Pharmacology of Embelin found in Widanga (Embelia ribes)
Pharmacology
of Embelin found in Widanga (Embelia ribes)
Introduction
Widanga
(Embelia ribes) was an important medicine in the chest of grandmothers.
It shows pleotropic pharmacological activities. Almost all of its
pharmacological actions are due to a phytochemical “Embelin” found in it. I
take an opportunity to describe the pharmacology of “Embelin”.
Embelin
is also known as emberine, embelic acid, potassium embelate benzoquinone etc.
Embelin
is found to be located on the outer coat of seed beneath a thin membranous
film, below the pericarp of the fruit.
Embelin
occurs as golden yellow needles sparingly soluble in water but soluble in
alcohol, chloroform and benzene. It is used to color silk and
wool.
Sublimation
and volatility are major characteristics of Embelin. It does not decompose
under normal pressure after being heated. It can be distilled with water
vapor which makes it easy to be extracted and purified.
Due
to poor water solubility, bioavailability of embelin is erratic. That is why
its clinical applications have limitations. On the other hand, its long alkyl
chain (undecyl) provides it with long lipophilic ability and high cell membrane
permeability which make it more stable and allow it enter the cells easily.
When
irradiated with light of appropriate wave length, embelin can be activated to
produce anti-inflammatory, anti-oxidant and anti-tumor
effects. [1], [2], [3], [4]
Recently
embelin has been synthesized in the laboratory. It will be of great advantage
for new drug development [5]
Anti-inflammatory
activity
In
an experimental study, embelin, a plant based benzoquinone derivative, shows an
appreciable anti-inflammatory and analgesic activity. [6]
In
a study embelin was condensed with various primary amines to yield ten new
derivatives along with monomethyl embelin. All these compounds and embelin, at
10 and 20 mg/kg body weight showed anti-inflammatory and analgesic activities.
Embelin and two of its derivatives almost completely abolished the acetic acid
induced writhing. However p-Sulfonylamine phenylamino derivative of embelin
showed better anti-inflammatory activity than embelin. [7]
TNF- α
is a pro-inflammatory chemical. TNF- α is synthesized as a
membrane anchored protein (pro-TNF- α). A protease enzyme
called TNF- α converting enzyme converts pro-TNF- α into a
soluble form that is released into the extracellular space. This soluble form
is responsible for the development of inflammation. By blocking this
cascade, Embelin found in fruits of Widanga (Embelia ribes) acts as a
natural anti-inflammatory agent. [8]
Antioxidant
Activity
In
an experimental study embelin was found to scavenge DPPH (2,2-diphenyl-1
picrylhydrazyl) radicals. It inhibited hydroxyl radical induced lipid
peroxidation and restored impaired manganese superoxide dismutase in
mitochondria of the hepatocytes in rats. Using nano second pulse radiolysis
technique suggests that embelin can act as a competitive antioxidant in
physiological conditions. [9], [10]
Using
different antioxidant tests, free radical scavenging activity and lipid
peroxidation in albino rats, a group of researchers evaluated the antioxidant
activity of embelin. By this study they concluded that embelin has a very
potent antioxidant property. [11]
Antibacterial
Activity
The
principal phytochemical in the ethanol extract of Widanga (Embelia ribes) is
embelin. At concentration of 100 mg/disc embelin showed
antibacterial activity
against Staphylococcus aureus,
Shigella flexneri and Shigella sonnei. This activity was superior to
kanamycin at 39 mg/ disc. Same kind of response was observed when
embelin was used at 100 mg/disc against Pseudomonas
aeruginosa at which it was superior to ciprofloxacin at 5
mg/disc. Embelin also shows strong antibacterial activity against Streptococcus
pyogenes, Salmonella typhi, Shiegella boydii, Proteus mirabilis and
mild antibacterial activity against Streptococcuc fecalis and Vibrio
cholera. Methanol and aqueous extracts of the plant show moderate activity
against multi-drug resistant Salmonella typhi.
In
summary it can be said that embelin show good antibacterial
activity against gram +ve and gram -ve organisms depending on the dose.
[12], [13], [14], [15]
In
another study, researchers isolated embelin in pure form from Widanga (Embelia
ribes). By using disc diffusion they found that pure embelin had strong
antibacterial activity against Streptococcus mitis and Bacillus
subtilis , weak antibacterial activity against Staphylococcus
aureus and no antibacterial activity against Escherichia coli.
