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Phytomedicine 18 (2011) 402–407

Contents lists available at ScienceDirect

Phytomedicine

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hort communication

ntidepressant-like effect of mitragynine isolated from Mitragyna speciosaorth in mice model of depression

. Farah Idayua, M. Taufik Hidayata,b,∗, M.A.M. Moklasa, F. Sharidaa,.R. Nurul Raudzaha, A.R. Shamimaa, Evhy Apryania

Human Anatomy Laboratory, Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, MalaysiaLaboratory of Physical Performance and Skills Analysis, Sports Academy, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia

r t i c l e i n f o

eywords:itragyna speciosaitragynine

mmobility timeorced swimming testail suspension testntidepressant-like activityPA axisorticosterone

a b s t r a c t

Mitragyna speciosa Korth. leaves have been used for decades as a traditional medicine to treat diarrhea,diabetes and to improve blood circulation by natives of Malaysia, Thailand and other regions of SoutheastAsia. Mitragynine is the major active alkaloid in the plant. To date, the role of mitragynine in psychologicaldisorders such as depression is not scientifically evaluated. Hence, the present investigation evaluates theantidepressant effect of mitragynine in the mouse forced swim test (FST) and tail suspension test (TST),two models predictive of antidepressant activity and the effect of mitragynine towards neuroendocrinesystem of hypothalamic-pituitary-adrenal (HPA) axis by measuring the corticosterone concentration ofmice exposed to FST and TST. An open-field test (OFT) was used to detect any association of immobility

in the FST and TST with changes in motor activity of mice treated with mitragynine. In the presentstudy, mitragynine at dose of 10 mg/kg and 30 mg/kg i.p. injected significantly reduced the immobilitytime of mice in both FST and TST without any significant effect on locomotor activity in OFT. Moreover,mitragynine significantly reduced the released of corticosterone in mice exposed to FST and TST at doseof 10 mg/kg and 30 mg/kg. Overall, the present study clearly demonstrated that mitragynine exerts anantidepressant effect in animal behavioral model of depression (FST and TST) and the effect appears to

ction

be mediated by an intera

ntroduction

Mental disorder particularly major depression causes a signifi-ant burden on health worldwide. The main symptom of depressions characterized by a pervasive low mood, feeling of helplessness,oss of interest and loss of pleasure in most of the usual activitiesBhutani et al. 2009). Stressful environment, adverse life-event andack of supporting relationship are some of the causal factor thatontributes to development of depression in human.

Interactions between monoamine neurotransmitters systemncluding 5-hydroxytryptamine (5-HT), noradrenaline (NA) andopamine (DA) in the brain along with their specific reuptakend receptor protein has gain so much interest in the spectrumf antidepressant studies (Yi et al. 2008). As far, antidepressant

rugs available in the market claimed to be effective in treatment ofepression. However, the main significant drawbacks of that syn-hetic antidepressant are due to their high incidence of dangerouside effects and inadequate for number of individuals (Binfaré et al.

∗ Corresponding author. Tel.: +603 89472356.E-mail address: taufik@medic.upm.edu.my (M. Taufik Hidayat).

944-7113/$ – see front matter © 2010 Elsevier GmbH. All rights reserved.oi:10.1016/j.phymed.2010.08.011

with neuroendocrine HPA axis systems.© 2010 Elsevier GmbH. All rights reserved.

2009). Therefore, other mechanism should be considered, as theymight provide potential effective target with higher efficacy fortreatment of depression, and perhaps with fewer drawbacks.

The hypothalamic-pituitary-adrenal (HPA) axis in the neu-roendocrine system is one of the complicated neurobiologicalmechanisms which play important roles as similar as monoamineneurotransmitters system in the new antidepressant development.Dysfunction or hyperactivity of HPA axis system provides signifi-cant indicator of depression together in the response to stressorsreflected by overproduction of glucocorticoid hormones mainlycorticosterone in rodent and cortisol in human (Xu et al. 2008).Hence, the normalization of the HPA axis system as another primemechanism of antidepressant actions appears to be one of the spe-cial interest.

