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ORIGINAL ARTICLE
Year : 2011  |  Volume : 134  |  Issue : 5  |  Page : 709-716

Antiparasitic activity of plumericin & isoplumericin isolated from Plumeria bicolor against Leishmania donovani


1 Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India
2 Department of Chemistry, University of Rajasthan, Jaipur, India

Date of Submission20-Jul-2010
Date of Web Publication20-Dec-2011

Correspondence Address:
Sarman Singh
Division of Clinical Microbiology, All India Institute of Medical Sciences, PO Box # 4938, Ansari Nagar, New Delhi 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-5916.91005

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   Abstract 

Background & objectives: The severe toxicity, exorbitant cost and emerging resistance of Leishmania species against most of the currently used drugs underscores the urgent need for the alternative drugs. The present study evaluates in vitro anti-leishmanial activity of Plumeria bicolor and its isolated compounds.
Methods: The in vitro anti-parasitic activity of chloroform extract of Plumeria bicolor, plumericin and isoplumericin were tested alongwith appropriate controls against promastigote and amastigote forms of Leishmania donovani using 96 well microtiter plate. The concentration used for assessing the anti-leishmanial activity of extract of Plumeria bicolor and both isolated compounds were 100 μg/ml and 15 μM, respectively. The viability of the cells was assessed by MTT assay. The cytotoxicity of these compounds was performed against J774G8 murine macrophage cells lines at the concentration of 30 μM.
Results: The Plumeria bicolor extract showed activity with the IC 50 of 21±2.2 and 14±1.6 μg/ml against promastigote and amastigote forms of L. donovani, respectively. Plumericin consistently showed high activity with the IC 50 of 3.17±0.12 and 1.41±0.03 μM whereas isoplumericin showed the IC50 of 7.2±0.08 μM and 4.1±0.02 μM against promastigote and amastigote forms, respectively. Cytotoxic effect of the chloroform extract of P. bicolor, plumericin and isoplumericin was evaluated in murine macrophage (J774G8) model with CC50 value of 75±5.3 μg/ml, 20.6±0.5 and 24±0.7 μM, respectively.
Interpretation & conclusions: Our results indicated that plumericin showed more potent activity than isoplumericin and might be a promising anti-leishmanial agent against L. donovani.

Keywords: Isoplumericin - Leishmania donovani - Plumeria bicolor - plumericin


How to cite this article:
Sharma U, Singh D, Kumar P, Dobhal M P, Singh S. Antiparasitic activity of plumericin & isoplumericin isolated from Plumeria bicolor against Leishmania donovani. Indian J Med Res 2011;134:709-16

How to cite this URL:
Sharma U, Singh D, Kumar P, Dobhal M P, Singh S. Antiparasitic activity of plumericin & isoplumericin isolated from Plumeria bicolor against Leishmania donovani. Indian J Med Res [serial online] 2011 [cited 2020 Apr 7];134:709-16. Available from: http://www.ijmr.org.in/text.asp?2011/134/5/709/91005

Leishmaniasis is a major public health problem causing significant morbidity and mortality in Africa, Asia and Latin America. Approximately, 12 million people are affected worldwide, with an increasing incidence of 2 million new cases diagnosed every year and 350 million people at risk, despite all efforts being made to fight the disease [1] . Leishmaniasis is caused by species of Leishmania, a unicellular kinetoplastid protozoan flagellate, which is transmitted through the bite of female phlebotomine sandfly species. It presents mainly in 3 clinical forms; visceral leishmaniasis (VL), cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL), of which VL is the most severe form of the disease, lethal if untreated and is caused by species of Leishmania donovani complex [2] . VL is endemic in the tropical and sub-tropical regions of Africa, Asia, Southern Europe, South and Central America. India accounts for half of the total 500,000 VL or kala-azar infections that are recorded annually worldwide [3] .

