Pharmacology of Chitraka (Plumbago zeylanica) Part 1

Pharmacology of Chitraka (Plumbago zeylanica) Part 1
By Dr. Hemant Vinze
                                  M. S.     

Introduction
Many experts in Ayurvedic System of medicine are not enthused with this wonder medicine, Chitraka (Plumbago zeylanica). They are not even aware of its pleiotropic pharmacological activity compared to some other Ayurvedic herbal stars. Well! Let not this obliviousness fool you!! Chitraka (Plumbago zeylanica) has withstood the test of time in Ayurvedic pharmacopoeia, especially as a digestant and is a powerful ally to many herbs in digestive formulations. Rightly so as Ayurveda recognizes that health begins in the digestive system.    
                             
General pharmacology

RP-HPLC method was used to analyze hydroalcoholic (35:65) extract of Chitraka (Plumbago zeylanica) to quantify plumbagin content in different parts of the plant. The results showed the content in the root, stem and leaf were: 0.3945 %, 0.0508 % 0.0314 % respectively. The workers find this method to be simple, accurate and suitable for the determination of plumbagin in Chitraka (Plumbago zeylanica). [1]
Chromatography and mass spectrometry were used for the pharmacokinetic study of plumbagin. Furthermore the oral bioavailability of plumbagin was found to be about 38.7 +/- 5% [2]
That properties and medicinal effects of medicinal plants vary according to seasons was well established and mentioned in Ayurvedic text books. Modern research has now confirmed it. Plumbagin is the major bioactive phytochemical in Chitraka (Plumbago zeylanica). Saraswathy A, et al confirmed that content of plumbagin varies due to change in season and storage. The study established that the concentration of plumbagin is more in February followed by January. Hence the root shows more efficiency if collected in February. The plumbagin content sharply declines after July. Medicinal efficiency of Chitraka (Plumbago zeylanica) also declines if stored after July. [3]
The review of research on “Rasaayana” effect of Chitraka (Plumbago zeylanica) published by Sanjana validated the “Adaptogenic” and “Aphrodisiac” activity of the herb. [4]

Anti-inflammatory activity

The phosphate buffered saline extract of roots of Chitraka (Plumbago zeylanica) was investigated for anti-inflammatory activity. The extract reduced swelling and inflammation of formaldehyde induced arthritis in rats. The study suggested anti-inflammatory activity of the extract of Chitraka (Plumbago zeylanica). [5]
Plumbagin in Chitraka (Plumbago zeylanica) modulates matrix metallopeptidase 9 (MMP-9), cyclo-oxygenase-2 (COX-2) and suppresses NF-κB activation and gene expression in peripheral blood mononuclear cell. These arrest the cell cycle progression. By these mechanisms Chitraka (Plumbago zeylanica) exhibits anti-inflammatory activity. This activity was attributed to suberosin in Chitraka (Plumbago zeylanica). [6]  

Antioxidant activity         

Aqueous and alcoholic extracts of Chitraka (Plumbago zeylanica) were used to assess its antioxidant activity. These extracts significantly inhibited lipid peroxidation induced by various agents in rat liver. The antioxidant activity was attributed to plumbagin. [7] 
A newly isolated flavonoid from Chitraka (Plumbago zeylanica) demonstrated a strong free radical scavenging and superoxide radical scavenging activity. This activity was found to be much superior to standard flavonoid quercetin. [8]
A study was designed to evaluate protective effect of Chitraka (Plumbago zeylanica) against cyclophosphamide-induced genotoxicity and oxidative stress in Swiss albino mice. The mice were pretreated with alcoholic extract of root of Chitraka (Plumbago zeylanica) for five days at doses of 250 and 500 mg/kg body weight. The pretreatment significantly reduced the micronucleated polychromatic erythrocytes (MnPCEs), increases the polychromatic erythrocytes/normochromatic erythrocyte (PCE/NCE) ratio in the bone marrow and decreased the levels of lipid peroxidation products with concomitant changes in the antioxidant status. The study showed that both the doses of Chitraka (Plumbago zeylanica) exerted protective effect against cyclophosphamide-induced genotoxicity and oxidative stress.   
[Note: PCE/NCE ratio is indicator of bone marrow toxicity induced by mutagens]   [9]  

