou et al ldquoMeta-analyses of comparativeefficacy of antidepressant medications on peripheral BDNFconcentration in patients with depressionrdquo PLoS ONE vol 12no 2 Article ID e0172270 2017

[81] H Park S Yoon J Choi et al ldquoThe antidepressant effects ofCirsium japonicum in ICR micerdquo Yakhak Hoeji vol 50 no 6pp 429ndash435 2006

[82] A Abdelhalim N Karim M Chebib et al ldquoAntidepressantanxiolytic and antinociceptive activities of constituents fromrosmarinus officinalisrdquo Journal of Pharmacy amp PharmaceuticalSciences vol 18 no 4 pp 448ndash459 2015

[83] M Lin H Li Y Zhao et al ldquoErgosteryl 2-naphthoate anergosterol derivative exhibits antidepressant effects mediatedby the modification of GABAergic and glutamatergic systemsrdquoMolecules vol 22 no 4 article no 565 2017

[84] R T Khisti C T Chopde and S P Jain ldquoAntidepressant-likeeffect of the neurosteroid 3120572-hydroxy-5120572-pregnan-20-one inmice forced swim testrdquo Pharmacology Biochemistry amp Behaviorvol 67 no 1 pp 137ndash143 2000

[85] J F Rodrıguez-Landa C M Contreras B Bernal-MoralesA G Gutierrez-Garcıa and M Saavedra ldquoAllopregnanolonereduces immobility in the forced swimming test and increasesthe firing rate of lateral septal neurons through actions on theGABA119860 receptor in the ratrdquo Journal of Psychopharmacology vol21 no 1 pp 76ndash84 2007

[86] J F Rodrıguez-Landa C M Contreras and R I Garcıa-RıosldquoAllopregnanolone microinjected into the lateral septum ordorsal hippocampus reduces immobility in the forced swim testParticipation of the GABAA receptorrdquo Behavioural Pharmacol-ogy vol 20 no 7 pp 614ndash622 2009

[87] D G Machado L E B Bettio M P Cunha et alldquoAntidepressant-like effect of rutin isolated from the ethanolicextract from Schinus molle L in mice Evidence for theinvolvement of the serotonergic and noradrenergic systemsrdquoEuropean Journal of Pharmacology vol 587 no 1-3 pp 163ndash1682008

[88] A Paulke M Noldner M Schubert-Zsilavecz and M Wur-glics ldquoSt Johnrsquos wort flavonoids and their metabolites show

Scientifica 13

antidepressant activity and accumulate in brain after multipleoral dosesrdquo Die Pharmazie vol 63 no 4 pp 296ndash302 2008

[89] S Yoshino AHaraH Sakakibara et al ldquoEffect of quercetin andglucuronidemetabolites on themonoamine oxidase-A reactionin mouse brain mitochondriardquo Nutrition Journal vol 27 no 7-8 pp 847ndash852 2011

[90] L An J Li S-T Yu et al ldquoEffects of the total flavonoidextract of Xiaobuxin-Tang on depression-like behavior inducedby lipopolysaccharide and proinflammatory cytokine levels inmicerdquo Journal of Ethnopharmacology vol 163 pp 83ndash87 2015

[91] S-H Lin M-L Chou W-C Chen et al ldquoA medicinal herbMelissa officinalis L ameliorates depressive-like behavior of ratsin the forced swimming test via regulating the serotonergic neu-rotransmitterrdquo Journal of Ethnopharmacology vol 175 articleno 9741 pp 266ndash272 2015

[92] A E Taiwo F B Leite G M Lucena et al ldquoAnxiolytic andantidepressant-like effects of Melissa officinalis (lemon balm)extract in rats Influence of administration and genderrdquo IndianJournal of Pharmacology vol 44 no 2 pp 189ndash192 2012

[93] V Lopez S Martın M P Gomez-Serranillos M E CarreteroA K Jager and M I Calvo ldquoNeuroprotective and neurologicalproperties of Melissa officinalisrdquo Neurochemical Research vol34 no 11 pp 1955ndash1961 2009

[94] G Rubio L San F Lopez-Munoz and P Garcıa-GarcıaldquoTratamiento de combinacion con reboxetina en pacientes condepresion mayor no respondedores o con respuesta parcial ainhibidores selectivos de la recaptacion de serotoninardquo ActasEspanolas de Psiquiatria vol 31 no 6 pp 315ndash324 2003

[95] S P Patil C Liu J Alban N Yang and X Li ldquoGlycyrrhizauralensis flavonoids inhibit brain microglial cell TNF-120572 secre-tion p-I120581B expression and increase brain-derived neurotropicfactor (BDNF) secretionrdquo Journal of Traditional ChineseMedicalSciences vol 1 no 1 pp 28ndash37 2014

[96] L C Souza M S Antunes C B Filho et al ldquoFlavonoidChrysin prevents age-related cognitive decline via attenuationof oxidative stress and modulation of BDNF levels in agedmouse brainrdquo Pharmacology Biochemistry amp Behavior vol 134pp 22ndash30 2015

[97] E Castren and M Kojima ldquoBrain-derived neurotrophic factorin mood disorders and antidepressant treatmentsrdquo Neurobiol-ogy of Disease vol 97 pp 119ndash126 2017

