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Pharmacognosy Reviews
Vol 1, Issue 1, Jan- May, 2007
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PHCOG MAG.: Plant Review
Withania somnifera (Ashwagandha): A Review
Girdhari Lal Gupta and A. C. Rana*
Department of Pharmacology, B. N. College of Pharmacy, Udaipur -313 002 (Rajasthan) India
Phone: +91-294-2413182 (O), +91-294-2413182 (Fax), +91-9351442522 (M)
E-mail Address: acrana4@yahoo.com
ABSTRACT
Withania somnifera, a commonly used herb in Ayurvedic medicine. Although the review articles on this plant are already
published, this review article is presented to compile all the updated information on its phytochemical and pharmacological
activities, which were performed by widely different methods. Studies indicate ashwagandha possesses antioxidant, anxiolytic,
adaptogen, memory enhancing, antiparkinsonian, antivenom, antiinflammatory, antitumor properties. Various other effects like
immunomodulation, hypolipidemic, antibacterial, cardiovascular protection, sexual behaviour, tolerance and dependence have
also been studied. These results are very encouraging and indicate this herb should be studied more extensively to confirm these
results and reveal other potential therapeutic effects. Clinical trials using ashwagandha for a variety of conditions should also be
conducted.
KEY WORDS: Withania somnifera, Withanolides, Phytochemistry, Pharmacological activities.
INTRODUCTION
Withania somnifera (WS), also known as ashwagandha, Indian
ginseng, and winter cherry, it has been an important herb in
the Ayurvedic and indigenous medical systems for over 3000
years. The roots of the plant are categorised as rasayanas,
which are reputed to promote health and longevity by
augmenting defence against disease, arresting the ageing
process, revitalising the body in debilitated conditions,
increasing the capability of the individual to resist adverse
environmental factors and by creating a sense of mental
wellbeing (1).
It is in use for a very long time for all age groups and both
sexes and even during pregnancy without any side effects (2).
Historically, the plant has been used as an antioxidant,
adaptogen, aphrodisiac, liver tonic, antiinflammatory agent,
astringent and more recently to treat ulcers, bacterial
infection, venom toxins and senile dementia. Clinical trials
and animal research support the use of WS for anxiety,
cognitive and neurological disorders, inflammation,
hyperlipidemia and Parkinson’s disease. WS chemopreventive
properties make it a potentially useful adjunct for patients
undergoing radiation and chemotherapy. Recently WS is also
used to inhibit the development of tolerance and dependence
on chronic use of various psychotropic drugs.
TAXONOMICAL CLASSIFICATION
Kingdom : Plantae, Plants;
Subkingdom : Tracheobionta, Vascular plants;
Super division : Spermatophyta, Seeds plants;
Division : Angiosperma
Class : Dicotyledons
Order : Tubiflorae
Family : Solanaceae
Genus : Withania
Species : somnifera Dunal
Botanical description: WS is a small, woody shrub in the
Solanaceae family that grows about two feet in height. It
can be found growing in Africa, the Mediterranean, and India.
An erect, evergreen, tomentose shrub, 30-150 cm high, found
throughout the drier parts of India in waste places and on
bunds. Roots are stout fleshy, whitish brown; leaves simple
ovate, glabrous, those in the floral region smaller and
opposite; flowers inconspicuous, greenish or lubrid-yellow, in
axillary, umbellate cymes; berries small, globose, orange-red
when mature, enclosed in the persistent calyx; seeds yellow,
reniform. The roots are the main portions of the plant used
therapeutically. The bright red fruit is harvested in the late
fall and seeds are dried for planting in the following spring.
Parts used: Whole plant, roots, leaves, stem, green berries,
fruits, seeds, bark are used.