The
researchers are of the opinion that embelin is not a very efficient
antibacterial compound but could give rise to more potent bioactive molecules
by biotransformation. [16]
In
Ayurveda Widanga (Embelia ribes Burm. f.) is famous for
antimicrobial activity. However another species of Widanga is also used for
antimicrobial activity. Taxonomically it is Embeliaro busta auct.
Nonroxb. Therefore though this other species shows antimicrobial activity
similar to that of Widanga (Embelia ribes Burm. f.); scientifically
the other species is an adulterant. Researchers have proved Widanga (Embelia
ribes Burm. f.) has more potent antimicrobial activity than the adulterant
species Embeliaro busta auct. Nonroxb.
Hence
the importance of chromosomal and genetic identification of herbs for effective
pharmacological actions. [17]
The
chemists developed semi-synthetic derivatives of embelin. The scientists
compared the antibacterial and anti-fungal activities of these two compounds
against 21 bacterial and 4 fungal pathogens. Both the compounds showed broad
spectrum antibacterial activity against gram positive and gram negative
bacteria at a concentration of 200 µg/ml. Among
the tested bacteria some strains of Escherichia coli,
Salmonella typhi, Staphylococcus aureus and Vibreo chloera were
found to be highly susceptible to the tested compounds with activity ranging
between 75 and 94% of that of that of ciprofloxacin. Similarly the tested
compounds showed anti-fungal activity against four pathogenic fungi. Their
antifungal activity was compared with that of griseofulvin. [18]
Recently
a series of dihydropyran and dihydropyridin derivatives of embelin were
synthesized. The obtained compounds showed antibacterial activity against Gram
positive and Gram negative bacteria; more significantly against
multi-drug-resistant Staphylococcus
aureus. [19]
Antifungal
Activity
Using
standard in vitro anti-fungal susceptibility methods, researchers
found that embelin shows anti-fungal activity against Candida lbicans, Candida
tropicalis, Candida parapsilosis, Candida alidus and A.
flavus [20]
Antiparasitic
Activity
By
definition, anthelmintics are drugs that expel / eradicate parasitic worms from
the body, by either inhibiting or killing them. Accordingly anthelmintics are
called as vermifuges (inhibiting drugs) or vermicides (killing drugs).
Honigberger reported Widanga, Embelia ribes Burm. as a
vermifuge. After him almost all researchers described Widanga, Embelia
ribes Burm. f. as 'vermifuge' anthelmintic. [21]
Watt
GA reported addition of powdered seeds of Widanga (Embelia ribes)
in curdled milk in combination with castor oil for effective eradication
of tape worms. [22]
Embelin
a benzoquinone shows anthelmintic activity. It is also ovicidal. Its activity
is comparable to livamisole. While the parasites develop genetic
resistance to levamisole, albendazole, ivermectin and mebendazole, the
researchers found that the parasites have not developed resistance to
embelin and Widanga (Embelia ribes) extract or powder. [23]
A
Herbal monograph reported, Embelin is effective against tape worm but
not against round worm or hookworm. [24], [25]
Furthermore,
embelin was found to active against Trypanosoma cruzi trypomastigotes.
[26]
The
aqueous extract of Widanga (Embelia ribes) containing embelin exhibited
anthelmintic activity against a variety of worms. This activity was
comparable to piperazine citrate. [27]
The
ethanolic extract of seeds of Widanga (Embelia ribes) was evaluated
for anthelmintic activity against round worm. In vitro graded doses
of the extract (10, 50, 100 and 200 µg/ml) showed a significant
anthelmintic activity against round worm. Levamisol and Ivermectin
were used as reference drugs. [28]
Mojumdar
V and Mishra SD reported nematidicidal activity of embelin. [29]
Antimalarial
activity
Benzoquinone
derivatives have been reported to possess antiplasmdial activity. Embelin being
a benzoquinone derivative was studied for its antimalarial activity. The
study suggested that embelin is a useful antimalarial phytochemical. [30]
Embelin
is found to be useful in the treatment of Plasmodium falciparum malaria.
[31]
According
to a group of researchers, embelin is not ideal to be suggested as an anti-malarial
agent to be used against Plasmodium falciparum malaria, but it
has a potential to ameliorate chloroquin resistance. [32]
Actions
on the Skin
A
study was designed to investigate the effects of embelin on lipopolysachharide-induced
TNF-α production in mice and in human keratocytes and also to study the effects
of embelin on acute and chronic skin-inflammations in mice. By blocking the
synthesis of TNF-α, embelin inhibited topical edema in the ear of mouse leading
to reduction in the skin weight and thickness, reduction in inflammatory
cytokine production, neutrophil-mediated myeloperoxidase activity. These
observations were supported by histopathological studies. Embelin was also
effective in reducing inflammatory damage induced by chronic exposure to TPA. Thus
embelin has anti-inflammatory activities in both acute and chronic dermatitis.