In the absence of any effective vaccine, the only mean to treat and control leishmaniasis is affordable medication. Most of the drugs currently being used for leishmaniasis, suffer from one or other limitations like exorbitant cost, difficult to administer, high toxicity or development of resistance [4],[5] . Therefore, there is an urgent need for safe, more effective and economically feasible drugs for the treatment of leishmaniasis. In this context, medicinal plants hold promise as sources of novel therapeutic agents [6] . WHO and the U.S. Food and Drug Administration (FDA) have recognized the importance of natural products and a number of compounds derived from nature are at various stages of multicenteric clinical trials all over the world. But not much scientific data are accumulated on their safety, purity and standardization; hence their efficacy and toxicity investigations are required [7].

Plumeria is a genus of shrubs and trees of the family Apocynaceae. The various Plumeria species are used for the cure of rheumatism, diarrhoea, blennorhoea, venereal disease [8] and reported to exhibit significant antibacterial, antifungal, antiviral [9] and anti-cancerous [10] activity.

In the present study, we undertook an evaluation of the anti-leishmanial activity of the chloroform extract from the stem bark of Plumeria bicolor, commonly known as "Champa". The active antileishmanial compounds were purified by bioactivity-guided fractionation of the extract, which were identified by mass spectral analysis. The in vitro anti-proliferative effect of the chloroform extract, its fractions and purified active compounds was evaluated against L. donovani.


   Material & Methods Top


Plant material: The stem bark of P. bicolor was collected from the campus of the University of Rajasthan, Jaipur, and botanical identification was done at the Department of Botany, University of Rajasthan and the voucher specimen was submitted at the herbarium (voucher specimen no. RUBL-20603).

Preparation of plant extract
: The methanol extract from the bark of P. bicolor was prepared at the All India Institute of Medical Sciences, New Delhi as described previously [10] , with slight modifications. The bark was dried in shade and grounded to fine powder. The powdered material (3 kg) was extracted with methanol (10×5 l) extensively for 72 h. The methanol extract was filtered and evaporated to dryness under reduced pressure in a rotary evaporator [Labmate (Asia) Pvt. Ltd. Model: RVC 2-18] at <40°C, which yielded a semi-solid brown mass. The concentrated mass was treated with acetonitrile to remove fats. Acetonitrile solvent was evaporated to dryness and the resulting mass (100 g) was stored at -20°C until further use.

Isolation and purification of active compounds: Fat free extract (100 g) was re-extracted with chloroform. The chloroform soluble portion afforded 30 g of extract after removal of the solvent. Half of the obtained extract was used for anti-parasitic activity and remaining half was subjected to repeated column chromatography for separation and isolation of pure compounds over silica gel column. For this, a column of 1.2 m in height with 5 cm in diameter and 800g silica gel G (60-120 mesh) was used. The column was eluted with different solvents using mixtures of benzene-chloroform-methanol in order of increasing polarity and P1-P8 fractions were collected. All these fractions were tested for their anti-parasitic activity against L. donovani.

Identification and structure elucidation of active compounds: The structures of the purified compounds from fraction P5, showing better anti-leishmanial activity than other fractions, were identified by mass spectrometry (Agilent 1100 Series LC/MSD API-ES spectrometer, Alpharetta, Georgia, USA), infrared analyses (FTIR-8400S Spectrophotometer, Shimadzu, Japan) and nuclear magnetic resonance (NMR) (JEOL AL-300 MHz Spectrometer, Tokyo, Japan) using 1 H NMR (300.40 MHz) and 13 C NMR (75.45 MHz) analyses in CDCl3 and by comparison of spectral data with those available in the literature.

Parasite and macrophage cell culture maintenance
: The L. donovani promastigote (MHOM/IN/1998/KE16), isolated from a VL patient from Bihar in eastern India [11] , was routinely maintained at 24°C in M-199 (GIBCO® , USA) medium containing penicillin (100U/ml), streptomycin (100μg/ml) (Invitrogen, USA) and supplemented with 10 per cent heat inactivated foetal calf serum (FCS; GIBCO® , USA). The infectivity of the parasite was maintained by periodic intravenous inoculation of the promastigotes in BALB/c mice. Briefly; the promastigotes in their mid log phase were harvested by centrifugation at 4500 g at 4° C in a refrigerated centrifuge. Pellets were re-suspended in PBS (pH 7.4) for intravenous infusion. Six to 10 wk old BALB/c male mice with body weight of 25-30 g, were injected intravenously (iv) in the lateral tail vein with about 1×107 log phase promastigotes. After 30-35 days of inoculation, animals were sacrificed, spleen and liver harvested and parasites culture isolated in Novy-MacNeal-Nicolle (NNN) medium followed by mass culture in M199 medium. J774G8 murine macrophage cells were maintained in RPMI 1640 (GIBCO® ) medium supplemented with 10 per cent FCS at 37°C in a humidified mixture of 5 per cent CO2 atmosphere (NuAire, Inc., USA).