[98] G Y Su J Y Yang F Wang et al ldquoAntidepressant-like effectsof Xiaochaihutang in a rat model of chronic unpredictable mildstressrdquo Journal of Ethnopharmacology vol 152 no 1 pp 217ndash226 2014

[99] S Ostadhadi M Ahangari V Nikoui et al ldquoPharmacologicalevidence for the involvement of the NMDA receptor and nitricoxide pathway in the antidepressant-like effect of lamotriginein the mouse forced swimming testrdquo Biomedicine amp Pharma-cotherapy vol 82 pp 713ndash721 2016

[100] V Butterweck S Nishibe T Sasaki and M Uchida ldquoAntide-pressant effects of apocynum venetum leaves in a forcedswimming testrdquo Biological amp Pharmaceutical Bulletin vol 24no 7 pp 848ndash851 2001

[101] J-C Zhang J Wu Y Fujita et al ldquoAntidepressant effectsof TrkB ligands on depression-like behavior and dendriticchanges in mice after inflammationrdquo International Journal ofNeuropsychopharmacology vol 18 no 4 2015

[102] M E Breuer L Groenink R S Oosting et al ldquoAntidepressanteffects of pramipexole a dopamine D3D2 receptor agonistand 7-OH-DPAT a dopamine D3 receptor agonist in olfactory

bulbectomized ratsrdquo European Journal of Pharmacology vol616 no 1-3 pp 134ndash140 2009

[103] Y Li Z R Zhu B C Ou et al ldquoDopamine D2D3 but notdopamineD1 receptors are involved in the rapid antidepressant-like effects of ketamine in the forced swim testrdquo BehaviouralBrain Research vol 279 pp 100ndash105 2015

[104] J Song X Hou X Hu et al ldquoNot only serotonergic system butalso dopaminergic system involved in albiflorin against chronicunpredictable mild stress-induced depression-like behavior inratsrdquo Chemico-Biological Interactions vol 242 pp 211ndash217 2015

[105] PWillner J Scheel-Kruger and C Belzung ldquoThe neurobiologyof depression and antidepressant actionrdquoNeuroscience amp Biobe-havioral Reviews vol 37 no 10 pp 2331ndash2371 2013

[106] L C Souza M G de Gomes A T R Goes et al ldquoEvidencefor the involvement of the serotonergic 5-HT1119860 receptors inthe antidepressant-like effect caused by hesperidin in micerdquoProgress in Neuro-Psychopharmacology amp Biological Psychiatryvol 40 no 1 pp 103ndash109 2013

[107] W Zhu SMa RQuD Kang andY Liu ldquoAntidepressant effectof baicalin extracted from the root of Scutellaria baicalensis inmice and ratsrdquo Pharmaceutical Biology vol 44 no 7 pp 503ndash510 2008

[108] M J Detke M Rickels and I Lucki ldquoActive behaviors in the ratforced swimming test differentially produced by serotonergicand noradrenergic antidepressantsrdquo Psychopharmacology vol121 no 1 pp 66ndash72 1995

[109] L T Yi H L Xu J Feng X Zhan L P Zhou and C C CuildquoInvolvement of monoaminergic systems in the antidepressant-like effect of nobiletinrdquo Physiology Behavior vol 102 no 1 p 12011

[110] R Lozano-Hernandez J F Rodrıguez-Landa J D Hernandez-Figueroa M Saavedra F R Ramos-Morales and J S Cruz-Sanchez ldquoAntidepressant-like effects of two commercially avail-able products of Hypericumperforatum in the forced swim testA long-term studyrdquo Journal of Medicinal Plants Research vol 4no 2 pp 131ndash137 2010

[111] J F Rodrıguez-Landa J Cueto-Escobedo J D Aguirre-ChinasandM O Perez-Vazquez ldquoA commercially available product ofHypericum perforatum acts on GABAA receptor to producesanxiolytic-like but not antidepressant-like effects in Wistarratsrdquo in Hypericum Botanical Sources Medical Properties andHealth Effects H R Davis Ed Davis Nova Publishers NewYork NY USA 2015

[112] E A Apaydin A R Maher R Shanman et al ldquoA systematicreview of St Johnrsquos wort for major depressive disorderrdquo System-atic Reviews vol 5 no 1 article no 148 2016

[113] J F Rodrıguez-Landa and CM Contreras ldquoA review of clinicaland experimental observations about antidepressant actionsand side effects produced by Hypericum perforatum extractsrdquoPhytomedicine vol 10 no 8 pp 688ndash699 2003

[114] N Karim I Khan N Ahmad M N Umar and NGavande ldquoAntidepressant anticonvulsant and antinocicep-tive effects of 31015840-methoxy-6-methylflavone and 31015840-hydroxy-6-methylflavone may involve GABAergic mechanismsrdquo Pharma-cological Reports vol 69 no 5 pp 1014ndash1020 2017

[115] M Anjaneyulu K Chopra and I Kaur ldquoAntidepressant Activ-ity of Quercetin A Bioflavonoid in Streptozotocin-InducedDiabetic Micerdquo Journal of Medicinal Food vol 6 no 4 pp 391ndash395 2003