Immunomodulatory activity

The aqueous extract of Chitraka (Plumbago zeylanica) displayed a significant suppression of ovalbumin-specific Ig G antibody response in a murine system. Chitraka (Plumbago zeylanica) was also found to suppress ovalbumin stimulated T cell proliferation. Thus Chitraka (Plumbago zeylanica) exhibitsed a potent immunomodulatory activity [10]

Antiallergic activity

The 70% ethanol extract of stem of Chitraka (Plumbago zeylanica) at doses of 500, 1000mg/kg body weight was found to inhibit systemic anaphylactic shock induced in mice by compound 48/80. At doses 1000mg/kg body weight the extract reduced skin reactions induced by histamine and serotonin in rats. The extract was found to inhibit mast cell dependent immediate allergic reactions.
Furthermore ethanol extract of stems of Chitraka (Plumbago zeylanica) was also found to suppress delayed type of hypersensitivity reaction. [11], [12]

Antimicrobial activity         

The aqueous, petroleum ether, dichloromethane, methanol extracts and aqueous residue of Chitraka (Plumbago zeylanica) displayed antibacterial effect against Salmonella gallinarum, Escherichia coli, Proteus vulgaris and Klebsiella pneumoniae. Alcoholic and aqueous extracts of root of Chitraka (Plumbago zeylanica) were effective against Bacillus subtilis, Escherichia coli, Proteus vulgaris, Salmonella typhimuricum, Pseudomonas aeruginosa and Staphylococcus aureus
The alcoholic extract of root of Chitraka (Plumbago zeylanica) was effective against multidrug resistant Escherichia coli, Salmonella paratyphi, Shigella dysenteriae and Staphylococcus aureus
The phytochemical plumbagin from Chitraka (Plumbago zeylanica) was found to augment the bactericidal activity of macrophages at low concentration. [13]
In a study Chitraka (Plumbago zeylanica) was used in combination with INH (isonicotinic acid hydrazide) against four atypical mycobacteria viz. Mycobacterium intracellularae, Mycobacterium smegmatis, Mycobacterium xenopei and Mycobacterium chelonei. The results showed that the potency of INH (isonicotinic acid hydrazide) increased four-fold. [14]

Aqueous, ethanol, ethyl acetate and acetone extracts of Chitraka (Plumbago zeylanica) demonstrated anti-Helicobacter pylori activity. All extracts exhibited bactericidal effect. [15]

The recent study showed that the root extract of Chitraka (Plumbago zeylanica) was effective against methicillin resistant Staphylococcus aureus (MRSA). This antibacterial activity was attributed to new compounds, neoisoshinanolone and 1-epineo-isoshinanolone separated from the crude petroleum-ether extract of roots of Chitraka (Plumbago zeylanica). [16]  
Aqueous extract of root of Chitraka (Plumbago zeylanica) does not exhibit antibacterial activity against organisms causing pneumonia. Petroleum ether extract and ethanol extract of Chitraka (Plumbago zeylanica) exhibited strong antibacterial activity against bacteria causing pneumonia. Of the two the petroleum ether extract showed stronger activity. Minimum inhibitory concentration value of petroleum ether extract was similar to commonly used broad spectrum antibiotics to treat pneumonia. [17]
Chitraka (Plumbago zeylanica) is used as a remedy for secondary syphilis and leprosy. The chloroform extract of root of Chitraka (Plumbago zeylanica)   extract showed a significant activity against penicillin-sensitive and penicillin-resistant strains of Neisseria gonorrhoeae. [18]

Antiviral activity

The 80% methanolic extract of Chitraka (Plumbago zeylanica) displayed antiviral activity against Coxsackie virus B3 (CVB 3), Influenza A virus and Herpes simplex virus type 1 Kupka (HSV-1) [19], [20]

Antifungal activity

A study showed that alcoholic extracts of Chitraka (Plumbago zeylanica) have strong antifungal activity against pathogenic yeast, Candida albicans; dermatophytes Epidermophyton floccosum , Microsporum gypseum and Tricophyton rubrum. The minimum inhibitory concentration (MIC) was found to be 4mg/ml.  [21]
In an in vitro study, ethanolic and methanolic extracts of Chitraka (Plumbago zeylanica) exhibited significant activity against Aaspergillus sp., Penicillium and Fusarium sp. Aqueous and acetone extracts showed moderate activity followed by petroleum ether extract. [22]