Recently, more herbal medicine has being used as alternativetherapy for depression (Kessler et al. 2001). Due to its naturalconstituent and availability, natural herbs which obtained from

natural sources are believed to provide less untoward effect profilesand provide greater effectiveness as compared to synthetic drugavailable over the market. Mitragyna speciosa Korth. is a tropicalplant endemic to Southeast Asia particularly in northern peninsulaof Malaysia, central and southern part of Thailand, and Indone-

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Fig. 1. Chemical structure of mitragynine.

ia (Jansen and Prast 1988; Mossadeq et al. 2009). It is popularlynown by local as ‘ketum’ in Malaysia and ‘kratom’ in Thailand. Thelant was classified under the coffee family of Rubiaceae. Mitrag-na speciosa leaves have been used by natives for its opium-likeffect and cocaine-like stimulant ability as anti-fatigue, anti-painnd as tonic to increase endurances or performances of work underot sunlight (Reanmongkol et al. 2007). It is traditionally usedy villagers as an alternative treatment for fever, malaria, cough,ypertension, diarrhea, to prolong sexual intercourse as well asubstitution for treatment of opiate addiction such as morphineChan et al. 2005; Assanangkornchai et al. 2004).

Mitragyna speciosa contains abundant of indole alkaloidsMatsumoto et al. 2008). Mitragynine (Fig. 1) was found to behe primary active alkaloid compound of the entire plant which

ight hold the key for the effects of Mitragyna speciosa (Takayama004). It has a molecule formula of 9-methoxy-corynantheidineC23H30N2O4) with the molecular weight of 398.50 (Chee et al.008). Previously, in two different studies, alkaloid extract andqueous extract of Mitragyna speciosa has been shown to haventidepressant-like effects in mouse models of behavioral despairests (Kumarnsit et al. 2007a, 2007b). However, antidepressant

echanism of the plant in both studies is not clearly demon-trated. In consideration of previous findings, mitragynine could bebeneficial option in prevention and treatment for stress-inducedisorder such as depression.

In the present study, we evaluated the antidepressant-like effectf mitragynine using two classical behavioral models of antide-ressants screening known as forced swimming test (FST) andail suspension test (TST) together with open-field test (OFT). Inccordance to the tests, the effect of mitragynine on serum cor-icosterone concentrations (an index of HPA axis status) was alsoimultaneously investigated in the present study.

aterials and methods

reparation of mitragynine from Mitragyna speciosa leaves

The fresh leaves of Mitragyna speciosa Korth. were collected fromts natural sources around Peninsula Malaysia particularly in Perlisnd Kedah. The plant was authenticated by botanist from Depart-ent of Botany, Faculty of Forestry, Universiti Putra Malaysia

UPM), Serdang, Malaysia, based on their microscopic and macro-copic characteristics. A voucher specimen (ATS 001) was depositedn the Herbarium of the Department of Botany, Faculty of Forestry,

niversiti Putra Malaysia (UPM), Serdang, Malaysia. Mitragynineas purified from the fresh leaves of Mitragyna speciosa Korth

ccording to the method described by previous study (Houghtonnd Ikram 1986; Ponglux et al. 1994; Reanmongkol et al. 2007).

icine 18 (2011) 402–407 403

The fresh leaves of Mitragyna speciosa (1 kg) were dried at45–50 ◦C, powdered and macerated with absolute methanol for72 hours. The extracts were mixed, filtered and evaporated usingrotary evaporator (Eyela N-1000, Tokyo Rikakikai CO., LTD., Tokyo,Japan) to yield 14.5% (w/w) of crude methanol extract. Themethanol extract was dissolved in 10% acetic acid solution, wellshaken, left to stand for 24 hours and filtered to give acidic fil-trate. The acidic filtrate was washed with petroleum ether, madeinto alkaline (pH 9) with 25% ammonia solution and extracted withchloroform. The combined chloroform extracts were washed withdistilled water, dried over anhydrous sodium sulphate and evap-orated to yield 0.73% (w/w) of crude alkaloid extract. The majoralkaloid was isolated by silica gel column chromatography elut-ing with diethyl ether was identified as mitragynine with standardspectroscopic methods (1H NMR, 13C NMR). Over all, the yield ofmitragynine was approximately 0.087% (w/w) of the fresh leavesweight.