[116] Q-Q Mao Z Huang X-M Zhong Y-F Xian and S-PIp ldquoBrain-derived neurotrophic factor signalling mediates the

14 Scientifica

antidepressant-like effect of piperine in chronically stressedmicerdquo Behavioural Brain Research vol 261 pp 140ndash145 2014

[117] A D Basterzi K Yazici E Aslan et al ldquoEffects of fluoxetine andvenlafaxine on serum brain derived neurotrophic factor levelsin depressed patientsrdquoProgress inNeuro-PsychopharmacologyampBiological Psychiatry vol 33 no 2 pp 281ndash285 2009

[118] C B Filho C R Jesse F Donato et al ldquoNeurochemical fac-tors associated with the antidepressant-like effect of flavonoidchrysin in chronically stressed micerdquo European Journal ofPharmacology vol 791 pp 284ndash296 2016

[119] S Kumar A Mishra and A K Pandey ldquoAntioxidant mediatedprotective effect of Parthenium hysterophorus against oxidativedamage using in vitro modelsrdquo BMC Complementary andAlternative Medicine vol 13 article 120 2013

[120] G Li P Jing Z Liu et al ldquoBeneficial effect of fluoxetinetreatment aganist psychological stress is mediated by increasingBDNF expression in selected brain areasrdquoOncotarget vol 8 no41 pp 69527ndash69537 2017

[121] T Rantamaki P Hendolin A Kankaanpaa et al ldquoPharmaco-logically diverse antidepressants rapidly activate brain-derivedneurotrophic factor receptor TrkB and induce phospholipase-C120574 signaling pathways in mouse brainrdquo Neuropsychopharma-cology vol 32 no 10 pp 2152ndash2162 2007

[122] K Hashimoto ldquoBrain-derived neurotrophic factor as abiomarker for mood disorders an historical overview andfuture directionsrdquo Psychiatry and Clinical Neurosciences vol64 no 4 pp 341ndash357 2010

[123] K Hashimoto ldquoRole of the mTOR signaling pathway in therapid antidepressant action of ketaminerdquo Expert Review ofNeurotherapeutics vol 11 no 1 pp 33ndash36 2011

[124] R S Duman and G K Aghajanian ldquoSynaptic dysfunction indepression potential therapeutic targetsrdquo Science vol 338 no6103 pp 68ndash72 2012

Medicinal ChemistryInternational Journal of

Hindawiwwwhindawicom Volume 2018

ToxicologyJournal of


PainResearch and TreatmentHindawiwwwhindawicom Volume 2018


Arthritis

Neurology Research International


StrokeResearch and TreatmentHindawiwwwhindawicom Volume 2018

Drug DeliveryJournal of



Advances in Pharmacological Sciences

Tropical MedicineJournal of


AddictionJournal of



BioMed Research International

Emergency Medicine InternationalHindawiwwwhindawicom Volume 2018


Anesthesiology Research and Practice

Journal of


Pharmaceutics

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Infectious Diseases and Medical Microbiology


Canadian Journal of


Autoimmune DiseasesScientica



MEDIATORSINFLAMMATION

of

Submit your manuscripts atwwwhindawicom

2 Scientifica

A C

BO

2

345

6

78 1

2

3

4

5

6

Figure 1 Basic structure of flavonoids and the system of numera-tion A and B are phenyls and C corresponds to pyrene Numbersindicate the numeration system of the basic structure of flavonoids

neurotransmitters and expression of neurotrophic factors inthe brain [9 10] The present review focuses on the results ofpreclinical research that indicate the potential antidepressanteffects of some flavonoids and describes the mechanismsof action that are involved in these effects We proposefuture scientific research in the area of pharmacotherapyto develop safe and effective antidepressant drugs based onnatural products to ameliorate the symptoms of depressionin humans

2 Background on Flavonoids

Flavonoids are phenolic compounds that are widely dis-tributed in vascular plants Many chemical compounds bothin their free form and in the form of glycosides have beenevaluated to determine their biological activity [11] Morethan 5000 types of flavonoids have been identified which arestructurally different and possess a wide range of biologicalactivities Flavonoids are chemical compounds with a lowmolecular weight whose base structure (Figure 1) comprisesa system of rings of diphenyl pyrene or phenyl benzopyreneaccompanied by two variable groups of hydroxyl phenolicradicals [12]

According to the chemical structure of flavonoids (Fig-ure 2) they can be classified as flavonoids flavones fla-vanones isoflavones and anthocyanidins [62] Studies inmammals and in vitro have shown that flavonoids exertantioxidant antiallergic hepatoprotective antiviral anticar-cinogenic neuroprotective antitoxic anxiolytic antiepilep-tic estrogenic and antidepressant-like effects by inhibitingsome enzymes [63ndash66] which is dependent on the dose andtype of flavonoid administered

3 Flavonoid Metabolism

The daily dietary intake of flavonoids in humans is approx-imately 1-2 g per day principally depending on individualalimentary habits [67] Most flavonoids are found in plants inthe120573-glycoside form After intake the processes of hydrolysisoccur but since the union-120573 in these sugars is resistantto the hydrolysis produced by pancreatic enzymes thismetabolic process occurs in the intestinal lumen throughactions of the lactase phlorizin hydrolase that is locatedin the membrane of enterocytes When phlorizin hydro-lase hydrolyzes flavonoids they become capable of crossingintestinal membranes through passive diffusion Another