In vitro anti-promastigote activity
: The chloroform extract was initially dissolved in dimethyl sulphoxide (DMSO; Sigma, USA) and further diluted with the M-199 medium after a sterilizing filtration. To examine the anti-leishmanial activity of the extract and purified compounds, logarithmic phase promastigotes of L. donovani (1×106 cells/ml) were seeded in 96-well microtiter plate in presence of the extract (100 μg/ml) and compounds (15 μm) and then incubated at 24°C for 48 h. After 48 h, the activity of extract and purified compounds was evaluated on parasite growth in the point of mobility of parasites and cell morphology, microscopically. The viability of parasites was also assayed colorimetrically by the mitochondrial oxidation of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide] assay as described previously [2],[12] with minor modifications. Briefly, MTT was dissolved in PBS (5 mg/ml) and sterilized by filtration (0.22 μm). MTT (400 μg/ml) was added to the plate and incubated for 4 h at 24°C. Finally, 100 μl of SDS-HCl (10% SDS in 0.01 N HCl) in each well, was added to dissolve the MTT formazan produced. The absorbance was measured at 570 nm with an ELISA reader and correlated with the number of living promastigotes, adequately standardized for each plate. Concentration of DMSO (0.5%) was maintained in all experiments as control and the growth in medium containing 0.5 per cent DMSO was taken as 100 per cent growth for comparison, while amphotericin B was used as the reference standard drug [2] . Each assay was performed in duplicate with three independent experiments. The anti-promastigote activity was expressed as the IC50 after 48 h of incubation. The IC50 value was calculated with a sigmoid dose-response curve.

In vitro anti-amastigote activity: In order to evaluate the effect of extract and purified compounds on intracellular amastigotes, J774G8 macrophage cells were used. J774G8 (5×10 5 cells/ml) macrophages were plated onto 13-mm coverslips in 24-well plates for 1 h at 37°C in a 5 per cent CO2 atmosphere. Non adherent cells were removed, and the macrophages were further incubated overnight in RPMI 1640 medium supplemented with 10 per cent FCS. Adherent cells were infected with L. donovani promastigotes (logarithmic growth phase) at a parasite/macrophage ratio of 10:1 and incubated for 1 h at 37°C in 5 per cent CO2 . Free promastigotes were removed by extensive washing with PBS (pH 7.2). After 24, 48, and 72 h, infected macrophages were treated at the different concentrations of extract and purified compounds. However, our observations did not find any significant difference in the results read at 48 and 72 h. Therefore, further assay readings were taken at 48 h. After 48 h, the monolayer was washed with PBS at 37°C, fixed in methanol, and stained with Giemsa. At least 200 macrophage cells per experiment were inspected by bright-field microscopy. The survival index was calculated by multiplying the percentage of macrophages with internalized parasites and the mean number of internalized parasites per macrophage [2] . These tests were performed in duplicate with three independent experiments.

Cytotoxicity assay: It was done as described previously [13] . Briefly, J774G8 mammalian macrophage cells were maintained in RPMI 1640 medium supplemented with 10 per cent FCS at 37°C in a humidified mixture of 5 per cent CO2 atmosphere. Macrophages (1×106 cells/ml) were seeded in 96-well microtiter plate in presence of isolated compounds, which were 2-fold serially diluted over six concentrations (30 to 0.93 μM/ml) in RPMI 1640 medium containing 10 per cent FCS, and then incubated for 48 h at 37°C in a humidified mixture of 5 per cent CO2 atmosphere. The control wells without any extract or compounds (untreated cells) were used as control and considered as 100 per cent viable cells. The cell viability was determined using the MTT assay. Each assay was performed in duplicate with three independent experiments.

