Comparative Study on the Activity of Agomelatine and/or ...psychopathology.imedpub.com/comparative-study-on... · of Agomelatine and/or Curcumin against Development of Depression

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2016Vol. 2 No. 4: 33

Research Article

DOI: 10.4172/2469-6676.100059

Acta PsychopathologicaISSN 2469-6676

1© Under License of Creative Commons Attribution 3.0 License | This article is available from: www.psychopathology.imedpub.com

Azza A Ali1,Zeinab A Rahman2,Asmaa I Alwakeel1,Marwa A Masoud2 and Amina K Elansary2

1 Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

2 PharmacologyDepartment,NationalOrganizationforDrugControlandResearch, Giza, Egypt

Corresponding author: Azza A Ali

[email protected]

Head of Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.

Tel: +20 01061905439

Citation: Ali AA, Rahman ZA, Alwakeel AI, etal.ComparativeStudyontheActivityofAgomelatineand/orCurcuminagainstDevelopment of Depression in Rats. Acta Psychopathol. 2016, 2:4

Comparative Study on the Activity of Agomelatine and/or Curcumin against

Development of Depression in Rats

AbstractBackground: The depressive disorders in both developed and developing countriesconstitutealargeproportionintheglobalburdenofdisease.CurcuministhefrequentlyusedherbTurmeric,whichwasproventopossessantidepressant,antioxidantandanti-inflammatoryeffects.Agomelatineisanovelantidepressantwithmelatonergic agonism and 5-HT2C antagonism and has lower side effectsthanfluoxetine.

Objective: Comparetheactivityofagomelatineandcurcuminaswellasinvestigatethepossible interactionbetween themagainst clonidine-induceddepression inrats.

Methods: Sixgroupsofratswereusedandreceivedtreatmentsfor14days;onenormalcontrolgroupreceivedsalinewhiletheotherfivegroupsgivenclonidine(0.8mg/kg I.P) from 8th to 14th day (depressed groups), one of them receivedsalineandtheothersreceivedeitheragomelatine(40mg/KgP.O),curcumin(100mg/KgP.O),combinationofbothagomelatine&curcuminorreceivedstandardantidepressantdrugfluoxetine(20mg/KgP.O)during14daysoftreatment.Twobehaviouralexperimentswereperformed;OpenFieldTestandForcedSwimmingTest.Brainmonoamines (5-HT,NEandDA),pro-inflammatorymediators (TNF-αandIL-6)andoxidativeparameters(MDAandGSH)wereevaluatedforallgroups.

Results: Clonidine decreased locomotor activity and strugglingwhile increasedimmobility time.Brainmonoamines andGSHwere also decreasedwhileMDA,TNF-αandIL-6were increased.Administrationofagomelatineand/orcurcuminreversed behavioural and biochemical changes in the brain induced by clonidine. Asregardingbehaviouralchanges;theeffectofcurcuminwasmorepronouncedthan fluoxetine. However co-administration of both agomelatine and curcuminshowed no more improvement than each one alone.

Conclusions: Agomelatineand/orcurcuminintheirtherapeuticdosesshowedhighefficiencyagainstdevelopmentofdepressioninrats,concomitantadministrationofbothhasnoadditiveeffectsthaneachofthem.However,theeffectofcurcuminwasmore pronounced than the standard antidepressant fluoxetine concerningthe behavioural changes.

Keywords:Depression;Clonidine;Agomelatine;Curcumin;Neurotransmitters

Received: June27,2016; Accepted:July20,2016; Published: July 31, 2016

IntroductionAsdefinedby theAmericanpsychiatric association, depressionis a heterogeneous disorder associated with psychological, behavioural and physiological symptoms [1]. It occurs in all ages,

genders and in all social backgrounds, it also occurs in animals. According to theWorld HealthOrganization, depression is theleading cause of disability and the 4th leading contributor to the global burden of disease with tendency to rise up to 2020 [2]. Major depression is a complex disease; it originates from the

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interactionbetweenageneticbackgroundof susceptibilityandsome environmental factors as stress. It is also characterized by dysfunctionsofmultiplesystems[3]includingneurotransmittersin which serotonin and norepinephrine are deficient [4],hormones, signalling pathways, neurotrophic and neuroplasticmolecules and even inflammatorymediators. According to theneuroinflammatory or macrophage/cytokine theory; increasedproduction of inflammatory cytokine causes depression viaaffectinganumberofneuralpathwaysincludingthoseinvolvedwith mood [5].