O

OH

O

O

OOH

O

O

O

O

O

OOH

Flavones Flavonols

Flavanones Flavan-3-ols

Flavanonol Isoflavones

Figure 2 General classification and basic structure of flavonoids

enzyme that facilitates the hydrolysis of flavonoids is cytosolic120573-glycosidase which hydrolyzes a high number of glycosides[68 69] Cytosolic 120573-glycosidase is located intracellularlyin erythrocytes therefore active transport is required tocross cellular membranes It is produced by sodium-glucosetransport protein which depends on sodium (SGLT-1) [69]

Hydrolyzed flavonoids (aglycones) are conjugatedthrough methylation sulphatation and glucuronidationBecause of their high conjugation hydrolyzed flavonoids aredetected in low concentrations in plasma [70] For examplehesperetin aglycone (the active form of the flavonoidhesperidin) is metabolized by the cytochrome isoforms P450CYP1A and CYP1B1 This first-pass metabolism principallyoccurs through intestinal cells [71] The metabolites ofhesperidinhesperetin are eliminated by renal route Theirmetabolites are found in urine but not feces suggesting thatthe high bacterial degradation of phenolic acids occurs at thelevel of the colon allowing passage to the systemic circulation[71] Particularly the elimination of the flavonoid chrysindepends on the outflow in which conjugated structuresare hydrolyzed through sulphatases and glucuronidasesin the intestine suggesting that chrysin has low intestinalabsorption in which it is detected in high concentrations infeces [72]

Some studies have shown that hydrolyzed flavonoids andtheir conjugated derivatives may cross the hematoencephalicbarrier and exert actions on the central nervous system [73]This may at least partially explain their multiple pharma-cological actions at the neuronal level that affect cognitionand emotional and affective states Numerous preclinicalstudies have shown that some flavonoids reduce depressive-like behavior and these effects are related to the activation ofneurotransmitter systems and trophic factors in the brain

Scientifica 3



































4 Scientifica









Scientifica 5











6 Scientifica









[31]






Baicalein




[36]

Chrysin


[10]


Fisetin



[38]



[40]




[42]



[44]


[45]




[47 48]

Scientifica 7

Table 2 Continued





[50]



[50]







8 ScientificaTa

ble3Eff

ecto

fflavon

oids

ondepressio

n-lik

ebehaviora


Mod

elof

depressio

nFlavon

oid(animal)

Doses

Treatm

entd

uration

Effect

Reference

Forced

swim

test1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Noeffect

[52]

Luteolin

(A)

10mgkgpo

30min

before

test

Antidepressant

[30]

50mgkgpo

23days

Antidepressant

[31]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Baicalein(B)

1020and40

mgkgip

14days

Antidepressant

[35]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Quercetin

(E)

50and100m

gkgip

21days

Antidepressant

[54]

40and80

mgkgpo

14days

Antidepressant

[55]

Quercetin

(I)

50mgkgip

21days

Antidepressant

[54]

Quercetin

(L)

25and50

mgkgpo

14days

Antidepressant

[56]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

13and10mgkgip

60min

before

test

Antidepressant

[41]

Isosakuranetin-5-O

-rutinoside(A)

15and30

mgkgpo

2118and1h

before

test

Antidepressant

[57]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Naringin(E)

50and100m

gkgip

14days

Antidepressant

[58]

Tailsuspensio

ntest1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Antidepressant

[52]

510and

20mgkgpo

14days

Antidepressant

[29]

Hesperid

in(H

)0103and1m

gkgip

21days

Antidepressant

[9]

Astilbin(G

)1020and40

mgkgip

21days

Antidepressant

[34]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

3and10mgkgip

60min

before

test

Antidepressant

[41]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

CUMS-sucroseintake2

Naringenin(A

)10

and20

mgkgpo

21days

Antidepressant

[28]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

Apigenin

(A)

7and14mgkgpo

49days

Antidepressant

[59]

78-D

ihydroxyflavone

(G)

10and20

mgkgip

28days

Antidepressant

[60]

Icariin

(B)

20and40

mgkgpo

35days

Antidepressant

[61]

1Th


ffectissuggestedby

ther

eductio

nin

immob

ilitytim

ewith


intheg

enerallocomotor

activ

ity2Th


ffectissuggestedby


intakeC

UMSchronicun

predictablemild

stress(A

)Adu

ltmaleICRmice(B)M

aleSprague-Daw

leyrats

(C)M

aleC5

7BL6J

mice(D

)Adu

ltmaleBA

LBc

mice(E)A

dultmaleWistar

rats

(F)A

dultmale

Kunm

ingmice(G

)Adu

ltmaleC

57BL

6mice(H

)Adu

ltmaleS

wiss

mice(I)M

ale2

1-day

streptozotocin-indu

ceddiabeticWistar

rats

(J)F

emaleC

57BL

6Jm

ice(K

)Mices

exandstr

ainweren

otidentifi

ed(L)