[33]
Wound
Healing Activity
In
a study on Swiss Albino Rat model, the wound healing activity of embelin
isolated from the ethanol extract of the leaves of Widanga (Embelia ribes)
was evaluated. The ethanol extract at 30 mg/ml showed rapid epithelization of
the incised wound and faster rate of wound contraction. In dead
space wounds also formation of granulation tissue was rapid and increased
strength of collagen tissue. Both the observations were supported by
histological study. [33]
Actions
on Musculoskeletal System
It
is well known that most malignant tumors metastasise in bones. Thereafter
osteoclastic activity increases resulting in osteolysis or destruction of the
bone. Embelin has been shown to bind and inhibit x-linked inhibitor of
apoptosis protein and prevent the bone loss. Embelin also has been shown to
induce the ostoblastic activity and the bone regeneration. [34]
Actions
on Hematopoetic System
Signal
transducer and transcription activator-3 (STAT-3) mediates cellular responses
to interleukins. Phosphatase and tensin (PTEN) homolog is a protein that, in
humans, is encoded by the PTEN gene. Mutations of this gene are a step in the
development of many cancers. [35]
By
down-regulating the expression of STAT-3 regulated gene products, embelin
suppresses the cell proliferation and survival of multiple myeloma via the
protein tyrosine phosphatase PTEN [36]
Actions
on the Eye
Muller
glia or Muller cells are a type of retinal glial cells. They maintain the
stability of the retinal extravascular environment. [37]
Hyperglycemia
induces alterations in the Muller cells such as cell proliferation and VEGF
production. This is the precursor of development of diabetic retinopathy.
Embelin counter acts these alterations and prevents the development of diabetic
retinopathy. [38]
Actions
on the Breast
MCF-7
is the acronym of Michigan Cancer Foundation-7. MCF-7 is a breast cancer
cell line isolated in 1970 from a 69 year old Caucasian woman. This cell line
is used in cancer research.
A
group of researchers found that embelin induced apoptosis of MCF-7 breast
cancer cells in the G2/M phase via the mitochondrial pathway in a
dose-dependent manner. However the exact mechanism of action remains
unclear. [39]
A
study shows that embelin primes inflammatory breast cancer cells (IBC cells)
for TNF-alpha-related-apoptosis-inducing-ligand (TRAIL) mediated
apoptosis by its direct action on the anti-caspase activity of X-linked
inhibitor of apoptosis protein (XIAP). [40]
Mortalin
is a protein involved in multiple basic mitochondrial processes, including
energy metabolism, free radical generation. p53 is a key tumor suppressor
protein that eliminates genetically unstable cells. Targeting mortalin by
embelin causes activation of tumor suppressor p53 and deactivation of
metastatic signaling in breast cancer. [41], [42]
Antipyretic
activity
By
various chemical reactions and chemical processes disalts and diamines of
embelin are developed. Embelin, its disalts and diamines exhibit anti-pyretic
and anti-inflammatory activity. [43]
Actions
on CNS
Action
on traumatic brain injury
Traumatic
brain injury is a serious problem. Both in children it can be life threatening
and even fatal. The survivors suffer from many complications. A study revealed
that embelin can be useful in the treatment of some complications. [44]
Effect
on autoimmune encephalomyelitis
A
study showed that embelin suppressed human CD 14(+) monocyte-derived dendritic
cells (DC) differentiation, maturation and endocytosis. Embelin also
inhibited the stimulatory function of mature dendritic cells on allogenic T cell
proliferation in vitro. Embelin also prevents the demyelination of nerves.
Thus embelin has potent anti-inflammatory and immunosupressive properties. This
makes it a potential therapeutic agent for the treatment of autoimmune
encephalitis and inflammatory diseases of CNS. [45]
Analgesic
activity
Embelin
is a non-norcotic analgesic effective by oral, intramuscular and intravenous
routes. Its action is not antagonized by naloxone indicating a different
central site of action. Furthermore in vivo studies indicate
that mu and kappa binding sites in the brain may be involved in the
analgesic action of embelin. Its analgesic action is as strong as
morphine. Embelin is not habit forming and not addictogenic and is remarkably
free from adverse effects. This makes it safe analgesic for long term
use. [46], [47], [48]
Anxiolytic
activity
A
study was aimed at evaluating anxiolytic activity of embelin isolated from
Widanga (Embelia ribes). The study group found embelin to be a potent
anxiolytic agent. Needless to say that the anxiolytic activity was dependent on
the dose used. [49]
Antidepressant
activity
To
evaluate the antidepressant activity of embelin, intraperitonial injections of
embelin were administered at 2.5 and 5 mg/kg body weight 30 minutes
prior to induction of experimental depression in Swiss albino mice of both
sexes. Embelin exhibited antidepressant activity. The effective dose was 5
mg/kg body weight which was as good as imipramine 15 mg/kg body weight.