Animal models of depression are widely used to study the antidepressant-like effects in rodents [6]. Clonidine is α2-adrenergicreceptoragonistandiswidelyusedasanti-hypertensiveagent. It produces behavioural depressive effects in laboratoryanimals includinghypo-activity, lossof interest and investmentin the environment both acutely and chronically [7]. It increases thesympatho-inhibitoryfunctionofcentralsympatheticneuronsthatleadstodecreaseinnorepinephrinereleaseandreductionofsympathetictone[8].

Agomelatine is amelatonergic antidepressant (agonist toMT1andMT2 receptors) with a rapid onset of action; it is one oftherecentdrugsintheantidepressantcategorywithlowersideeffects than fluoxetine [9]. Melatonin is a hormone with freeradicalscavengingandantioxidantpropertiesandshowsitseffectthroughMT1andMT2receptors[10].Italsoplaysanimportantroleinthevariousneuropeptidesandneurohormonesthataffectthe immune system [11]. Administration of melatonin in ratsincreases GABA levels in the cerebellum and cerebral cortex [12]. Agomelatinealsoactas5-HT2Cantagonist[13].Itiswellknownthat, 5HT2C antagonism is beneficial for alleviating differentsymptoms associated with 5HT2C overstimulation, includinginsomnia,anxietyandsexualdysfunction.Thus, theadditiveorperhapseventhesynergisticactionofagomelatineatboththemelatonin and 5HT2C receptors appears to be necessary for its efficacyintreatingdepression[14].

Curcumin is an active ingredient in Curcuma longa Linn,morecommonly known as the Asian yellow spice Turmeric [15]. Curcumin has been demonstrated to be amulti-target naturalcompound, which may modulate numerous pathways [16] eitherdirectlyby influencingnumerous signallingmoleculesorindirectly by modulating gene expression [17]. Curcumin hasbeen shown to have anti-oxidant and anti-inflammatory [18],immune-modulatory [19],anti-cancer [20]andneuroprotectiveactivities[21].Theantidepressantactivityofcurcuminhasbeenexplored in various animal models of depression such as forced swimming test and chronic stress model [22, 23]. Curcumin is widely consumed by the general human population and isalso being employed as therapeutic agents to alleviate variousneurological disorders [24].

Thus, the aim of the current study was to investigate theeffectofagomelatineand/or curcuminon thebehaviour,brainneurotransmitters, anti-oxidant and anti-inflammatory markersusing clonidine-induced depression model in rat as well as to compare their activities with the standard antidepressantfluoxetine.

Materials and MethodsAnimalsThe study was performed in accordance with the ethical guidelines of Faculty of Pharmacy, Al-Azhar University, Egypt. Sixty AdultmaleSprague-Dawleyrats,weighing200-220gmswereutilized.Rats were obtained from the breeding colony of the NationalOrganization for Drug Control and Research, Giza, Egypt. Theywere kept under the sameadequate environmental conditionsatatemperatureof25±1°Cwithalternatively12hourlightanddark cycles and provided with their daily dietary requirements consisting of standard diet pellets (El-Nasr Chemical Co., AbuZaabal, Cairo, Egypt) contained not less than 20% protein, 5%fibre,3.5%fat,6.5%ashandavitaminmixture,waterwasgivenad-libitum. Rats were housed in stainless-steel cages (three to fourpercage)andkeptattheanimalhouseforanacclimationperiod of one week prior testing. Experiments were usuallycarriedoutatafixedtimearound9AM:3PM.

Drugs and chemicalsClonidinehydrochloride,fluoxetinehydrochlorideandcurcuminwere purchased from Sigma-Aldrich Chemical Co. (St.Louis,MO, USA). Agomelatine was obtained from SEDICO Co. forPharmaceuticals Industries, Egypt. All test substances werefreshlydissolvedinsalineexceptagomelatineandcurcuminwerepreparedin50%DMSO/Saline.

Experimental designRandomlychosenmaleratsweredividedintosixgroups(10rats/each). Inallgroupsexceptnormalcontrolone,depressionwasinducedbyadministrationofclonidine (0.8mg/kg I.P) [7] from8th to 14th day of treatment. All rats treated daily for 14 days as following;Group1:Normalcontrol(receivedsalineonly),Group2:Depressedcontrolgroup(receivedsaline)Group3:Depressedstandard treated group (received fluoxetine 20 mg/Kg P.O)[25], Group 4: Depressed agomelatine treated group (receivedagomelatine40mg/KgP.O) [26],Group5:Depressedcurcumintreatedgroup(receivedcurcumin100mg/KgP.O)[27],Group6:depressedcombinationormixture-treatedgroup(receivedbothagomelatine&curcumin).