Synonyms:
Sanskrit: Ashwagandha, Turangi-gandha; English: Winter
Cherry; Hindi: Punir, asgandh; Bengali: Ashvagandha;
Gujrati: Ghodakun, Ghoda, Asoda, Asan; Telgu: Pulivendram,
Panneru-gadda, panneru; Tamil: Amukkura, amkulang,
amukkuram-kilangu, aswagandhi, Karnataka:
Viremaddlinagadde, Pannaeru, aswagandhi, Kiremallinagida;
Goa: Fatarfoda; Punjabi: Asgand, isgand; Bombay: Asgund,
asvagandha; Rajasthani: Chirpotan
PHYTOCHEMISTRY
Chemical constituents of WS are always of an interest for the
researchers. The biologically active chemical constituents
are alkaloids (ashwagandhine, cuscohygrine, anahygrine,
tropine etc), steroidal compounds, including ergostane type
steroidallactones, withaferin A, withanolides A-y,
withasomniferin-A, withasomidienone, withasomniferols A-C,
withanone etc. Other constituents include saponins
containing an additional acyl group (sitoindoside VII and VIII),
and withanolides with a glucose at carbon 27 (sitoindoside IX
and X) (3, 4). Apart from these contents plant also contain
chemical constituents like withaniol, acylsteryl glucosides,
starch, reducing sugar, hantreacotane, ducitol, a variety of
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amino acids including aspartic acid, proline, tyrosine, alanine,
glycine, glutamic acid, cystine, tryptophan, and high amount
of iron. Withaferin A, chemically characterized as 4b,27-
dihydroxy- 5b-6b-epoxy-1-oxowitha-2, 24-dienolide, is one of
the main withanolidal active principles isolated from the
plant. WS showed chemogenetic variation and so far three
chemotype I, II and III had been reported (5). These are
chemically similar but differ in their chemical constituents
especially in withanolide content. In Indian variety thirteen
Dragendroff positive alkaloids have been obtained. The
reported alkaloids are anaferine ( bis (2-piperidylmethyl)
ketone); isopelletierine; tropine; pseudotropine; 3α-
tigloyloxtropine; 3- tropyltigloate; cuscohygrine; dl-
isopelletierine; anahygrine; hygrine; mesoanaferine; choline;
somniferine; withanine; withananine; hentriacontane;
visamine; withasomnine, a pyrazole derivative from West
Germany; pseudowithanine and ashwagandhine. Withaniol
(mixture of withanolides) and number of withanolides
including withaferine-A; withanolide N and O; withanolide D;
withanolide p and 8; withanolide Q and R; withanolide y, 14α-
hydroxy steroids and withanolides G, H, I, J, K and U (6).
Seven new withanolide glycosides called withanosides I, II, III,
IV, V, VI and VII had been isolated and identified (7). Much of
WS pharmacological activity has been attributed to two main
withanolides, withaferin A and withanolide D. For
physicochemical analysis, thin-layer chromatography (TLC)
was used to identify the steroidal actones (withanolides)
present in ashwagandha. The solvent system used was
chloroform:methanol:water (64:50:10, v/v) and spots were
finally identified with vanillin– phosphoric acid (8). The
percentage of steroidal lactones was estimated
spectrophotometrically.
Sitoindoside Vll : R=R1 : R3=H : R4 = Palmitoyl
Sitoindoside Vlll : R=R2 : R3=H : R4
Withaferin A : R=H
Sitoindoside lX: R1 = D-glucoside; R2=H
Sitoindoside X: R1 = D-glucoside; R2=Palmitoyl = Palmitoyl
Structures of key bioactive ingredients
PHARMACOLOGY
Although a lot of pharmacological investigations have been
carried out based on the ingredients presents but a lot more
can still be explored, exploited and utilized. A summary of
the findings of these studies is presented below.
Antioxidant effect
The brain and nervous system are relatively more susceptible
to free radical damage than other tissues because they are
rich in lipids and iron, both known to be important in
generating reactive oxygen species. Free radical damage of
nervous tissue may be involved in normal aging and
neurodegenerative diseases, e.g., epilepsy, schizophrenia,
Parkinson’s, Alzheimer’s, and other diseases. The active
principles of WS, sitoindosides VII-X and withaferin A
(glycowithanolides), have been tested for antioxidant activity
using the major free-radical scavenging enzymes, superoxide
dismutase (SOD), catalase (CAT), and glutathione peroxidase
(GPX) levels in the rat brain frontal cortex and striatum.