Since,
the anxiolytic effect of embelin was shown to be mediated through GABA system,
similar mechanism of antidepressant action cannot be ruled out. [50]
Antipsychotic
activity
In
Ayurveda Widanga (Embelia ribes) was claimed to be useful in the
treatment of diseases of the nervous system. In a study on rodents, embelin was
administered orally to the study animals at 5 and 10 mg/kg body weight once a
day for 15 days before exposing them to apomorphine injections. The study
showed that embelin restored the elevated levels of dopamine, noradrenaline and
serotonin to normal. Embelin wast more effective at the dose of 10 mg/kg body
weight than at the dose of 5 mg/kg body weight. Researchers concluded that
embelin possesses antipsychotic activity. In the research paper researchers did
not explain the exact pharmacological mechanism of anti-psychotic activity of
embelin. Further research is needed in this regard. [51]
Anticonvulsant
activity
In
experimental animals, embelin administered by intraperitonial injections at
2.5, 5 and 10 mg / kg body weight significantly inhibited seizures
induced by phentylenetetrazole and electroshocks. The effect was dependent on
the dose of embelin used. The anticonvulsant activity of embelin was
comparable to phenytoin and diazepam. The observations suggest that embelin can
be useful in the treatment of grand mal and petit mal epilepsy. [52]
Actions
on Sickness behavior
Sickness
behaviour is a coordinated set of adaptive behavioural changes that develop in
illness especially during the course of infection. A study was undertaken to
investigate actions of embelin on lipopolysaccharide (LPS)-induced sickness
behaviour in adult Swiss albino mice. The animals were pre-treated with 10
and 20 mg/kg body weight of embelin for 3 days and then challenged with LPS
400 µg/kg body weight. Anti-inflammatory, antioxidant, anxiolytic and
neuroprotective actions of embelin attenuated the behavioural changes induced
by LPS. Embelin reduced anorexia, prevented anhedonia (inability to feel
pleasure), ameliorated brain oxidative stress markers. The study demonstrated
protective effects of embelin on LPS-induced sickness behaviour in mice. [53]
Effect
on focal ischaemia
In
cerebral ischaemia the brain
receives inadquately oxygenatd blood and in inadequate
quantity too. This generates reactive oxygen species that inflict brain damage.
Embelin is a potent antioxidant. Its chemical structure resembles that of
co-enzyme Q 10. Patel and Gohil investigated the effect of embelin on focal
cerebral ischaemia using middle cerebral artery occlusion model in male Wistar
rats. The occlusion resulted in infarct in the middle cerebral artery
territory. Male Wister rats were then treated with embelin at doses of 50, 75
and 100 mg/kg body weight. Embelin not only decreased the area of infarct but
also increased super oxide dismutase (SOD) levels [54]
Effects
on global ischaemia-reperfusion injury
A
study was designed to investigate the protective effect of embelin on global
ischaemia-reperfusion brain injury in rats. Transient global ischaemia
was induced by occluding both internal carotid arteries for 30 minutes followed
by 24 hour reperfusion. Physical, biochemical and histoppathological changes
were recorded. The animals pretreated with emnelin at doses of 25 and 50 mg/kg
body weight were protected from ill effects of ischaemia. Their locomotor
activity was preserved. Pretreatment and treatment with embelin also reduced
the lipid peroxidation and increased glutathione-S-transferase activity in the
brain. The histopathological studies revealed decreased area of cerebral
infarction. These findings suggest that embelin is a potent neuroprotective
agent and may prove to be useful in prevention and treatment of stroke. [55]
Ischaemic
stroke
Embelin
has been shown to relieve some effects of ischaemic stroke. [56]
Effects
in Huntington's disease
Huntington's
disease (HD) is a progressive neurodegenerative disorder associated with severe
degeneration of basal ganglia neurones, which affects muscle
coordination. It leads to decline in mental function and behavioural symptos.