Rats were taken to the test situation one hour before eachexperiment for adaptation before examination of the testingparametersandafterremovingfoodandwater fromthehomecage. Behavioural experiments were performed after thelast injection; Open-Field Test (OFT) at day one then ForcedSwimming Test (FST) at the third day. At the fifth day (19th day from the beginning of injection), rats were sacrificed bydecapitationandbrainwascarefullyremoved,blottedandchilled.Neurotransmitters content (5-HT, NE and DA), oxidative stressbiomarkers(MDAandGSH)andcytokinesconcentration(TNF-αandIL-6)weremeasuredinbraintissueafterhomogenization.

Behavioural experimentsOpen-Field Test (OFT): It represents amild stressful condition[28],itisageneraltestformotoractivity,excitability,emotionalityand exploratory behaviour in rodents [29]. It consists of a square

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wooden box 80 cm x 80 cm × 40cm height [30], with red sides and whitefloor.Thefloorofthefieldwasdividedbyblacklinesinto16 equal squares 4 × 4 [31, 32]. The test was performed under white light in a quiet room. The experiment performed between 9:00AM-3:00PM.Experimentalanimalsweretakenfromtheircages alternately, placed into the central squares of the open-field and videotaped for 3 min [31]. The OFT was thoroughlywipedusing10%isopropylalcoholanddriedbeforeapplicationofanewratinordertoobviatepossibleeffectonitsbehaviourdue to odour remained from previous one [33]. The behaviour of theexperimentalratintheOFTwascontinuouslyrecordedduringthe3min.oftheobservationperiod[31]usingcodedsymbolsforthe following parameters:

Latency- Time from putting the animal at the middle of thearenauntildecidedtomove[34],measured insecondsusingastopwatch.

Ambulationfrequency-Numberofsquarescrossedbytheanimal[28, 32], it was scored as a total count during a 3 min. period.

Rearingfrequency-Numberoftimetheanimalstoodstretchedonitshindlimbswithandwithoutforelimbssupport[28,30];itwasscoredduringa3min.observationperiod.

Grooming frequency-Number of time of face washing andscratching with the hind leg and licking of the fur and genitals bytheanimal[30,35],itwasscoredduringa3min.observationperiod.

Forced Swimming Test (FST): It is a behavioural test used frequently to evaluate the potential efficacy of prospectiveantidepressant drugs in rats or mice [36, 37]. The swimmingpool consists of a Plexiglas cylinder of 40cm height and 22 cm diameterwith a rounded lid. The tankwas filled up to 25 cmwithtapwaterthermostaticallycontrolledtobe25°Csotheratscouldnotsupportthemselvesbytouchingthebottomwiththeirfeet [38]. The test was performed under white light in a quiet room. The experiment performed between 9:00 AM-3:00 PM.Theprocedure for theusedFSThaspreviouslybeendescribed[39].Twoswimmingsessionswereconducted:aninitial10-minpre-test followed 24 hours later by a 5-min test. Following both swimmingsessions,theratswereremovedfromcylinders,lefttodry, and returned to their home cages. The water in the cylinders waschangedaftereveryothertrialtoavoidconfoundingresultsfrom urine or feces. Test sessions were videotaped for later scoring for the following parameters:

Immobilitytime-Timeinsecondsduringwhichanimalremainedfloatingpassivelyinthewaterinanuprightposition[32].

Struggling Time-The time in seconds during which the animalattemptstojumpoutofthetank,attemptstoclimbthewallsanddive into the tank [39].

Biochemical parametersEstimation of serotonin, norepinephrine and dopamine contents: Serotoninaswell as catecholamines (norepinephrineand dopamine) was determined in rat’s brain according tothe method of [40] using spectro-photoflourometer RF-5000Shimadzu, Japan. Rats were sacrificed 24 hours after the last

testquicklywithminimumdisturbance,toavoidanysubstantialchanges in brain amines concentrations, which may occurwithinafewminutes[41].Sacrificedanimalswereimmediatelydissected for brains on an ice-cold plate. They were either subjectedforanalysisimmediatelyorstoredat-80°Ctillthetimeof analysis. Then brains were weighed and homogenized in ice-coldsolutionofacidifiedn-butanoltoobtain10%homogenate.Homogenizationwasperformedusingglasshomogenizerfittedwith a glass pestle [Glas-Col (099ck5424)]. Duplicate internalstandard of serotonin, norepinephrine and dopamine was preparedthenneurotransmitterswereextractedfromthetissuesendingtotheaqueousphasewhichwasdividedintotwoportions,thefirstwasusedforthedeterminationofserotoninwhiletheother was used for the assessment of both norepinephrine and dopamine.SerotoninderivativewasestimatedbyreactionwithOrtho-phthalaldehyde while norepinephrine and dopamine derivativewasestimatedbyoxidationofiodine.