FemaleS

wiss

mice

Scientifica 9











Acknowledgments


10 Scientifica

References































Scientifica 11































12 Scientifica
































Scientifica 13































14 Scientifica
















Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


Scientifica 3



































4 Scientifica









Scientifica 5











6 Scientifica









[31]






Baicalein




[36]

Chrysin


[10]


Fisetin



[38]



[40]




[42]



[44]


[45]




[47 48]

Scientifica 7

Table 2 Continued





[50]



[50]







8 ScientificaTa

ble3Eff

ecto

fflavon

oids

ondepressio

n-lik

ebehaviora


Mod

elof

depressio

nFlavon

oid(animal)

Doses

Treatm

entd

uration

Effect

Reference

Forced

swim

test1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Noeffect

[52]

Luteolin

(A)

10mgkgpo

30min

before

test

Antidepressant

[30]

50mgkgpo

23days

Antidepressant

[31]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Baicalein(B)

1020and40

mgkgip

14days

Antidepressant

[35]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Quercetin

(E)

50and100m

gkgip

21days

Antidepressant

[54]

40and80

mgkgpo

14days

Antidepressant

[55]

Quercetin

(I)

50mgkgip

21days

Antidepressant

[54]

Quercetin

(L)

25and50

mgkgpo

14days

Antidepressant

[56]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

13and10mgkgip

60min

before

test

Antidepressant

[41]

Isosakuranetin-5-O

-rutinoside(A)

15and30

mgkgpo

2118and1h

before

test

Antidepressant

[57]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Naringin(E)

50and100m

gkgip

14days

Antidepressant

[58]

Tailsuspensio

ntest1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Antidepressant

[52]

510and

20mgkgpo

14days

Antidepressant

[29]

Hesperid

in(H

)0103and1m

gkgip

21days

Antidepressant

[9]

Astilbin(G

)1020and40

mgkgip

21days

Antidepressant

[34]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

3and10mgkgip

60min

before

test

Antidepressant

[41]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

CUMS-sucroseintake2

Naringenin(A

)10

and20

mgkgpo

21days

Antidepressant

[28]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

Apigenin

(A)

7and14mgkgpo

49days

Antidepressant

[59]

78-D

ihydroxyflavone

(G)

10and20

mgkgip

28days

Antidepressant

[60]

Icariin

(B)

20and40

mgkgpo

35days

Antidepressant

[61]

1Th


ffectissuggestedby

ther

eductio

nin

immob

ilitytim

ewith


intheg

enerallocomotor

activ

ity2Th


ffectissuggestedby


intakeC

UMSchronicun

predictablemild

stress(A

)Adu

ltmaleICRmice(B)M

aleSprague-Daw

leyrats

(C)M

aleC5

7BL6J

mice(D

)Adu

ltmaleBA

LBc

mice(E)A

dultmaleWistar

rats

(F)A

dultmale

Kunm

ingmice(G

)Adu

ltmaleC

57BL

6mice(H

)Adu

ltmaleS

wiss

mice(I)M

ale2

1-day

streptozotocin-indu

ceddiabeticWistar

rats

(J)F

emaleC

57BL

6Jm

ice(K

)Mices

exandstr

ainweren

otidentifi

ed(L)

FemaleS

wiss

mice

Scientifica 9











Acknowledgments


10 Scientifica

References































Scientifica 11































12 Scientifica
































Scientifica 13































14 Scientifica
















Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


4 Scientifica









Scientifica 5











6 Scientifica









[31]






Baicalein




[36]

Chrysin


[10]


Fisetin



[38]



[40]




[42]



[44]


[45]




[47 48]

Scientifica 7

Table 2 Continued





[50]



[50]







8 ScientificaTa

ble3Eff

ecto

fflavon

oids

ondepressio

n-lik

ebehaviora


Mod

elof

depressio

nFlavon

oid(animal)

Doses

Treatm

entd

uration

Effect

Reference

Forced

swim

test1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Noeffect

[52]

Luteolin

(A)

10mgkgpo

30min

before

test

Antidepressant

[30]

50mgkgpo

23days

Antidepressant

[31]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Baicalein(B)

1020and40

mgkgip

14days

Antidepressant

[35]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Quercetin

(E)

50and100m

gkgip

21days

Antidepressant

[54]

40and80

mgkgpo

14days

Antidepressant

[55]

Quercetin

(I)

50mgkgip

21days

Antidepressant

[54]

Quercetin

(L)

25and50

mgkgpo

14days

Antidepressant

[56]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

13and10mgkgip

60min

before

test

Antidepressant

[41]

Isosakuranetin-5-O

-rutinoside(A)

15and30

mgkgpo

2118and1h

before

test

Antidepressant

[57]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Naringin(E)

50and100m

gkgip

14days

Antidepressant

[58]

Tailsuspensio

ntest1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Antidepressant

[52]

510and

20mgkgpo

14days

Antidepressant

[29]

Hesperid

in(H

)0103and1m

gkgip

21days

Antidepressant

[9]