3-Nitropropionic acid (3-NP) causes severe neurotoxicity in animals which
resembles Huntington's disease in humans. A study was designed to study the
protective effect of embelin in 3-NP induced neurotoxicity in adult Wistar
rats. Neurotoxicity was induced in Wistar rats by administering of 3-NP at the
dose of 15 mg/kg body weight for 7 days. From 8 th day onwards
the animals were co-treated with embelin (10 and 20 mg/kg body weight) for
7 days. The animals treated with embelin showed improvement in
neurological symptoms and behaviour. [57]
Effect
on Multiple Sclerosis (MS)
A
chronic progressive damage to the sheaths of nerve cells in the brain, spinal
cord, optic nerve etc. is termed as multiple sclerosis (MS).
It is an autoimmune disease due to chronic inflammation. Xue et al
demonstrated that embelin possesses a strong therapeutic potential for
autoimmune anti-inflammatory conditions in multiple sclerosis (MS). [58]
Effect
on malignant glioma
Embelin
has been reported to exhibit therapeutic activity against cancers. In a study
embelin induced apoptosis in glioblastoma and astrocytes.[59]
A
study was designed to investigate whether embelin could have a therapeutic
effect in glioma. The study showed that embeiln suppressed the
proliferation of human glioma cells. In addition, embelin induced apoptosis in
human glioma cells by inhibiting NF-κ B. The results indicate
that embelin could be a potent novel therapeutic modality for glioma. [60]
Actions
on CVS
To
investigate the cardioprotective effect of and possible mechanism of action of
embelin on isproterenol-induced myocardial infarction
in rats, rats were pretreated for three days with embelin at a dose of
50 mg/kg body weight. There after isoproterenol was injected subcutaneously at
the dose of 85 mg/kg body weight at an interval of 24 hours for 2 consecutive
days. Serum was analysed for cardiac specific injury biomarkers, lipids and
lipoprotein contents. Heart tissues were isolated for histopathology,
antioxidant and mitochondrial respiratory enzyme activity assays and
westernblot analysis. Results showed that pretreatment with embelin
significantly protected the myocardium from isoproterenol-induced cardiaca
injury. This suggests that embelin may have a potential benefit in preventing
ischaemic heart disease. [61]
In
another study on rabbits some researchers investigated the protective effects
of embelin on myocardial ischaemia-reperfusion injury following cardiac arrest.
Following cardiac arrest, hemodynamics, pro-inflammatory cytokines, cardiac
troponins, necrosis ratio, apoptotic index, nuclear factor-kappa B p65 and
histological damage were evaluated. They found that animals treated with
embelin showed improvement in myocardial morphology. These results
were attributed to anti-inflammatory activity of embelin. [62]
Embelin
has the ability to lower elevated systolic blood pressure. [63]
Actions
on RS
A
study was aimed at investigating the effect of embelin on lipopolysachharide
(LPS)-induced acute respiratory distress syndrome in rats. Embelin was
administered orally to rats at 5, 10 and 20 mg/kg body weight for four days
before lipopolysachharide (LPS) challenge. The results
showed that embelin prevented pO2 down-regulation and pCO2 augmentation.
Embelin also attenuated histopathological changes in the lung in acute respiratory
distress syndrome. This was attributed to anti-inflammatory and protective
effect of embelin against LPS-induced airway inflammation and obstruction. [64]
Embelin
induces apoptosis in lung cancer cells via activation of p38/JNK pathway.
Reactive oxygen species play a crucial role in embelin- activity. [65]
Actions
on GI System
Administration
of embelin orally at 75 mg/kg per day for 15 to 30 days to male rats caused
significant elevation in the uptake of D-glucose, L-alanine, L-leucin
and calcium in the small intestine. Embelin also produced significant increase
in enzymes sucrase, maltase, lactase, alkaline phosphatase and leucine
aminopeptidase. All these changes returned to control levels on withdrawal of
the drug.[66]
In
an experimental study, intra-rectal administration of 3% acetic acid for 7 days
induced ulcerative colitis in rats. When treated with embelin at doses
of 25, 50 and 100 mg /kg body weight there was a significant remission in the
colitis. The treatment also reduced significantly the colonic myeloperoxidase
activity, lipid peroxides and serum lactose dehydrogenase. The treatment also
increased the decreased glutathione. The histopathological also supported the
remission of the disease. The protective effect of embelin was attributed to
the anti-inflammatory and antioxidant activities of the phytochemical. [67]
In
another experimental study, colitis was induced in BALB/c mice by feeding them
with 5% dextran sodium sulfate (DDS) for 7 days in drinking water. Embelin was
then administered orally for 7 days to these animals at 10, 30 and 50 mg/kg
body weight doses. The treatment significantly suppressed weight
loss, diarrhea, bleeding and infiltration of of immune cells. The
histopathological showed that embelin reduced the mucosal edema and the loss
of crypts induced by dextran sodium sulfate. Furthermore embelin inhibited the abnormal
secretions and mRNA expressions of pro-inflammatory cytokines. [68]
Actions
on the Pancreas
Tumor
necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in
a wide variety of cancer cells. TRAIL does not exert toxic effects on
normal cells. Therefore TRAIL may be a suitable agent for anti cancer therapy.