Estimation of brain malondialdehyde (MDA) and reduced glutathion (GSH) contents: DeterminationofMDAwas carriedout according to the previously described method [42] with a slightmodificationintheincubationperiod[43].Determinationofbrainreducedglutathione(GSH)wasdoneusingatestreagentkit(Biodiagnostic,Egypt)accordingtothedescribedmethod[44]andaccordingtothemanufacturer’sinstructions.BrainMDAandGSHcontentswereestimatedin10%brainhomogenateincoldsaline that was centrifuged at 4000 rpm for 15 mins at 4°C.

Estimation of brain tumor necrosis factor-alpha (TNF-α) and interleukine-6 (IL-6) contents: Tumor Necrosis Factor-alpha (TNF-α)determinationwasdoneusing a test reagent kit(eBioscienceco.,NorthAmerica)accordingtothemanufacturer’sinstructions. Interleukien-6 (IL-6) was determined using a testreagent kit (WKEAmed supplies corp, China) according to themanufacturer’s instructions. Brain TNF-α and IL-6 contentswere estimated in 10% brain homogenate in cold saline thatwascentrifugedat4000rpmfor15minsat4°C.Calculationsinthe tested samples were determined as pg/g. tissue from thestandard curve constructed.

Statistical AnalysisData was expressed as the mean ± SEM. Statistical analysiswas carried out by onewayANOVA followedby Tukey-Kramermultiple comparisons test to calculate significance of thedifferencebetweentreatments,valuesofP<0.05wereconsideredsignificant.StatisticalanalysiswasdoneusingGRAPHPADPRISMsoftware(version5,SanDiego,CA,USA).

ResultsPerformance in the open-field testAs illustrated in Figures 1i-1iv, administration of clonidinesignificantly increasedlatencytimeto300.54%while itshowedasignificantreductionintheambulation,rearingandgroomingfrequencies to 8.77%, 32.88% and 42.91% respectively ofnormal control value. Treatment with agomelatine, curcuminand their combination significantly decreased the latency timeto 30.27%, 22.72% and 37.81% while significantly increased

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the ambulation frequency to 901.89%, 986.39% and 643.35%respectively as compared to the depressed control values.Rearingfrequencywasalsoincreasedto232.40%,243.13%and268.24%respectivelyascomparedtodepressedcontrolvalues.Therewas a significant increase in the grooming frequency ofagomelatineandagomelatine/curcumintreatedratsto233%and283%respectivelyascomparedtodepressedcontrolrats.

Performance in the forced swimming testAs shown in Figures 2i and 2ii,clonidineadministrationinducedasignificantelevationinimmobilitytimeto209.55%whilecausedasignificantreductioninstrugglingtimeto23.37%ascomparedto the normal control rats. Treatment with agomelatine andcurcumin either separately or in combination significantlydecreased the immobility time to 74.67%, 58.74%and 64.93%while significantly increased the struggling time to 253.89%,343.89% and 304.05% respectively as compared to depressedcontrol rats.

Brain monoamines contentsAs illustrated in Figures 3i-3iii, administration of clonidinesignificantlydecreasedserotonin,norepinephrineanddopaminecontentsto53.25%,72.08%and69.62%respectivelyascompared

to the normal control rats. Treatment with agomelatine andcurcumin either separately or in combination significantlyincreasedserotonincontentto188.88%,193.33%and151.11%andnorepinephrinecontentto182.37%,153.07%and139.54%respectively of the depressed control values. Treatment withagomelatine and curcumin separately significantly increaseddopamine content to 67.6% and 144.19% respectively ascomparedtodepressedcontrolratswhilethereco-administrationdidnotshowsignificantincrease.

Brain MDA and GSH contentsAs illustrated in Figures 4i and 4ii, depression induced by administration of clonidine caused significant increase in brainMDA content reached to 112.24% with significant decreasein brain GSH content to 82.10% as compared to the normalcontrol contents. Administration of agomelatine and curcumineitherseparatelyorincombinationsignificantlydecreasedbrainMDAcontentto86.91%,83.58%and88.28%whilesignificantlyincreasedbrainGSHcontentto118.71%,114.57%and116.61%respectively as compared to depressed control contents.Howeverco-administrationofagomelatineandcurcumindidnotsignificantly alter either brainMDA content orGSH content ascompared to each treatment alone.