Reagent and chemicals

Mitragynine was dissolved in 20% (v/v) Tween-80 (poly-oxyethylene sorbitan monooleate, Sigma–Aldrich Co.). Fluoxetinehydrochloride, amitriptyline hydrochloride and amphetaminehydrochloride were purchased from Sigma Chemical Co. (USA) andwere used as reference drugs. All drugs were dissolved in physio-logical saline (NaCl 0.9%). All other reagents used in the study wereof analytical grade.

Animals

Male mice from the ICR strain purchased from Northern RKSupplier, Sri Kembangan, Selangor, weighing 25–35 g were used.Animals were placed at Animal house, Faculty of Medicine andHealth Sciences, Universiti Putra Malaysia Serdang, Selangor,Malaysia, housed 8 per cage under a normal 12-h/12-h light/darkschedule with the lights on at 07:00 a.m and had free access to waterand food pellets. They were allowed at least 7 days to adapt to thelaboratory prior to the administration. Experiments were carriedout between 9:00 a.m. and 3:00 p.m. All studies were conducted inaccordance with Animal Care Committee, Faculty of Medicines andHealth Sciences, Universiti Putra Malaysia, Serdang. The minimumnumber of animals and duration of observations required to obtainconsistent data were employed. All efforts were made to minimizeanimal suffering and to reduce the number of animal used.

Drugs administration

The animals were randomly assigned into control and sixexperimental groups (8 mice per group) as follows: vehicle-treated; mitragynine 5 mg/kg; mitragynine 10 mg/kg; mitragy-nine 30 mg/kg; fluoxetine 20 mg/kg; amitriptyline 10 mg/kg andamphetamine (1 mg/kg). Mitragynine and all drugs were intraperi-toneally (i.p.) administered once. Mitragynine was dissolved in 20%Tween-80 and diluted to the desired concentration on the dayof testing while fluoxetine, amitriptyline and amphetamine weredissolved in normal saline (0.9% NaCl). Vehicle and mitragyninewere injected i.p., 30 min before testing. Fluoxetine was admin-istered i.p., 60 min before testing, amitriptyline was administeredi.p., 30 min before testing and amphetamine was administered i.p.,15 min before undertaking the test.

The test was conducted according to the reported methodologyoriginally described by Porsolt with minor modification (Porsoltet al. 1977). Briefly, mice were individually forced to swim in an

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in FST and TST produced no significant difference in number ofcrossing activity of mice in OFT. The clinically effective antidepres-sant fluoxetine at 20 mg/kg and amitriptyline at 10 mg/kg whichsignificantly reduced the duration of immobility time of mice FSTand TST produced no significant difference in number of crossing

04 N. Farah Idayu et al. / Phy

pen cylindrical container (diameter 14 cm, height 20 cm), with aepth of 15 cm of water at 25 ± 1 ◦C. The immobility time, defineds the absence of escape-oriented behaviors, such as swimming,as scored during 6 min with the help of stop-watch, as describedreviously by (Eckeli et al. 2000; Zomkowsi et al. 2004; Kaster etl. 2007). Each mouse was judge to be immobile when it ceasedtruggling and remained floating motionless in the water, makingnly those movements necessary to keep its head above water. Thearameter obtained was the number of seconds spent immobile.he water in the containers was changed after each trial.

ail suspension test (TST)

The total duration of immobility induced by tail suspensionest was measured according to the method described by Sterut al. (1985). Mice both acoustically and visually isolated wereuspended 50 cm above the floor by adhesive tape placed approx-mately 1 cm from the tip of the tail. The total immobility period

as scored manually during 6 minutes test session with the help oftop-watch. Immobility was defined as the absence of any limb orody movements, except for those caused by respiration or whenhey hung passively and completely motionless. The parameterbtained was the number of seconds spent immobile. Parametersed was the number of seconds spent immobile.

pen-field test (OFT)