In various pancreatic cancer cell lines TRAIL induced apoptosis.
However the cancer cells soon developed resistance. Embelin reduced the
resistance to TRAIL by the pancreatic cancer cells. [69]
Actions
on the Liver
Hepatoprotection
The
rat liver is susceptible to damage induced by carbon tetrachloride (CCl4)
through production of reactive metabolites, namely trichlormethyl-free
radicals. After the induction of liver damage by carbon tetrachloride the
animals were treated with embelin by oral administration of 25 mg/kg body
weight from day 1 to 15. With embelin treatment the peroxidative damage was
minimal. The antioxidant activity of embelin was found to be useful to protect
the liver against carbon chloride- induced hepatotoxicity in rats. The
hepatoprotection by embelin was superior to that by silymarin. [70]
Another
group of researchers use N-Nitrosodimethylamine and Carbon tetrachloride to
induce hepatootxicity. They then treated the animals with embelin. Their results
were similar as described above. [71]
Alcoholic
and non alcoholic liver disease
Anti-inflammatory,
antioxidant and free radical scavenging activity of embelin is useful in
protecting the liver against alcoholic and non alcoholic liver disease.
The effective dose of embelin is found to be 50 mg/kg body weight. [72]
Hepato-biliary
malignancy
Anti-inflammatory
is useful in the treatment of certain hepatic malignancies and cancer cell
metastasis. [73]
Embelin
causes inhibition of cancer cell proliferation but does not induce cancer cell
apoptosis. By this mechanism embelin inhibits proliferation of
cholangiocarcinoma. [74]
Embelin
50 mg /kg body weight (in combination with curcumin 100 mg/ kg body weight)
prevented the induction of hepatic hyperplastic nodules, body weight loss,
hypoproteinemia and elevation of liver enzymes in adult male Wistar rats. [75]
Actions
on Metabolism
To
evaluate efficacy of embelin in the treatment of obesity, male Wistar rats were
fed on high fat diet for 28 days. Obese rats were then treated
with embelin, 50 mg/ kg body weight for 21 days. Embelin treatment reduced body
weight, reduced BMI, normalized blood pressure, serum lipid
levels as well as coronary artery risk and atherogenic index. Embelin
reduced serum glucose levels by 24.77 %, insulin by 35 % and
leptin by 43.39%. Furthermore, embelin treatment significantly decreased the
byproduct or degradation products of fat metabolism (TBARS) in the
liver. Embelin increased the levels of superoxide dismutase (SOD), glutathione
(GSH). The effects of embelin were similar to 10 mg/ kg body weight of
orlistat. Embelin could be valuable in the development of new
drug therapies to prevent and treat obesity, hyperlipidemia, diabetes, some
complications of diabetes and oxidative stress. [76]
Antidiabetic
activity
Streptozotocin-induced
diabetic rats were treated with embelin at 25 and 50 mg/kg body weight per day
for 3 weeks. They showed a significant reduction in plasma
glucose, glycosylated haemoglobin and pro-inflammatory mediators. Embelin also
improved altered architecture of β-islet cells of pancreas
and hepatocytes. This activity is attributed to the anti-inflammatory activity
of embelin. The study suggests that embelin can be a useful adjuvant for the
treatment of type 2 diabetes. [77]
Another
group of researchers induced diabetes in rats by using alloxan. They treated
the animals with embelin. Their results were similar to the results mentioned
above [78]
Embelin
50 mg/kg body weight administered to type 2 diabetic rats not only controlled
the blood sugar but also modulated the altered lipid lipid profile.
Embelin also reduced the weight, regulated insulin resistance, altered β
cell dysfunction, inhibited adiponectin activity and regulated insulin mediated
glucose uptake in epididymal adipose tissue. These effects were attributed to
antioxidant activity of embelin. [79]
Embelin
increases the antioxidant status in the pancreas. This prevents the β cell
apotosis and protects them. The histopathological study of pancreas of the
diabetic rats shows degenerated pancreas with reduced β cell counts, while
embelin treatment was shown to significantly protect the β cells. [80]
Actions
on Urinary System
A
study was designed to evaluate the nephroprotective and anti-polyuric activity
of embelin on lithium-induced nephrogenic diabetes insipidus (NDI).