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Figure 3 (i-iii) Effect of agomelatine (ago) and/or curcumin (cur) in comparison to fluoxetine (flx) on clonidine (clo)-inducedchangesinserotonin(i),norepinephrine(ii)anddopamine(iii)contentsinratbrain.Datawasexpressedasmeans±sem.Numberofanimals ineachgroup (n)=10.A,b,c,d: significantlydifferent fromcorrespondingnormalcontrol (saline),depressed control (clo), (flx)-treated rats,mixture-treated (mix) groups respectively atp>0.05usingonewayanovafollowedbytukey–kramermultiplecomparisontest.

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Brain TNF-α and IL-6 contentsAs illustrated in Figures 5i and 5ii, administration of clonidinesignificantly elevated brain TNF-α and brain IL-6 content to152.32%and137.60% respectivelyas compared to thenormalcontrolrats.Administrationofagomelatineandcurcumineitherseparatelyor incombinationsignificantlydecreasedbothbrainTNF-α content to 51.79%, 65.43% & 71.20% and brain IL-6contentto59.38%,41.95%&45.58%respectivelyascomparedto depressed control rats. Agomelatine administration aloneshowedsignificantdecreaseinbrainTNF-αcontentascomparedtoagomelatineandcurcuminco-administration.

DiscussionDepression is an important public health issue [45] due to its high prevalence [46], the markedly reduced quality of life in both patientsandtheir relatives[47]andthehigheconomicburden[48]. Inthepresentstudy, injectionofclonidinedaily forsevendays resulted in depression-like behaviour in rats as indicated by significant increase in latency time as well as decrease inambulation, rearingandgrooming in theOFTwhile in the FST,therewasanincreaseinimmobilitytimewithadecreaseinthestrugglingtime.Thesedatawereinaccordancewiththepreviousstudies on clonidine-induced depression in rats using FST [49]or using both FST and OFT [50]. It is worthy tomention that,increased passive behaviour response in the forced swimming test such as immobility and decreased active behaviour likeswimmingor struggling are thought tobea clear indicationofdepressive like symptoms [51].

Results of the current study also showed that, clonidine induced analteration inneurotransmitters in the formofadecrease inbrainserotonin(5-HT),dopamine(DA)andnorepinephrine(NE)contents. Clinical studies have revealed that the monoamines (5-HT,DA,NE)haveacrucialroleinthedevelopmentofdepression[52].Severalstudiesreportedthat5-HTandNEhaveshoweda

drastic decrease in rats treated with clonidine (0.8mg/kg I.P)forsevendays[49,53,54].Thebiochemicalbasisofclonidine–induced behavioural changes is probably due to decrease in NE release in the CNS [55]. A close inter-relation was shownto exist between NE and 5-HT [56]. It is known that clonidine administrationdecreased5-HTtransmissionbydirectactivationof α2-heteroreceptors on 5-HT terminals [57]. The dopaminehypothesis indicates that the dopaminergic system strongly interacts with the norepinephrine and serotoninergic systems in the pathophysiology of depression [58].

In the present work, clonidine also produced alterations inoxidativestressbiomarkersaswellaspro-inflammatorycytokinesin the brain of rats which was manifested by an increase in malonaldehyde (MDA), TNF-α and IL-6 contents accompaniedwithadecreaseinreducedglutathione(GSH)content.Inanotherresearch, it is reported that clonidine resulted in an increase in MDAandIL-6accompaniedwithareductioninGSHbraincontentswithout any significant change in TNF-α [54].Additionally, it isreported that clonidine induced significant increase in TRABSand TNF-α contents accompanied with significant depletionof GSH content [49]. Several pro-inflammatory cytokineswerefound to be up-regulated in depressed individuals and both oxidative and inflammatory pathways had been shown to bepositivelycorrelatedwitheachotherformingaviciousandself-enforcing cycle [59]. Reactive oxygen species were also foundto activate pro-inflammatorymediators such as IL-1b, IL-6 andnuclearfactor-kappaB[60].Moreover, inflammatorymediatorsreleased by microglia in response to stress induce neurotoxicity, neurodegeneration and dysfunction of serotonergic andnoradrenergic systems [61].

