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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