Diabetes insipidus was induced in rats by administering lithium chloride 4
mg/kg body weight per day for 6 days. After induction embelin 50 and 100 mg/kg
body weight was administered orally once a day for 21 days. At 0, 7, 14 and 21
days the body weight, protein in urine, creatinine in urine, blood
urea nitrogen serum creatinine levels were assessed.The results showed that
embelin 50 and 100 mg/kg body weight showed increase in body weight and
decrease in protein and creatinine in urine and normalization of blood
urea nitrogen and serum creatinine.
Histopathological examination of the kidney showed reduced vascular
degeneration of tubules and slight degeneration and dilatation of renal
tubules. These effects of embelin were due to its antioxidant activity. The
decreased urine excretion may be due to the blocking of sodium channels.
[81]
Actions
on Male Reproductive System
Embelin
administered by subcutaneous route at 0.3, 0.4 and 0.5 mg /kg body weight for
35 days to experimental animal model reduced sperm count and altered the
testicular histology. Embelin was found to possess anti-androgenic activity.
Embelin was used by some couples as an oral contraceptive.
This is very cheap and can be a useful oral contraceptive for village-couples.
[82]
Daily
subcutaneous injection of embelin isolated from the seed extract of Widanga
(Embelia ribes) at a dose of 20 mg/kg body weight to male albino rats for 15-30
days revealed the inhibition of: (1) motile sperm count in the epididymis (2)
the enzyme activity of glycolysis (3) energy metabolism (4) fertility
parameters. These changes were reversible. Treatment with embelin causes
both in vitro and in vivo morphological changes in
spermatozoa: (1) decapitation of spermatozoal head (2) discontinuity of outer
membranous sheath in the mid-piece and the tail region and (3) alteration in
the shape of the shape of the cytoplasmic droplet in the tail. Embelin also
caused a significant reduction in the sperm count, motility of the sperms and
weight of the testes. All these contribute to antifertility activity of embelin
in male albino rats. [83]
Having
confirmed the efficacy of embelin as an effective contraceptive or
antifertility agent, the next challenge was to determine the effective
therapeutic dose. After studying various biochemical, hormonal and
histopathological parameters and different routs of administration the doses
finalized were: (1) Intramuscular injection- 5.0 mg/kg body weight (2) Oral
administration (suspension)-10 mg/kg body weight (3) Oral tablet of base 50
mg/kg body weight (4) Subcutaneous injection (minimum effective dose)-20 mg /kg
body weight [84]
Actions
on the prostate
Embelin
ameliorates testosterone-induced hyperplasia in rats. [85]
Embelin
induces apoptosis in PC3 cell line of the prostate cancer cells. But the exact
mechanism is not known. [86]
Embelin
enhances therapeutic efficacy of ionising radiation in prostate cancer [87]
Actions
on Female Reproductive System
In
an experimental study on female Sprgue-Dawlee rats having regular
estrous cycle, embelin at doses of 10 and 20 mg/kg body weight decreased the
plasma levels of estrogen and progesterone. This anti-fertility effect in
females is due to suppression of ovarian function. [88], [89]
Treatment
of female rats with embelin reduces the serum levels of estradiol and
progesterone. Embelin also reduces the weight of ovaries uterus.
These effects of embelin interfere with the implantation of fertilized ovum in
the uterus. [90]
That
herbal therapy is safe and devoid of side effects is a myth. Administration of
embelin at a dose of 120 mg/kg body weight to female rats for six
weeks caused severe pathological changes in the liver and kidneys such as
marked necrotic changes, perinuclear vacuolation, tubular damage. The adrenals
showed marked hypertrophy. There was increase in acid and alkaline phosphatase.
However the histological features of spleen remained unchanged.