Ontheotherhand,mostofthecurrentlyusedantidepressantshaveadelayedonsetofaction[62]aswellasavarietyofundesirableside effects such as sedation, decrease of blood pressure, increaseofweight,indigestionorsexualdysfunction.Thisoftenresultsinpatients’poorcomplianceandbreak-upofmedication

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with recurrence of depressive symptoms and increase in suicidal risk [63].Agomelatinehasbeenused in the currentwork; it isanantidepressantwithrapidonsetofactionandrelativelylowerside effects, it protected rats from the behavioural alterationsproducedbyclonidineasshownbynormalizedlatencytimeandgroomingfrequencyaswellasincreasedambulationandrearingfrequencies in OFT. It also decreased the immobility time andincreasedthestrugglingtimeinFST.Thesedataareinaccordancewiththepreviousstudiesconcerningitsantidepressantactivitiesas well as some related stress-induced behavioural changes [64-66].Theantidepressant-likeeffectofagomelatinedependsonitsinteractionwithmelatoninreceptors[67].

Thepresentdataalsorevealedthatagomelatineadministrationreversedthedecreaseinmonoamine(5-HT,NE,andDA)contentsin the brain of depressed rats. These findings are in partialagreement with other study in which agomelatine elicited asustained increase in dialysis levels of DA and NE in the frontal cortexoffreelymovingrats,whereas5-HTwasnotsignificantlymodified [68]. However, these findings are in completeagreementwithanotherstudywhichrevealedthatagomelatinethroughitsmelatonergicagonisticactivitycausedenhancementof DA and 5-HT neurotransmission and increased brain dopamine [26].Bertaina-Angladeetal.[69]attributedtheantidepressant-like activity of agomelatine not only to its agonistic activity atmelatoninergic(MT1/MT2)receptorsbutalsotoitsantagonisticactivity at 5-HT2C receptors. Antagonism at 5-HT2C receptorsleads to enhancement of dopaminergic and adrenergic input to the frontal cortex, inductionof hippocampal neurogenesis andultimatelytoagomelatine’santidepressanteffect[14].

The present data displayed that agomelatine compensatedoxidative stress and inflammation caused by clonidine asdemonstrated by raised brain GSH content aswell as reducedbrainMDA,TNF-αand IL-6 contents. Thesefindingareparallelto those showed that agomelatine reversed the increase in

TNF-α and IL-6 levels [70]. Additionally, it is reported thatadministration of agomelatine reversed the decrease in GSHlevel and the increase in TNF-α and IL-6 levels in rat’s brains[71]. Similar published findings also reported the same resultsexcept that therewasnoeffecton IL-6 level [72].AgomelatineprotectionagainstoxidativestressandinflammationappearstobemediatedthroughMT1andpossiblyMT2receptors[73,74].Consequently, through affecting these receptors, agomelatineresetthedisturbedrhythmsandsleep–wakerhythms.Impairedsleephasbeen shown toadversely affectoxidative stress [75],mitochondrialintegrityandfunction[76]aswellasinflammation[77]; mechanisms that play pathophysiological roles in moodandanxietydisorders.Improvementofsleepbyagomelatinecantherefore improve oxidative, mitochondrial, and inflammatoryprocesses which are contributed to the pathophysiology of major depression [78].Moreover, agomelatine as an immune-regulatory agent, acts on the whole temporal progression of the inflammatory response [79]which includes an early phasecharacterizedbythereleaseofpro-inflammatorycytokinesanda later phase that may be characterized by changes in microglia aswellasinsystemsthatmayliedownstreamcytokineinduction[80]. Togetherwith these results, it is suggested that the anti-inflammatory effect of agomelatine involves oxidant-cleansingproperties[72].

Finally,theeffectivenessofthenovelantidepressantagomelatineis considered to be due to its dual action of preserving sleepquality and efficiency through melatonergic MT1 and MT2activation as well as elevating mood and activity throughserotoninergic5-HT2Cantagonism[78]. It isworthytomentionthat;agomelatineshowsmorecompleteprofilethanfluoxetinein correcting theneurochemical andbehavioural abnormalitiesof the depressed rats [66].

Curcumin, a naturally occurring phenolic compound, is commonly usedasaspice,additiveandfoodcolorant[81]. Inthepresent

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i. TNF- α content (pg/g. tissue) ii. IL-6 content (pg/g. tissue)

Figure 5 (i-ii) Effect of agomelatine (ago) and/or curcumin (cur) in comparison to fluoxetine (flx) on clonidine (clo)-inducedchangesintnf-α(i)andil-6(ii)contentsinratbrain.Datawasexpressedasmeans±sem.Numberofanimalsineachgroup (n)=10. A, b, c, d: significantly different from corresponding normal control (saline), depressed control (clo),(flx)-treatedrats,mixture-treated(mix)groupsrespectivelyatp>0.05usingonewayanovafollowedbytukey–kramermultiplecomparisontest.