Astilbin(G

)1020and40

mgkgip

21days

Antidepressant

[34]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

3and10mgkgip

60min

before

test

Antidepressant

[41]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

CUMS-sucroseintake2

Naringenin(A

)10

and20

mgkgpo

21days

Antidepressant

[28]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

Apigenin

(A)

7and14mgkgpo

49days

Antidepressant

[59]

78-D

ihydroxyflavone

(G)

10and20

mgkgip

28days

Antidepressant

[60]

Icariin

(B)

20and40

mgkgpo

35days

Antidepressant

[61]

1Th


ffectissuggestedby

ther

eductio

nin

immob

ilitytim

ewith


intheg

enerallocomotor

activ

ity2Th


ffectissuggestedby


intakeC

UMSchronicun

predictablemild

stress(A

)Adu

ltmaleICRmice(B)M

aleSprague-Daw

leyrats

(C)M

aleC5

7BL6J

mice(D

)Adu

ltmaleBA

LBc

mice(E)A

dultmaleWistar

rats

(F)A

dultmale

Kunm

ingmice(G

)Adu

ltmaleC

57BL

6mice(H

)Adu

ltmaleS

wiss

mice(I)M

ale2

1-day

streptozotocin-indu

ceddiabeticWistar

rats

(J)F

emaleC

57BL

6Jm

ice(K

)Mices

exandstr

ainweren

otidentifi

ed(L)

FemaleS

wiss

mice

Scientifica 9











Acknowledgments


10 Scientifica

References































Scientifica 11































12 Scientifica
































Scientifica 13































14 Scientifica
















Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


Scientifica 5











6 Scientifica









[31]






Baicalein




[36]

Chrysin


[10]


Fisetin



[38]



[40]




[42]



[44]


[45]




[47 48]

Scientifica 7

Table 2 Continued





[50]



[50]







8 ScientificaTa

ble3Eff

ecto

fflavon

oids

ondepressio

n-lik

ebehaviora


Mod

elof

depressio

nFlavon

oid(animal)

Doses

Treatm

entd

uration

Effect

Reference

Forced

swim

test1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Noeffect

[52]

Luteolin

(A)

10mgkgpo

30min

before

test

Antidepressant

[30]

50mgkgpo

23days

Antidepressant

[31]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Baicalein(B)

1020and40

mgkgip

14days

Antidepressant

[35]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Quercetin

(E)

50and100m

gkgip

21days

Antidepressant

[54]

40and80

mgkgpo

14days

Antidepressant

[55]

Quercetin

(I)

50mgkgip

21days

Antidepressant

[54]

Quercetin

(L)

25and50

mgkgpo

14days

Antidepressant

[56]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

13and10mgkgip

60min

before

test

Antidepressant

[41]

Isosakuranetin-5-O

-rutinoside(A)

15and30

mgkgpo

2118and1h

before

test

Antidepressant

[57]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Naringin(E)

50and100m

gkgip

14days

Antidepressant

[58]

Tailsuspensio

ntest1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Antidepressant

[52]

510and

20mgkgpo

14days

Antidepressant

[29]

Hesperid

in(H

)0103and1m

gkgip

21days

Antidepressant

[9]

Astilbin(G

)1020and40

mgkgip

21days

Antidepressant

[34]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

3and10mgkgip

60min

before

test

Antidepressant

[41]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

CUMS-sucroseintake2

Naringenin(A

)10

and20

mgkgpo

21days

Antidepressant

[28]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

Apigenin

(A)

7and14mgkgpo

49days

Antidepressant

[59]

78-D

ihydroxyflavone

(G)

10and20

mgkgip

28days

Antidepressant

[60]

Icariin

(B)

20and40

mgkgpo

35days

Antidepressant

[61]

1Th


ffectissuggestedby

ther

eductio

nin

immob

ilitytim

ewith


intheg

enerallocomotor

activ

ity2Th


ffectissuggestedby


intakeC

UMSchronicun

predictablemild

stress(A

)Adu

ltmaleICRmice(B)M

aleSprague-Daw

leyrats

(C)M

aleC5

7BL6J

mice(D

)Adu

ltmaleBA

LBc

mice(E)A

dultmaleWistar

rats

(F)A

dultmale

Kunm

ingmice(G

)Adu

ltmaleC

57BL

6mice(H

)Adu

ltmaleS

wiss

mice(I)M

ale2

1-day

streptozotocin-indu

ceddiabeticWistar

rats

(J)F

emaleC

57BL

6Jm

ice(K

)Mices

exandstr

ainweren

otidentifi

ed(L)

FemaleS

wiss

mice

Scientifica 9











Acknowledgments


10 Scientifica

References































Scientifica 11































12 Scientifica
































Scientifica 13































14 Scientifica
















Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


6 Scientifica









[31]






Baicalein




[36]

Chrysin


[10]


Fisetin



[38]



[40]




[42]



[44]


[45]




[47 48]

Scientifica 7

Table 2 Continued





[50]



[50]







8 ScientificaTa

ble3Eff

ecto

fflavon

oids

ondepressio

n-lik

ebehaviora


Mod

elof

depressio

nFlavon

oid(animal)

Doses

Treatm

entd

uration

Effect

Reference

Forced

swim

test1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Noeffect

[52]

Luteolin

(A)