[91]
Anticancer
activity
Embelin
is reported to decrease tumor size and inhibit activity of serum enzymes viz.
acid phosphatase, T-glutamyl transferase, lactate dehydrogenase, aldose etc. in rats with
experimental fibrosarcoma. Embelin interferes with carbohydrate and aminoacid
metabolism in tumor bearing animals. The osteoclasts are responsible for the
osteolysis in bone metastases of the tumor. RANKL (receptor activator for
nuclear factor κB ligand), a member of the TNF superfamily and an
activator of the NF- κB signaling pathway, has emerged as a major mediator
of bone loss, commonly associated with cancer and other chronic inflammatory
diseases. [92], [93]
Nuclear
factor-kappa B (NF- κB) regulates several gene associated with
inflammation, proliferation, carcinigenesis and apoptosis. Embelin
inhibits tumor necrosis factor alpha (TNF-α) induced NF- κB
activation. Thus embelin prevents carcinogenesis. Furthermore, embelin
down-regulates gene products involved in cell
survival, proliferation, invasion and metastasis of the tumor. [94]
Mortalin
is a protein involved in multiple basic mitochondrial processes, including
energy metabolism, free radical generation. p53 is a key tumor
suppressor protein that eliminates genetically unstable cells. Targeting
mortalin by embelin causes activation of tumor suppressor p53 and
deactivation of metastatic signaling. [95], [96]
TNF-α
is synthesized as a membrane anchored protein, pro-TNF-α . The soluble
component of pro-TNF-α is then released in the extra-
cellular space by the action of a protease, TNF-α converting enzyme. This
the first step in development of inflammation and cancer. Embelin
inhibits TNF-α converting enzyme and cancer cell metastasis. [97]
In
the normal quiescent state of vasculature, only 0.01% of endothelial cells
(ECs) are proliferating. However during angiogenesis the endothelial
cells proliferate markedly. This proliferation depends on mitochondrial
oxidative phosphorylation. This neo-angiogenesis is the key stage
in tumor growth. The antooxidant activity of embelin inhibits endothelial
mitochondrial respiration and impairs neo-angiogenesis and tumor growth.
[98]
Safety
and Toxicity
Mice
treated with embelin administered orally at doses of 50-100 mg/kg body weight
did not show acute toxicity. The subcutaneous dose of 10
mg/kg body weight for 10 weeks was also well tolerated by animals without any
side effect. Embelin administered orally to rats from 10 mg to 3
g/kg body weight did not show any adverse effect on heart, liver, kidney and
bone marrow. The female rats of reproductive age having normal cycles however
did show toxicity even on short term use. Administration of 120 mg/kg
body weight was a safe dose, however higher dose was unsafe. The dose
also caused liver and kidney damage. Embelin can cause hormonal
disturbances in males and females. Embelin can cause morphological alterations
in the adrenals, testes and ovaries. It can be said, embelin is safe to
use even for long term use in therapeutic doses. [99]
Contraindications
Embelin
is cotraindicated during pregnancy, lactation.
Newly
married couples should not use embelin as a contraceptive.
Dosages
Intramuscular
injection-
5.0 mg/kg body weight
Oral
administration (suspension)-10 mg/kg body weight
Oral
tablet of
base 50 mg/kg body weight
Subcutaneous
injection (minimum effective dose)-20 mg /kg body weight
Embelin
Derivatives
The
success in synthesis of embelin researchers were inspired to develop
derivatives of embelin. By combining embelin with various metals such as
sodium, potassium, copper, cobalt, nickel, zinc etc. salts of embelin were
synthesized. These derivatives showed a better pharmacological actions than
natural embelin. Natural embelin exhibited anticancer activity. The search
for better and better anticancer drugs is incessant. This led to develop better
anticancer derivatives of embelin. I wish to present a short review of embelin
derivatives and their pharmacology.
Antiinflammatory,
analgesic, antioxidant and free radical scavenging activities
Recently
embelin was condensed with various aromatic substituted primary amines to yield
ten new derivatives. At 10-20 mg/kg body weight these compounds
show anti-inflammatory, analgesic, antioxidant and free radical
scavenging activities. [100]
Antibacterial
activity
Aromatic
aldehyde derivatives of embelin show antibacterial activities against gram
positive and gram negative bacteria including multidrug
resistant Staphylococcus aureus. [101]
Cobalt
[Co(II)], Nickel [Ni(II)] Copper [Cu (II)] and Zinc [Zn (II)] derivatives of
embelin show antibacterial activity against Staphylococcus
aureus and Pseudomonas aeruginosa. At higher concentrations
these derivatives show antibacterial activity comparable to rifampicin. [102]
In
a study various derivatives of mbelin showed antimicrobial activity
against Staphylococcus aureus and Pseudomonas aeruginosa,
Escherichia coli and Candida albicans.[103]
Antidiabetic
activity
Nanoparticles
of embelin and its metal complexes exhibit potent antidiabetic activity.
[104],
[105]
Anticancer
activity
All
derivatives of embelin exhibit anticancer activity against a variety of cancer.
Many research papers are available for references on this subject. [106], [107]
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