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study,administrationofcurcuminguardedratsfromdepressioncausedbyclonidine injection.Thiseffectwasevidencedbythedecline in latency time along with the increase in ambulationand rearing frequencies in the OFT and the decline in the immobilitytimeaswellastherise inthestrugglingtimeintheFST.Theseresultsareinaccordancewiththepreviousdatawhichdemonstratedthatcurcuminsignificantlyreversedthedecreasein locomotor activity of rats induced by chronic mild stress[82].Also,administrationof curcumin to chronicunpredictablemild stress exposed rats ameliorated the decreased locomotor activities due to stress exposure as well as significantlydecreasedimmobilitydurationwithcomplementary increase inswimmingtime[27,83].According toWangetal. [84]studies,thedurationofimmobilityintheFSTwasdecreasedasaresultof pre-treatment with curcumin in lipopolysaccharide-induced depressive-likebehaviour inmicewithnosignificantdifferenceinthelocomotoractivity.Moreover,administrationofcurcuminsimultaneously with applying chronic unpredictable stress did notaffectthenumberofcrossingandrearingofratsinOFT[85].Curcuminhasalipophilicproperties,thusiteasilycrossestotheblood-brain barrier or cell membranes [86, 87] and as a result possessespossiblebeneficialeffects inexperimentalmodelsofdepression [88]. The antidepressant effect of curcumin mightbeattributed to its suppressionof central5-HT1A,5-HT1Band5-HT7 receptors in rats [89].

Current study showed also that curcumin administrationimproved central neurotransmitter (5-HT, NE, and DA)contents in the brain of the depressed rats. These results are in accordance with the study which shows that treatment with curcumin produces significant increase in 5-HT, NE and DA inthebrainofdepressedrats[27].Inaddition,pre-treatmentwithcurcuminshowedsignificantimprovementintheneurochemicalcontents in the brain of animals [90-92]. It is suggested that, the neuroprotectiveeffectsofcurcuminmayinvolvethemodulationof central monoaminergic neurotransmitter systems [27].Increased levels of serotonin, dopamine and norepinephrine by curcumin can be attributed to monoamine oxidase inhibitoryeffects onMAO-A andMAO-B enzymes [25, 93]. The effect ofcurcumin on serotonin appeared to be dose-dependent, at high doses curcumin also increased dopamine and to a lesser extentnoradrenaline.Additionally,theeffectofcurcuminontheserotonergicsystemwaspossiblyrelatedto its interactionwith5-HT1A/1B and 5-HT2C receptors [25]. Curcumin also elevatesbrain DA levels and interact with D1 and D2 receptors [94].

Thepresentdataalsodisplayedthat,curcuminraisedbrainGSHand reducedbrainMDA,TNF-αand IL-6contentsascomparedto clonidine-treated rats. Besides, the reduction of brainMDAand IL-6bycurcuminwasmorepronounced than thatofthe used standard antidepressant fluoxetine. Similar resultsshowed that chronic treatment with curcumin significantlyattenuatedoxidativedamageas indicatedbyreduction inMDAandrestorationofthereducedGSHlevels,italsodecreasedtheinflammationasindicatedbyreductioninthehighlevelofTNF-αcaused by olfactory bulbectomy in rats [88]. Along with this, curcumineffectively inhibits geneexpressionof these cytokine

[82]andattenuatesmicroglia activationandoverproductionofTNF-α [84] as well as produces dose-dependent reduction inTNF-α levels in thebrainof reserpine-depressed rats [27]. It isbelievedthat theanti-inflammatorypropertiesofcurcuminaremost likelythroughthedose-dependent inhibitionofmicroglialactivationanddown-regulationofIL-1β,IL-6andTNF-αinbothtranscriptional and translational levels [95]. Curcuminwas alsofoundtobeascavengerof theformedreactiveoxygenspeciesprobably more than vitamin E and A [91]. It penetrates the inner mitochondrial membrane freely due to its lipophilic nature [24] and protects themitochondria against various oxidative stressconditions[96,97].