Decreased activity of these enzymes leads to accumulation of
toxic oxidative free radicals and resulting degenerative
effects. An increase in these enzymes would represent
increased antioxidant activity and a protective effect on
neuronal tissue. Active glycowithanolides of WS were given
once daily for 21 days, dose-related increased in all enzymes
were observed; the increases comparable to those seen with
deprenyl (a known antioxidant) administration. This implies
that WS does have an antioxidant effect in the brain, which
may be responsible for its diverse pharmacological properties
(9). In another study, an aqueous suspension of WS root
extract was evaluated for its effect on stress-induced lipid
peroxidation (LPO) in mice and rabbits. LPO blood levels
were increased by lipopolysaccharides (LPS) from Klebsiella
pneumoniae and peptidoglycans (PGN) from Staphylococcus
aureus. Simultaneous oral administration of WS extract
prevented an increase in LPO (10). Apart from hepatic lipid
peroxidation (LPO), the serum enzymes, alanine
aminotransferase, aspartate aminotransferase and lactate
dehydrogenase, were assessed as indices of hepatotoxicity.
Silymarin (20 mg/kg, p.o.) was used for comparison. Iron
overload induced marked increase in hepatic LPO and serum
levels of the enzymes, which was attenuated by
glycowithanolides (WSG) in a dose-related manner, and by
silymarin (11).
Anxiety and depression
Anxiolytic and antidepressant actions of the bioactive WSG,
isolated from WS roots, in rats were assessed. WSG was
administered orally once daily for 5 days and the results were
compared by those elicited by the benzodiazepine lorazepam
for anxiolytic activity, and by the tricyclic antidepressant,
imipramine. WSG induced an anxiolytic effect was
comparable to lorazepam, in the elevated plus-maze, social
interaction and feeding latency in an unfamiliar environment,
tests. WSG also reduced rat brain levels of tribulin, an
endocoid marker of clinical anxiety, when the levels were
increased following administration of the anxiogenic agent,
pentylenetetrazole. WSG also exhibited an antidepressant
effect, comparable with that induced by imipramine, in the
forced swim-induced 'behavioural despair' and 'learned
O
H
R
CH2OR4
OR3
OR3
OR3
O
R1=
R2=
O
OH
OHCH2OR
O
O
OH OH
OH
R2O
R =
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helplessness' tests. The investigations supported the use of
WS as a mood stabilizer in clinical conditions of anxiety and
depression in Ayurveda (12).
Chronic stress
Chronic stress (CS) can result in a number of adverse
physiologic conditions including cognitive deficit,
immunosuppression, sexual dysfunction, gastric ulceration,
irregularities in glucose homeostasis, and changes in plasma
corticosterone levels. In a rat model of chronic stress WS and
Panax ginseng extracts were compared for their ability to
attenuate some effects of chronic stress. Both botanicals
were able to decrease the number and severity of CS-induced
ulcers, reverse CS-induced inhibition of male sexual behavior,
and inhibit the adverse effects of CS on retention of learned
tasks. Both botanicals also reversed CS-induced
immunosuppression, but only the Withania extract increased
peritoneal macrophage activity in the rats. The activity of
the Withania extract was approximately equal to the activity
of the Panax ginseng extract. WS, however, has an advantage
over Panax ginseng in that it does not appear to result in
ginseng- abuse syndrome, a condition characterized by high
blood pressure, water retention, muscle tension, and
insomnia (13). In another study, WS methanolic extract for
15 days significantly reduced the ulcer index, volume of
gastric secretion, free acidity, and total acidity. A significant
increase in the total carbohydrate and total
carbohydrate/protein ratio was also observed. Study also
indicated an increase in antioxidant defense, that is, enzymes
SOD, CAT, and ascorbic acid, increased significantly, whereas
a significant decrease in lipid peroxidation was observed. WS
inhibited stress-induced gastric ulcer more effectively as
compared to the standard drug ranitidine (14). In a study by
Bhattacharya et al (15) chronic electroshock stress (14 days)
significantly decreased the nor-adrenaline (NA) and dopamine
(DA) levels in frontal Cortex, pons-medulla, hypothalamus,
hippocampus and striatal, hypothalamal region, respectively,
and increased the 5-hydroxytryptamine (5HT) level in frontal
cortex, pons medulla, hypothalamus and hippocampus.
Chronic stress also increased the rat brain tribulin activity.
EuMil, a polyherbal formulation consisting WS as one of its
ingredients for 14 days treatment normalized the perturbed
regional NA, DA, 5HT concentrations, induced by chronic
stress. EuMil also significantly attenuated the stress-induced
increase in the rat brain tribulin activity.