Antiparasitic activity

Plumbagin a naphthoquinone isolated from Chitraka (Plumbago zeylanica) was reported to display strong activity against Leishmania donovani and Leishmania amazenosis at concentrations 0.42 and 1.1 mg/ml. Plumbagin and its dimmers, 3-3’-bis-plumbagin have been used in cutaneous leishmaniasis in some Amazonian towns such as Bolivia.
At the dose of 1.5 mg/ml plumbagin displayed a strong trypanocidal activity against six strains of Tripanosomal species. [23]
The methanolic extract of root bark of Chitraka (Plumbago zeylanica) at a concentration of 1000 μg /mL exhibited antitrypanosomal activity. [24]
The methanolic and aqueous extract of root of Chitraka (Plumbago zeylanica) showed dose dependent anthelmintic activity. The methanolic extract showed higher activity compared to aqueous extract.
The leaf extract of Chitraka (Plumbago zeylanica) also displayed anthelmintic activity, but it was much less compared to root extract.
At concentration 20m/mL methanolic extract of root of Chitraka (Plumbago zeylanica) paralysed and killed worms. This activity was comparable to piperazine citrate and albendazole. [25]
Plumbagin a naphthoquinone isolated from Chitraka (Plumbago zeylanica) was effective against Plasmodium falciparum species causing a serious type of malaria. [26]
Patil et al (2010) tested crude chloroform, dichloromethane and methanol extracts of leaves and root of Chitraka (Plumbago zeylanica) for larvicidal activity. They found that the extracts had larvicidal activity against larvae of Ades aegypti and Anophelis stephens. The extracts affected the lifecycle by inhibition of pupal development and subsequently emergence of adult mosquitoes. This was dependent on the concentration of the extract. The larval mortality was observed after 24 hours of exposure.    [27]
1. In a study on parasites, plumbagin inhibited the motility and survival of some nematodes.
2. Plumbagin had a biphasic effect on the development on Ascaris summ larve
3. Plumbagin partially inhibited the devevelopment of embryos from eggs of Ascaris summ    [28]
Chaweeborisuit P et al reported a strong anthelmintic effect of plumbagin. Furthermore plumbagin was lethal to worms resistant to levamisole, albendazole and ivermectin. [29]

Actions on the skin

Plumbagin isolated from Chitraka (Plumbago zeylanica) inhibits ultraviolet radiation (UVR)-induced development of squamous cell carcinoma of the skin. Pretreatment with Chitraka (Plumbago zeylanica) inhibited ultraviolet radiation (UVR)-induced DNA binding of activating protein-1, nuclear factor-   κ B, Stat 3 transcription factors and Stat 3-regulatedmolecules. This suggests that plumbagin may be a novel agent for the prevention of skin cancer.  [30]

Actions on wound healing

The stages of wound healing are (1) inflammatory phase (2) proliferation phase (3) fibroblastic phase and (4) maturation phase. Researchers observed that many tribal people use Chitraka (Plumbago zeylanica) for wound healing. The observation inspired scientists to validate the efficacy of Chitraka (Plumbago zeylanica) in the process of wound healing. Devender Rao et al found methanolic extract of root of Chitraka (Plumbago zeylanica) has a significant wound healing activity in Wistar albino rats.
Reddy SJ et al prepared 10% w/v extract of Chitraka (Plumbago zeylanica) in saline and applied it topically to incision and excision wounds in rats. They found that tensile strength was better in remodeling phase than the tensile strength of the untreated wounds. [31], [32]
In an experimental study excision wounds of albino rats were treated with ointment containing Chitraka (Plumbago zeylanica). The ointment was observed to promote wound healing. The results were comparable to wounds treated with Soframycin cream. [33]
It is welknown now that low oxidative stress and low levels of reactive oxygen species are key factors in normal wound healing. Antioxidants are postulated to control oxidative stress in wounds and thereby accelerate wound healing. By their anti-inflammatory and antioxidant activities the phytochemicals such as alkaloids, terpenoids, flavonoids etc. in the root extract of Chitraka (Plumbago zeylanica) accelerate wound healing. [34]