Existingdatademonstratedthatco-administrationofagomelatineandcurcumindecreasedlatencytimewithconcomitantincreasein ambulation, rearing and grooming frequencies in the OFT.Beyond, the immobility timewas declined and struggling timewasamelioratedintheFST.However,theimprovementintheOFTandFSTparametersweresimilartoeitherofthetreatmentaloneexceptfortheambulationfrequencyintheOFTwhichwaslowerwith both treatments while grooming was improved as compared to curcumin group. Moreover, the present study showed thatthebraincontentsof5-HT,NE,andDAweresignificantlyraisedin rats received combination of agomelatine and curcumin.Yet theoutcomewas still lower than that foreachdrugalone.Additionally,currentinvestigationdatarevealedthatbrainvaluesofoxidativestressbiomarkers(MDA,GSH)andpro-inflammatorycytokines(TNF-α,IL-6)inratsgivenagomelatinecombinedwithcurcuminwereanaloguetothatresultedafteradministrationofagomelatineorcurcuminseparately.

Combinationofcurcuminwithotherantidepressantshasshownto synergistically increase the serotonin level and enhanceantidepressant-like activity in various animal models [98].Previous researchers also detected that curcumin enhanced the antidepressant actions of escitalopram and had nosignificantadverseeffects indepressedsubjects [99].Take intoconsideration that in contrast to imipramine, fluoxetine andtianeptineaswellasagomelatineactson twopharmacologicalsubstrates;melatoninand5HT2Creceptors[100].Consequently,itsapplicationproducesmoredistinctbehaviouralandmoleculartherapeuticprofilesthanthatofotherantidepressants.

In the present study, no additive or pronounced effects weredetected by concomitant administration of curcumin andagomelatinewhichmaybe attributed to dose related reasons;forreachingtheceilingeffectorduetotheadaptivemechanismsoccurredatthesynapticlevelbytheirrepeatedadministration.However,thereisnopublisheddataregardingtheeffectofthecombinedtreatmentsofcurcuminandagomelatine.Additionally,agomelatine’ssystemicexposureincreasesproportionatelywithdose. However, at a significantly higher doses (>200 mg andabove), saturationoffirstpassmetabolismoccurs, andplasmalevels may increase disproportionately [101]. Clinically, druginteractionsareunlikely,with theexceptionofco-administeredpotentcytochromeP1A2(CYP1A2)enzymeinhibitors,whichmayincreaseagomelatine’splasmalevel[102].Itisworthytomention

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that, curcumin shows a competitive type of inhibition towardsCYP1A2 [103].

On the other hand, agomelatine acts as: MT1/MT2 receptoragonist, 5-HT2C receptor antagonist [69], enhances dopaminergic and adrenergic input, induces hippocampal neurogenesis [14], decreases pro-inflammatory cytokines [70], alters microgliaactivity following LPS injection [80] and has antioxidantproperties [72]. Meanwhile, curcumin performs its actionthroughinteractionwith5-HT1A/1B,5-HT2C[25]andD1andD2receptorsaswell [94].Additionally,curcumin inhibitsmicroglialactivationanddown-regulatesIL-1β,IL-6andTNF-αtranscription[95]. Curcumin also possess powerful antioxidant activity [91].Consequentlyandinthelightofwhatwasmentioneditcanbespeculated that agomelatine and curcumin shared the samelong-term adaptive mechanisms induced by their repeatedadministration, hence there was no enhanced effects in theircombinedadministration.Furtherresearcheshavebeenneededtoexplorethemolecularalterationsinducedbyagomelatineandcurcumin in various models of depression in rats as well as the mechanisms of depressive-like phenotype reversion in the brain.

ConclusionClonidine administration causes several depressive-likesymptomsanddeleteriouseffectsonneurobehavioralfunctions;it also induces inflammationandoxidative stress in rat’sbrain.Agomelatineorcurcuminintheusedtherapeuticdoseshavehighefficiencyagainstclonidine-inducedabnormalities.Theeffectofcurcuminismorepronouncedthanthatoffluoxetineconcerningthebehavioural changes.However, concomitant administrationof both agomelatine and curcumin against development ofdepression in rats has no pronounced or additive effects thaneach of them.

Conflict of InterestThe authors declare that they have no conflicts of interest todisclose.

Financial SupportThisresearchhasnotreceivedanyspecificgrantfromanyfundingagency in thepublic, commercial or not for profit sectors. Thework has been done on the expense of the authors.

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Comparative Study on the Activity of Agomelatine and/or ...psychopathology.imedpub.com/comparative-study-on... · of Agomelatine and/or Curcumin against Development of Depression

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