In order to rule out any unspecific locomotor effect of mitragy-ine on antidepressant-like effect of these compounds, mice weredministered with the same regimen as in the FST or TST. Theirocomotor activities (crossing activity) were evaluated in the open-eld paradigm. Before each test, animals were kept in the testoom at least 1 hour before the open-field test (OFT) for habit-ation. The ambulatory behavior was assessed in open-field testescribed by Rodrigues et al. (1996) and Peng et al. (2007) withlight modifications. The main apparatus consisted of square arena50 cm × 50 cm × 40 cm) high with grey surface covering every wall.he floor of the arena was divided equally into twenty-five squares10 cm × 10 cm) marked by black lines. All animals were used onlynce in this test. These animals were different from those usedn the FST and TST. Each mouse was placed individually into theenter of the arena and allowed to explore freely. The numberf squares crossed with all paws (crossing) were observed andounted in 60 minutes. During the test session, the locomotor orrossing activity of mice was recorded and saved using video cam-ra for permanent record (Moklas et al. 2008). The square arenaas cleaned with a solution of 10% alcohol between tests and dried

fter occupancy by each mouse in order to hide animal clues ando prevent each mouse from being influenced by the odors presentn the urine and feces of the previous mouse.

orticosterone assay

Blood from each mouse was withdrawn immediately afterxposure to force swim test (FST) and tail suspension test (TST)espectively. In order to avoid fluctuations on hormone levels dueo circadian rhythm, mice were bled at 12:00 p.m. to 13:00 p.m. onhe day of sacrifice. Blood was collected through cardiac puncturend sampled into plain tubes and was kept in room tempera-ure. It was centrifuged at 3000 rpm for 10 minutes to separatehe serum and red blood cells. The serum was kept frozen at

20 ◦C freezer and stored it until assayed was performed. Serum

orticosterone concentrations were determined using a commer-ially available enzyme immunoassay kits (corticosterone ELISA,BL International GMBH, Hamburgh Germany) used for the quanti-ative determinants of corticosterone in serum or plasma following

icine 18 (2011) 402–407

the manufacturer’s instructions. The sensitivity of the assay was<1.631 nmol/l. Intra-assay and inter-assay coefficients of variationswere less than 4.09% and 6.36% respectively. Data were expressedas nmol/l.

Statistical analysis

Data were expressed as the mean ± standard error of mean(S.E.M.). Comparisons between experimental and control groupswere performed by one-way analysis of variance (ANOVA) followedby Tukey’s HSD test when appropriate. P < 0.05 was considered sig-nificant.

Results

Effects of mitragynine on immobility time of FST

After 30 minutes of treatment, mitragynine significantlyreduced (P < 0.05) the duration of immobility time at 10 mg/kg and30 mg/kg respectively as compared to control. Antidepressant drugof selective serotonin reuptake inhibitor, fluoxetine at 20 mg/kgand tricyclic antidepressant drug amitriptyline at 10 mg/kg thatused as positive control, administered by i.p. route caused signifi-cant reduction (P < 0.05) in the immobility time of mice forced swimtest (FST) as compared with control (Fig. 2).

Effects of mitragynine on immobility time of TST

Mitragynine at 10 mg/kg and 30 mg/kg significantly reduced(P < 0.05) immobility time of mice in tail suspension test (TST) ascompared to the control (vehicle). The clinically effective antide-pressant fluoxetine at 20 mg/kg and amitriptyline at 10 mg/kg thatused as positive control produced a marked significant reduction(P < 0.05) in the duration of immobility time as compared with con-trol (Fig. 3).

Effects of mitragnine on locomotor activity of OFT

Treatment with mitragynine at 10 mg/kg and mitragynine at30 mg/kg which significantly reduced duration of immobility time

Fig. 2. Effects of mitragynine (5 mg/kg, 10 mg/kg and 30 mg/kg), fluoxetine(20 mg/kg) and amitriptyline (10 mg/kg) on immobility time in the mouse forcedswim test (FST). Mitragynine was intraperitoneally (i.p.) administered 30 minutesbefore FST. Each column represents the mean ± S.E.M. of immobility period (s) of 8animals in each group (n = 8). *P < 0.05 compared to control.