10mgkgpo

30min

before

test

Antidepressant

[30]

50mgkgpo

23days

Antidepressant

[31]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Baicalein(B)

1020and40

mgkgip

14days

Antidepressant

[35]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Quercetin

(E)

50and100m

gkgip

21days

Antidepressant

[54]

40and80

mgkgpo

14days

Antidepressant

[55]

Quercetin

(I)

50mgkgip

21days

Antidepressant

[54]

Quercetin

(L)

25and50

mgkgpo

14days

Antidepressant

[56]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

13and10mgkgip

60min

before

test

Antidepressant

[41]

Isosakuranetin-5-O

-rutinoside(A)

15and30

mgkgpo

2118and1h

before

test

Antidepressant

[57]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Naringin(E)

50and100m

gkgip

14days

Antidepressant

[58]

Tailsuspensio

ntest1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Antidepressant

[52]

510and

20mgkgpo

14days

Antidepressant

[29]

Hesperid

in(H

)0103and1m

gkgip

21days

Antidepressant

[9]

Astilbin(G

)1020and40

mgkgip

21days

Antidepressant

[34]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

3and10mgkgip

60min

before

test

Antidepressant

[41]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

CUMS-sucroseintake2

Naringenin(A

)10

and20

mgkgpo

21days

Antidepressant

[28]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

Apigenin

(A)

7and14mgkgpo

49days

Antidepressant

[59]

78-D

ihydroxyflavone

(G)

10and20

mgkgip

28days

Antidepressant

[60]

Icariin

(B)

20and40

mgkgpo

35days

Antidepressant

[61]

1Th


ffectissuggestedby

ther

eductio

nin

immob

ilitytim

ewith


intheg

enerallocomotor

activ

ity2Th


ffectissuggestedby


intakeC

UMSchronicun

predictablemild

stress(A

)Adu

ltmaleICRmice(B)M

aleSprague-Daw

leyrats

(C)M

aleC5

7BL6J

mice(D

)Adu

ltmaleBA

LBc

mice(E)A

dultmaleWistar

rats

(F)A

dultmale

Kunm

ingmice(G

)Adu

ltmaleC

57BL

6mice(H

)Adu

ltmaleS

wiss

mice(I)M

ale2

1-day

streptozotocin-indu

ceddiabeticWistar

rats

(J)F

emaleC

57BL

6Jm

ice(K

)Mices

exandstr

ainweren

otidentifi

ed(L)

FemaleS

wiss

mice

Scientifica 9











Acknowledgments


10 Scientifica

References































Scientifica 11































12 Scientifica
































Scientifica 13































14 Scientifica
















Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


Scientifica 7

Table 2 Continued





[50]



[50]







8 ScientificaTa

ble3Eff

ecto

fflavon

oids

ondepressio

n-lik

ebehaviora


Mod

elof

depressio

nFlavon

oid(animal)

Doses

Treatm

entd

uration

Effect

Reference

Forced

swim

test1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Noeffect

[52]

Luteolin

(A)

10mgkgpo

30min

before

test

Antidepressant

[30]

50mgkgpo

23days

Antidepressant

[31]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Baicalein(B)

1020and40

mgkgip

14days

Antidepressant

[35]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Quercetin

(E)

50and100m

gkgip

21days

Antidepressant

[54]

40and80

mgkgpo

14days

Antidepressant

[55]

Quercetin

(I)

50mgkgip

21days

Antidepressant

[54]

Quercetin

(L)

25and50

mgkgpo

14days

Antidepressant

[56]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

13and10mgkgip

60min

before

test

Antidepressant

[41]

Isosakuranetin-5-O

-rutinoside(A)

15and30

mgkgpo

2118and1h

before

test

Antidepressant

[57]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Naringin(E)

50and100m

gkgip

14days

Antidepressant

[58]

Tailsuspensio

ntest1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Antidepressant

[52]

510and

20mgkgpo

14days

Antidepressant

[29]

Hesperid

in(H

)0103and1m

gkgip

21days

Antidepressant

[9]

Astilbin(G

)1020and40

mgkgip

21days

Antidepressant

[34]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

3and10mgkgip

60min

before

test

Antidepressant

[41]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

CUMS-sucroseintake2

Naringenin(A

)10

and20

mgkgpo

21days

Antidepressant

[28]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

Apigenin

(A)

7and14mgkgpo

49days

Antidepressant

[59]

78-D

ihydroxyflavone

(G)

10and20

mgkgip

28days

Antidepressant

[60]

Icariin

(B)

20and40

mgkgpo

35days

Antidepressant

[61]

1Th


ffectissuggestedby

ther

eductio

nin

immob

ilitytim

ewith


intheg

enerallocomotor

activ

ity2Th


ffectissuggestedby


intakeC

UMSchronicun

predictablemild

stress(A

)Adu

ltmaleICRmice(B)M

aleSprague-Daw

leyrats

(C)M

aleC5

7BL6J

mice(D

)Adu

ltmaleBA

LBc

mice(E)A

dultmaleWistar

rats

(F)A

dultmale

Kunm

ingmice(G

)Adu

ltmaleC

57BL

6mice(H

)Adu

ltmaleS

wiss

mice(I)M

ale2

1-day

streptozotocin-indu

ceddiabeticWistar

rats

(J)F

emaleC

57BL

6Jm

ice(K

)Mices

exandstr

ainweren

otidentifi

ed(L)