Statistical analysis
: Data represented the mean ± SD of duplicate samples from three independent assays. The IC50 values were calculated using dose-response curves in Graph Pad Prism 3.0 software (CLa Jolla, California, USA).


   Results Top


Bioactivity-guided fractionation : The anti-leishmanial activity of all P1-P8 fractions was seen (data not shown). The activity was concentrated on fraction P5, which was obtained on eluting the column with chloroform and methanol (8:2 v/v). The solvent was removed and compounds A and B were obtained at different melting points and crystallized with methanol which gave white crystals.

Isolation and characterization of active compound A: Compound A was crystallized with methanol as white crystals (35% yield) and its melting point was 196-198°C and molecular formula was C15 H14 O6 . It was characterized as isoplumericin [10],[14]-[16] .

Isolation and characterization of active compound B: It was obtained after eluting the column with chloroform and methanol (8:2) which was crystallized with methanol. It gave white crystals (65% yield) and its melting point was 210-212°C.The molecular formula was C15 H14 O6 . It was characterized as plumericin [10],[14],[15],[16] .

Anti-promastigote activity: For in-vitro anti-leishmanial assay, extract was dissolved in DMSO. The control experiments were performed using DMSO at the same concentration (0.5%) which was used to test the extract. The tested concentration of DMSO did not affect the growth of parasites. Moreover, there were no observable cytopathological changes found as compared to the control group cells, the chloroform extract of P. bicolor, isoplumericin and plumericin were used to evaluate the anti-leishmanial activity. Chloroform extract of P. bicolor was found to be active with the IC50 of 21±2.2 μg/ml [Figure 1] against promastigote form of L. donovani. The isoplumericin and plumericin showed significant activity with an IC50 of 7.2±0.08 μM and 3.17±0.12 μM, respectively [Figure 2] and [Figure 3]. The plumericin showed more potent activity than isoplumericin. Amphotericin B was used as a reference standard drug which showed IC50 of 0.08±0.02 μM against promastigote form. At the concentration of 6 μM/ml and higher, plumericin induced clear cytopathological changes in promastigote form of L. donovani such as ovoid cells, loss of flagellum, granulation, and rounding of the cells and some other morphological changes in parasites such as decreased mobility of promastigotes, round to oval shaping, decrease in size with dense cytoplasm and enlarged nuclei [Figure 4].
Figure 1: Anti-leishmanial activity of chloroform extract from the bark of Plumeria bicolor against L. donovani.

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Figure 2: Anti-leishmanial activity of isoplumericin against L. donovani.

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Figure 3: Anti-leishmanial activity of plumericin against L. donovani.

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Figure 4: PI stained promastigotes were photographed using a microscope with an Olympus microphotographic system (A) untreated cells at 400X using a light microscope, (B) plumericin treated cells detected in the orange range of 562-588 nm band pass filter at 400X using fluorescence microscope, and (C, D, E & F) plumericin treated cells showing deformities at 400X using a light microscope. Arrows show (A) live cells, (B) dead cells, (C-F) deformed cell morphology.

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Anti-amastigote activity: The chloroform extract of P. bicolor and purified isoplumericin and plumericin treatment of macrophages infected with amastigote form showed that the extract and both purified compounds inhibit the growth of parasites [Figure 5]. After 48 h, the percentage of macrophages with internalized parasites was higher for the control than for the macrophages infected and treated with the extract and both compounds. The mean number of internalized parasites per macrophage treated with the extract and both compounds was markedly lower than that for the control. The survival index indicated that the extract and both compounds inhibited the parasite growth in the macrophages. Thus, the extract showed 50 per cent inhibition of cell survival (IC50 ) at a concentration of 14±1.6 μg/ml [Figure 1] and plumericin showed more potent leishmanicidal activity with IC50 of 1.41±0.03 μM than isoplumericin with IC50 of 4.1±0.02 μM [Figure 2] and [Figure 3]. Amphotericin B was used as a reference standard drug which showed IC50 of 0.06±0.01 μM against amastigote form of L. donovani.
Figure 5: Giemsa stained cells were photographed at 1000X magnification using a light microscope with an Olympus microphotographic system (A) Uninfected macrophages, (B) Untreated infected macrophages showing amastigotes within macrophages, and (C & D) amphotericin B and plumericin treated infected macrophages respectively, showing clearance of amastigotes.