Actions on Mouth

The ethanolic extract of Chitraka (Plumbago zeylanica) has been successfully used to treat oral Candida albicans (Oral candidiasis, Thrush) infection. Furthermore Chitraka (Plumbago zeylanica) is effective in the treatment of Fluconazole resistant candiasis. [35]
A study revealed that Chitraka (Plumbago zeylanica) suppressed cell growth of oral squamous cell carcinoma cells (OSCC). This activity is dose dependent. This activity is attributed to plumbagin. [36]
Plumbagin induces cell cycle arrest, autophagy and apoptosis in squamous cell carcinoma of the tongue. [37]
Actions on the Breast
By exhibiting proapoptotic, anti-angiogenic and anti-metastatic effects on cancer cells, plumbagin shows effective anticancer activity against human breast cancer. Plumbagin causes cell cycle arrest at G1 phase. [38]
The glucose regulated protein 78 (GRP 78) is a major chaperone of endoplasmic reticulum. In many types of cancers including breast cancer GRP 78 is upregulated. GRP 78 overexpression confers chemoresistance to anti-estrogen agents. A study shows that plumbagin inhibits GRP 78 activity and induces plumbagin-mediated cancer-cell death. Plumbagin induces apoptosis in breast cancer ells, inhibits invasion and migration of breast cancer cells and sensitizes the breast cancer cells to tamoxifen. [39]
Plumbagin suppresses invasion and migration of breast cancer cells via inhibition of STAT 3 signaling and down-regulation of inflammatory cytokine expression. [40]
In a study plumbagin suppressed the invasion of HER-2 overexpressing breast cancer cells. Plumbagin inhibited NF-κB transcriptional activity. Thus plumbagin suppressed proliferation, invasion and migration of breast cancer.  [41]
In a study plumbagin showed potent anti-proliferative activity against breast cancer cells. Furthermore plumbagin increased the intracellular levels of reactive oxygen species (ROS) suggesting that ROS plays a crucial role in anti-proliferative activity.  [42]
Recent research has revealed that RANKL (Receptor activator of nuclear factor κB ligand) also known as tumor necrosis factor ligand superfamily member 11 (TNF SF 11) affects immune system and controls bone regeneration and remodelling. RANKL is an apoptosis regulator gene that plays a major role in cancer-associated bone resorption. Thus plumbagin, a vitamin K analogue is a potent inhibitor of osteoclastogenesis induced by breast cancer cells, suppresses RANKL signaling and arrests breast cancer-induced osteolytic metastasis. [43]
Another group of researchers demonstrated that plumbagin inhibited breast cancer cell proliferation at G2-M phase and induced autophagic cell death. They found that pretreatment of cancer cells with bafilomycin an autophagy inhibitor suppressed plumbagin-mediated cell death. Therefore according to them, plumbagin did not induce apoptotic cell death but induced autophagic cell death. [44]
Breast cancer is a major cause of cancer related suffering and death in women world-wide. The heterogeneity of breast cancer further complicates the target-based therapies. Furthermore triple negative breast cancers represent a highly aggressive subtype. They are difficult to treat as they need pleotropic agents that target receptor-positive as well as receptor-negative cancer cells. Plumbagin is one such effective agent especially for the treatment of triple negative breast cancer cells. Plumbagin inhibits the growth of breast cancer cells with no adverse effects on normal epithelial cells of the breast. Plumbagin induces breast-cancer cell death by inactivation of Bcl-2 and and DNA binding activity of NF-κB. According to this group of researchers, plumbagin is useful for prevention and treatment of breast cancer.  [45]