N. Farah Idayu et al. / Phytomedicine 18 (2011) 402–407 405

Fig. 3. Effects of mitragynine (5 mg/kg, 10 mg/kg and 30 mg/kg), fluoxetine(pbo

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Fig. 5. Effects of mitragynine (5 mg/kg, 10 mg/kg and 30 mg/kg), fluoxetine

20 mg/kg) and amitriptyline (10 mg/kg) on immobility time in the mouse tail sus-ension test (TST). Mitragynine intraperitoneally (i.p.) administered 30 minutesefore the test. Each column represents the mean ± S.E.M. of immobility period (s)f 8 animals in each group (n = 8). *P < 0.05 compared control.

ctivity as compared to control. However, psychostimulant drug,mphetamine hydrochloride at 1 mg/kg which served as refer-nce drug in open-field test (OFT) significantly increased (P < 0.05)he number of crossing activity of mice as compared with controlFig. 4).

ffects of mitragynine on serum corticosterone levels in micexposed to FST

Swim stress procedure evoked a significant increased (P < 0.05)n serum corticosterone levels of control mice as comparedo other treatment. Mitragynine elicited a significant reductionP < 0.05) in increased serum corticosterone levels induced by

orced swim test (FST). Mitragynine treatment of 5 mg/kg, 10 mg/kgnd 30 mg/kg significantly reduced (P < 0.05) the serum corticos-erone levels in mice as compared with control. Amitriptyline at0 mg/kg and fluoxetine at 20 mg/kg decreased the serum cor-

ig. 4. Effects of mitragynine (5 mg/kg, 10 mg/kg and 30 mg/kg), fluoxetine20 mg/kg), amitriptyline (10 mg/kg) and amphetamine (1 mg/kg) on number ofrossings in open-field test (OFT) in 60 min. Mitragynine was intraperitoneally (i.p.)dministered 30 minutes before OFT. Each column represents the mean ± S.E.M ofumber of crossing (s) of 8 animals in each group (n = 8). *P < 0.05 compared toontrol.

(20 mg/kg), amitriptyline (10 mg/kg) on serum corticosterone levels in the miceexposed to forced swim test (FST). Each column represents the mean ± S.E.M. ofserum corticosterone concentration (nmol/l) of 8 animals in each group (n = 8).*P < 0.05 compared to control.

ticosterone levels (P < 0.05) significantly as compared to control(Fig. 5).

Effects of mitragynine on serum corticosterone levels in miceexposed to TST

A significant increased (P < 0.05) in serum corticosterone con-centrations were observed in mice exposed to TST of controlvehicle-treated mice. Mitragynine at 10 mg/kg and 30 mg/kg sig-nificantly reduced (P < 0.05) the serum corticosterone levels inmice as compared with control. Treatment of mice with fluoxetineat 20 mg/kg and amitriptyline at 10 mg/kg significantly reduced(P < 0.05) the serum corticosterone in TST as compared with control(Fig. 6).

Discussion

Behavioral studies have been shown to play an important partin the evaluation and development of antidepressant drugs (Xuet al. 2008). Forced swimming test (FST) and tail suspension test(TST) are among behavioral models that widely and routinely usedfor screening new antidepressant compound (Cryan et al. 2005).

In the present study, statistically significant results were obtainedin FST with treatment of mitragynine at 10 mg/kg and 30 mg/kg(33% and 48% reduction respectively). Positive control antidepres-sant drugs fluoxetine and amitriptyline produced significant result

Fig. 6. Effects of mitragynine (5 mg/kg, 10 mg/kg and 30 mg/kg), fluoxetine(20 mg/kg), amitriptyline (10 mg/kg) on serum corticosterone levels in the miceexposed to tail suspension test (TST). Each column represents the mean ± S.E.M.of serum corticosterone concentration (nmol/l) of 8 animals in each group (n = 8).*P < 0.05 compared to control.

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n immobility time (57% and 76% reduction respectively) similarith previous study (Reneric and Lucki 1998). The highest dose ofitragynine shows comparable effect as fluoxetine and amitripty-

ine in terms of its antidepressant actions revealing mitragynineight share some pharmacological mechanisms with established

ntidepressant drugs in this investigation.Similar outcome were obtained in TST as mitragynine extract

t doses 10 mg/kg and 30 mg/kg significantly reduced the immo-ility time (47% and 58% reduction respectively). Fluoxetine at0 mg/kg and amitriptyline at 20 mg/kg decreased the immobilityime (75% and 76% reduction respectively). These results indicatehat mitragynine extract has a dose-dependent antidepressant-ike effect that is comparable to established antidepressant drugs.ence, the antidepressant action of mitragynine could possibly

hrough one of the mechanisms precipitated by established antide-ressant agents that manage to be detected in TST.