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Cytotoxicity assay: The cytotoxicity of both isoplumericin and plumericin was tested against murine macrophage (J774G8) model. After 48 h, the viability was checked by MTT assay. Cytotoxicity assay showed that the P. bicolor extract, isoplumericin and plumericin caused cytotoxic effect with CC50 value of 75±5.3, 20.6±0.5 and 24±0.7 μM, respectively.


   Discussion Top


In the absence of new and the current therapeutics against leishmaniasis, herbal products could be an inspiration of new prototype for the drug development [17] . The biological and pharmacological activities of the plant iridoids have been reviewed, including antibacterial, antifungal, antiviral, anti-inflammatory, analgesic, antirheumatic, hepatoprotective and antitumour activities [18],[19] . The genus Plumeria (Apocynaceae) is known as a source of iridoids. In this study, chloroform extract prepared from the bark of this plant showed significant anti-leishmanial activity. Two active leishmanicidal compounds were purified by bioactivity-guided fractionation of the extract, which were identified by spectroscopic analysis as isoplumericin and plumericin. Isoplumericin and plumericin had previously been isolated from different genera of Apocynaceae such as Plumeria, Allamanda and Himatanthus[20],[21],[22] . Isoplumericin and plumericin have been previously reported to have antifungal, anticancerous, antiviral and antibacterial actions [23] . The anti-parasitic activity of plumericin from Himatanthus sucuuba (Apocynaceae) has been demonstrated against L. amazonensis, responsible for cutaneous leishmaniasis [24] .

In the present study, plumericin showed more potent activity than isoplumericin against promastigote and amastigote forms of L. donovani. Microscopic evaluation of parasites treated with plumericin (6μM) for 24 h showed that approximately >40 per cent of the cell population became ovoid whereas control promastigotes retained classical morphology. At the end of 48 h, >70 per cent of the cells showed loss of flagellum, granulation, and round morphology with substantial reduction in size as compared to control promastigotes, suggesting cytoplasmic condensation and shrinkage, established marker of apoptosis [25], which may be the possible cause of cell death, an effect exerted by plumericin. This compound caused a reduction in the macrophage infection and its effect on infected macrophages should be of great interest, since the radical group orientation influences the anti-parasitic activity of some compounds [26] . The strong activity of the tetracyclic iridoid plumericin can be explained by the presence of an α-methylene γ-lactone moiety, susceptible to undergo a Michael-type addition with biological nucleophiles[27] . Cytotoxicity assay showed that plumericin causes negligible cytotoxic effect against J774G8 murine macrophages at the concentrations used. This selectivity assay showed that the action of the isolated compound is specific for the protozoans and is not toxic for mammalian cells. The demonstration of the anti-leishmanial properties of plumericin adds another facet to the broad range of biological activities of these iridoids, which have recently been the challenging target of various synthetic approaches [28] , because, most of the synthetic drugs like amphotericin B are known for their severe side effects such as nephrotoxicity. Intravenously administered amphotericin B has some common side effects with the first few doses which are associated with severe multiple organ damage in therapeutic doses [29] .

This study shows a potent leishmanicidal activity of plumericin than isoplumericin which may provide promising lead against leishmaniasis. Further studies will be required to evaluate plumericin, whether it can be used as single anti-leishmanial compound or as fortifying agent with existing synthetic compounds for the development of anti-leishmanial agent. Also it would be very interesting to isolate or synthesize structurally related compounds in order to establish structure- activity relationships.