Actions on Hematopoetic system

Sickle cell disease is a genetic blood disorder. It is characterized by red blood cells (RBCs) that assume an abnormal rigid sickle shape. Sickling decreases the flexibility of red blood cells culminating in risky, life threatening and fatal complications. Thousands of children die of this disease.  
The change in shape of red blood cells from spherical to sickle shape is multifactorial. In short it can be said, mutation in chromosome 11 results in polymerization and precipitation of sickle hemoglobin (HbS) within the red blood cells and distortion of cell membrane result in sickle shaped red blood cells.  [46], [47]
Sickle cell disease is wide spread in Africa, Jamaica, Central India, Saudi Arabia, Britain, Italy, Greece and America. The main clinical features are anemia, mild jaundice, hepato-splenomegaly, acute respiratory distress, bone and joint pain, growth retardation and many life threatening complications. [48]
The potential anti-sickling agents either from natural sources and/or synthetic molecules may be useful for reducing the morbidity of patients. Extracts of Chitraka (Plumbago zeylanica) exhibit significant anti-sickling activity at concentrations of 0.1, 1.0 and 10.0 mg /mL. Therefore, the use of herbs by traditional medical practitioners for the treatment of anemia (? Sickle cell disease) in South-West Nigeria is justified. Modern day researchers have now proved anti-sickling activity of crude, aqueous and methanol extracts of root of Chitraka (Plumbago zeylanica).  [49]
Administration of the extract of Chitraka (Plumbago zeylanica) at 2mg/kg bodyweight and naphthoquinone 2 mg/kg body weight in albino rats for 31 days prolonged the bleeding time. The administration did not alter the platelet count but the platelet adhesiveness was significantly decreased. Even at dosage lower than 2mg/kg body weight the chronic administration of Chitraka (Plumbago zeylanica) prolonged the bleeding time by altering platelet adhesiveness and the coagulation.  [50]
Zhao YL and Lu DP proved the effectiveness of Chitraka (Plumbago zeylanica) against acute polymyelocytic leukemia (APL). The effectiveness was attributed to the phytochemical plumbagin. They demonstrated that 2-15 μmol/L of plumbagin inhibited the proliferation of NB4 cells in a dose dependent manner. Plumbagin induced chromosome condensation and fragmentation of DNA of cells. Cell cycle analysis showed that NB4 cells were blocked in G2/M phase of cell cycle.  [51]
Of many beneficial pharmacological effects plumbagin showed activity against mouse lymphoma L5178Y cells. At concentrations as low as 0.25 ηg/ml plumbain induced significant DNA damage in lymphoma cells. This effect was attributed to antioxidative activity of plumbagin at low concentrations. [52]

A study showed that plumbagin elevated the levels of reactive oxygen species (ROS). This led to induction of apoptosis in chronic myelogenous leukemia (CML). [53]

Actions on Musculoskeletal system

In experimental studies substances known as adjuvants (olive oil, liquid paraffin, squalee, killed micobacteria etc.) are used to induce arthritis (mimicking rheumatoid arthritis). In a study adjuvant induced arthritic rats were treated with ethyl acetate extract of Chitraka (Plumbago zeylanica). The result showed that the herbal extract effectively suppressed arthritis by decreasing delayed type hypersensitivity response. Furthermore Chitraka (Plumbago zeylanica) extract also prevented the development of adjuvant induced arthritis.  [54]
In another study, adjuvant-induced arthritic rats were treated with 20 mg/kg body weight of Chitraka (Plumbago zeylanica) daily from day 0 to day 13. The results demonstrated that Chitraka (Plumbago zeylanica) inhibited the development of delayed hypersensitivity response in arthritic rats. The treatment also brought the T cell proliferation to normal levels. [55]
 To evaluate antiarthritic activity of Chitraka (Plumbago zeylanica), collagen type II arthritis was induced in DBA/1 mice. The animals were then treated with ethyl acetate fraction of the root extract of Chitraka (Plumbago zeylanica). The treatment stimulated T cell proliferation to normal levels in arthritic mice. [56]
In a study on rats, plumbagin upregulated the expression of p53 in U2OS cells and p21 in the two osteosarcoma cell lines causing cell cycle arrest. Plumbagin also generated reactive oxygen species (ROS) in osteosarcoma cell lines that triggered the mitochondrial apoptotic path way. Thus plumbagin inhibits the growth of osteosarcoma cells mostly by antioxidant 
activity.  [57]  

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[56] Poosarla A et al, Alleviation of collagen-induced arthritis by Plumbago zeylanica in mice, Pharmaceutical Biology, Volume: 45, Issue: 1, Pages: 54-59, Jan 2007.            
[57] Linqiang Tian et al, Plumbagin induces apoptosis via the p53 pathway and generation of reactive oxygen species in human osteosarcoma cells, Molecular Medicine Reports 5: 126-132, 2012.









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