Agents that able to enhance locomotor activity in OFT includingtimulants, convulsants and anticholinergic tend to produce a falseositive result in FST and TST (Bourin et al. 2001; Butterweck et al.003). In fact, hyperkinesia also causes false positive effect in FSTnd TST by shortening the immobility time in both tests (Takahashit al. 2008). Therefore, OFT was used to exclude these false effectshat could be associated with hyperkinesia (Kwon et al. 2009). The

ain difference between antidepressants and psycho-stimulant ishat antidepressants would not cause general increased in motorctivity (Borsini and Meli 1988). As a classical stimulant agent,mphetamine produces effects via elevation of mood and energyhyperactivity) (Rothman and Baumann 2003). Mitragynine seemsnable to produce acute toxicity or psycho-stimulant side effectelated with hyperkinesia in the brain. In addition, the finding sug-ested that reduction of immobility time elicited by mitragyninen FST as well as in TST was specifically arises via its antidepres-ant mechanism. This outcome is similar with previous study whicheported alkaloid and methanol extract of Mitragyna speciosa leavesroduced no significance effect over locomotor activity and onentobarbital-induced sleep in mice (Reanmongkol et al. 2007).

Forced swimming in FST induced alterations in the HPA axis,hereby increase the cortisol level of mice (Shalam et al. 2007).eduction of HPA axis hyperactivity by antidepressants is crucial inefining its therapeutic effects. In the present study, we observedhat mitragynine significantly reduced the corticosterone concen-ration in mice exposed to FST and TST, in a way similar to previousutcomes obtained using different antidepressant compounds (Yit al. 2007). Indeed, the present study shows mitragynine reducedhe corticosterone level of mice similar to classical antidepressantrugs, amitriptyline and fluoxetine. These results are somewhatimilar to clinical studies that revealed amitriptyline caused signif-cant decreased of salivary cortisol in depressed patient (Deuschlet al. 2003) while fluoxetine produced the initial recovery of HPAxis in depression (Inder et al. 2001).

Previous study also demonstrated that antinociceptive effect ofitragynine is mediated through descending noradrenergic and

erotonergic systems receptors suggesting that mitragynine mighte able to stimulate the release of endogenous noradrenalineNA) and serotonin (5-HT) from nerve terminals of descending

onoaminergic neuron (Matsumoto et al. 1996). In fact, numeroustudies have reported that most classical antidepressants producentinociceptive actions (Casas et al. 1995; Rodrigues-Filho andakahashi 1999). Taken together those findings, we suggest thathe antidepressant-like action of mitragynine might be through theestoration of monoamine neurotransmitter levels including sero-

onin, noradrenaline and dopamine in mice. However, based onur behavioral approach, we could not make definitive conclusionsn the detailed mechanism of mitragynine on monoamine levels.hus, further studies should be taken to confirm this particularssue.

icine 18 (2011) 402–407

In conclusion, our results obviously show that administration ofmitragynine is able to produce an antidepressant-like effect in FSTand TST, which not due to effect of psycho-stimulant or hyperkine-sia. Besides, we provide convincing evidence that the effect is due tointeraction with neuroendocrine HPA axis systems. Taken together,our findings are somewhat in accordance with clinical results, fur-ther suggesting that mitragynine may exert a role in the modulationof depression and has psychotherapeutic value in management ofdepression disorder. However, some consideration should be tak-ing into account that FST and TST is not the only model of depressionby which the results obtained using this model should be consid-ered and interpreted with caution due to some differences amongexperimental animals and clinical studies in human. Hence, furtherinvestigations are necessary to evaluate the effect of mitragynine inother animal’s behavioral model including relevant antidepressantdoses of mitragynine on its safety and efficacy level.

Acknowledgements

This study was supported by Fundamental Research GrantsScheme, Universiti Putra Malaysia, UPM Serdang, Selangor,Malaysia.

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