   Acknowledgment Top


This study was supported by a grant from Central Council for Research in Unani Medicine (CCRUM), Department of AYUSH, Ministry of Health & Family Welfare, Government of India, New Delhi. The financial assistance in the form of research fellowship to the first author (US) from Indian Council of Medical Research (ICMR), New Delhi, is acknowledged.

 
   References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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BMC Complementary and Alternative Medicine. 2017; 17(1)
[Pubmed] | [DOI]
8 Effect of functionalities on the crystal structures of new zinc(ii) dithiocarbamates: a combined anti-leishmanial and thermal decomposition study
Krishna K. Manar,Chote L. Yadav,Neeraj Tiwari,Rakesh K. Singh,Akhilesh Kumar,Michael G. B. Drew,Nanhai Singh
CrystEngComm. 2017;
[Pubmed] | [DOI]
9 “Click” on PLGA-PEG and hyaluronic acid: Gaining access to anti-leishmanial pentamidine bioconjugates
Angela Scala,Anna Piperno,Nicola Micale,Placido G. Mineo,Antonio Abbadessa,Roberta Risoluti,Germano Castelli,Federica Bruno,Fabrizio Vitale,Antonio Cascio,Giovanni Grassi
Journal of Biomedical Materials Research Part B: Applied Biomaterials. 2017;
[Pubmed] | [DOI]
10 Effects of trans-stilbene and terphenyl compounds on different strains of Leishmania and on cytokines production from infected macrophages
Federica Bruno,Germano Castelli,Fabrizio Vitale,Elisa Giacomini,Marinella Roberti,Claudia Colomba,Antonio Cascio,Manlio Tolomeo
Experimental Parasitology. 2017;
[Pubmed] | [DOI]
11 In vitro Antileishmanial Activity of trans-Stilbene and Terphenyl Compounds
Germano Castelli,Federica Bruno,Fabrizio Vitale,Marinella Roberti,Claudia Colomba,Elisa Giacomini,Laura Guidotti,Antonio Cascio,Manlio Tolomeo
Experimental Parasitology. 2016;
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12 Plumericin inhibits proliferation of vascular smooth muscle cells by blocking STAT3 signaling via S-glutathionylation
Elke H Heiss,Rongxia Liu,Birgit Waltenberger,Shafaat Khan,Daniel Schachner,Paul Kollmann,Kristin Zimmermann,Muris Cabaravdic,Pavel Uhrin,Hermann Stuppner,Johannes M Breuss,Atanas G Atanasov,Verena M Dirsch
Scientific Reports. 2016; 6: 20771
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13 Anti-leishmanial activity of Ni(ii), Pd(ii) and Pt(ii) ß-oxodithioester complexes
Manoj Kumar Yadav,Gunjan Rajput,Khushboo Srivastava,Rakesh K. Singh,Rajnikant Mishra,Michael G. B. Drew,Nanhai Singh
New J. Chem.. 2015; 39(8): 6358
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14 Green Synthesis of Silver and Titanium Dioxide Nanoparticles Using Euphorbia prostrata Extract Shows Shift from Apoptosis to G0/G1Arrest followed by Necrotic Cell Death in Leishmania donovani
Abdul Abduz Zahir,Indira Singh Chauhan,Asokan Bagavan,Chinnaperumal Kamaraj,Gandhi Elango,Jai Shankar,Nidhi Arjaria,Selvaraj Mohana Roopan,Abdul Abdul Rahuman,Neeloo Singh
Antimicrobial Agents and Chemotherapy. 2015; 59(8): 4782
[Pubmed] | [DOI]
15 Antioxidant Potential of Plumieride against CCl4-Induced Peroxidative Damage in Rats
Dharmendra Singh,Priya Arya,Ashutosh Sharma,Ved Aggarwal,Mahabeer Dobhal,Radhey Gupta
Antioxidants. 2014; 3(4): 798
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16 Bioassay-guided Isolation of Antifungal Plumericin from Allamanda Species (Apocynaceae)
Farah F. Haron,Kamaruzaman Sijam,Dzolkhifli Omar,Mawardi Rahmani
Journal of Biological Sciences. 2013; 13(3): 158
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