FemaleS

wiss

mice

Scientifica 9











Acknowledgments


10 Scientifica

References































Scientifica 11































12 Scientifica
































Scientifica 13































14 Scientifica
















Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


8 ScientificaTa

ble3Eff

ecto

fflavon

oids

ondepressio

n-lik

ebehaviora


Mod

elof

depressio

nFlavon

oid(animal)

Doses

Treatm

entd

uration

Effect

Reference

Forced

swim

test1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Noeffect

[52]

Luteolin

(A)

10mgkgpo

30min

before

test

Antidepressant

[30]

50mgkgpo

23days

Antidepressant

[31]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Baicalein(B)

1020and40

mgkgip

14days

Antidepressant

[35]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Quercetin

(E)

50and100m

gkgip

21days

Antidepressant

[54]

40and80

mgkgpo

14days

Antidepressant

[55]

Quercetin

(I)

50mgkgip

21days

Antidepressant

[54]

Quercetin

(L)

25and50

mgkgpo

14days

Antidepressant

[56]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

13and10mgkgip

60min

before

test

Antidepressant

[41]

Isosakuranetin-5-O

-rutinoside(A)

15and30

mgkgpo

2118and1h

before

test

Antidepressant

[57]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Naringin(E)

50and100m

gkgip

14days

Antidepressant

[58]

Tailsuspensio

ntest1

Naringenin(A

)1020and50

mgkgpo

60min

before

test

Antidepressant

[52]

510and

20mgkgpo

14days

Antidepressant

[29]

Hesperid

in(H

)0103and1m

gkgip

21days

Antidepressant

[9]

Astilbin(G

)1020and40

mgkgip

21days

Antidepressant

[34]

Vitexin(D

)1020and30

mgkgpo

60min

before

test

Antidepressant

[53]

Fisetin

(A)

510and

20mgkgpo

60min

before

test

Antidepressant

[38]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

78-D

ihydroxyflavone

(G)

3and10mgkgip

60min

before

test

Antidepressant

[41]

Baicalein(F)

12and4m

gkgip

Sing

leinjectionor

21days

Antidepressant

[36]

Kaem

pferol(A

)30

mgkgpo

14days

Antidepressant

[24]

Quercitrin

(A)

30mgkgpo

14days

Antidepressant

[24]

Liqu

iritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

Isoliquiritin

(K)

1020and40

mgkgpo

30min

before

test

Antidepressant

[51]

CUMS-sucroseintake2

Naringenin(A

)10

and20

mgkgpo

21days

Antidepressant

[28]

Icariin

(B)

60mgkgpo

21days

Antidepressant

[32]

20and40

mgkgpo

35days

Antidepressant

[42]

Astilbin(C

)1020and40

mgkgip

21days

Antidepressant

[34]

Chrysin

(J)

5and20

mgkgpo

28days

Antidepressant

[10]

Orie

ntin

(F)

20and40

mgkgpo

21days

Antidepressant

[40]

Apigenin

(A)

7and14mgkgpo

49days

Antidepressant

[59]

78-D

ihydroxyflavone

(G)

10and20

mgkgip

28days

Antidepressant

[60]

Icariin

(B)

20and40

mgkgpo

35days

Antidepressant

[61]

1Th


ffectissuggestedby

ther

eductio

nin

immob

ilitytim

ewith


intheg

enerallocomotor

activ

ity2Th


ffectissuggestedby


intakeC

UMSchronicun

predictablemild

stress(A

)Adu

ltmaleICRmice(B)M

aleSprague-Daw

leyrats

(C)M

aleC5

7BL6J

mice(D

)Adu

ltmaleBA

LBc

mice(E)A

dultmaleWistar

rats

(F)A

dultmale

Kunm

ingmice(G

)Adu

ltmaleC

57BL

6mice(H

)Adu

ltmaleS

wiss

mice(I)M

ale2

1-day

streptozotocin-indu

ceddiabeticWistar

rats

(J)F

emaleC

57BL

6Jm

ice(K

)Mices

exandstr

ainweren

otidentifi

ed(L)

FemaleS

wiss

mice

Scientifica 9











Acknowledgments


10 Scientifica

References































Scientifica 11































12 Scientifica
































Scientifica 13































14 Scientifica
















Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


Scientifica 9











Acknowledgments


10 Scientifica

References































Scientifica 11































12 Scientifica
































Scientifica 13































14 Scientifica
















Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


10 Scientifica

References































Scientifica 11































12 Scientifica
































Scientifica 13































14 Scientifica
















Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


Scientifica 11































12 Scientifica
































Scientifica 13































14 Scientifica
















Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


12 Scientifica
































Scientifica 13































14 Scientifica
















Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


Scientifica 13































14 Scientifica
















Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


14 Scientifica
















Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of








Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


Documents

Advances in the Preclinical Study of Some Flavonoids as ...downloads.hindawi.com/journals/scientifica/2018/2963565.pdf · ReviewArticle Advances in the Preclinical Study of Some Flavonoids