Nootropic effect
Effects of sitoindosides VII-X and withaferin isolated from
aqueous methanol extract of roots of cultivated varieties of
WS were studied on brain cholinergic, glutamatergic and
GABAergic receptors in rats. The compounds slightly
enhanced acetylcholinesterase (AChE) activity in the lateral
septum and globus pallidus, and decreased AChE activity in
the vertical diagonal band. These changes were accompanied
by enhanced M1-muscarinic-cholinergic receptor binding in
lateral and medial septum as well as in frontal cortices,
whereas the M2- muscarinic receptor-binding sites were
increased in a number of cortical regions including cingulate,
frontal, parietal, and retrospinal cortex. The data suggest
the compounds preferentially affect events in the cortical and
basal forebrain cholinergic-signal transduction cascade. The
drug-induced increase in cortical muscarinic acetylcholine
receptor capacity might partly explain the cognition-
enhancing and memory-improving effects of WS extracts in
animals and in humans (16). In a study by Zhao et al (17)
Withanoside IV (a constituent of WS; the root of WS) induced
neurite outgrowth in cultured rat cortical neurons. Oral
administration of withanoside IV significantly improved
memory deficits in Abeta-injected mice and prevented loss of
axons, dendrites, and synapses. Sominone, an aglycone of
withanoside IV, was identified as the main metabolite after
oral administration of withanoside IV. Sominone induced
axonal and dendritic regeneration and synaptic reconstruction
significantly in cultured rat cortical neurons damaged by
Abeta. Withanoside IV may ameliorate neuronal dysfunction
in Alzheimer's disease and that the active principle after
metabolism is sominone. In another study reserpine treated
animals also showed poor retention of memory in the
elevated plus maze task paradigm. Chronic WS administration
significantly reversed reserpine-induced retention deficits
(18). In different study with WS root extract improved
retention of a passive avoidance task in a step-down paradigm
in mice. WS also reversed the scopolamine-induced
disruption of acquisition and retention and attenuated the
amnesia produced by acute treatment with electroconvulsive
shock (ECS), immediately after training. Chronic treatment
with ECS, for 6 successive days at 24 h intervals, disrupted
memory consolidation on day 7. Daily administration of WS
for 6 days significantly improved memory consolidation in
mice receiving chronic ECS treatment. WS, administered on
day 7, also attenuated the disruption of memory consolidation
produced by chronic treatment with ECS. On the elevated
plus-maze, WS reversed the scopolamine-induced delay in
transfer latency on day 1. On the basis of these findings, it is
suggested that WS exhibits a nootropic-like effect in naive
and amnesic mice (19).
Antiparkinsonian properties
Parkinson's disease is a neurodegenerative disease
characterized by the selective loss of dopamine (DA) neurons
of the substantia nigra pars compacta. The events, which
trigger and/or mediate the loss of nigral DA neurons,
however, remain unclear. Neuroleptic-induced catalepsy has
long been used as an animal model for screening drugs for
Parkinsonism. Administration of haloperidol or reserpine
significantly induced catalepsy in mice. WS significantly
inhibited haloperidol or reserpine-induced catalepsy and
provide hope for treatment of Parkinson's disease (20). In
another study, 6-Hydroxydopamine (6-OHDA) is one of the
most widely used rat models for Parkinson's disease. There is
ample evidence in the literature that 6-OHDA elicits its toxic
manifestations through oxidant stress. Antiparkinsonian
effects of WS extract has been reported due to potent
antioxidant, antiperoxidative and free radical quenching
properties in various diseased conditions. Rats were
pretreated with the WS extract orally for 3 weeks. On day
21, 6-OHDA was infused into the right striatum while sham
operated group received the vehicle. Three weeks after 6-
OHDA injections, rats were tested for neurobehavioral activity
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and were killed 5 weeks after lesioning for the estimation of
lipidperoxidation, reduced glutathione content, activities of
glutathione-S-transferase, glutathione reductase, GPX, SOD
and CAT, catecholamine content, dopaminergic D2 receptor
binding and tyrosine hydroxylase expression. WS extract
reversed all the parameters significantly in a dose-dependent
manner (21). In a study by Naidu et al (22) tardive dyskinesia
is one of the major side effects of long-term neuroleptic
treatment. The pathophysiology of this disabling and
commonly irreversible movement disorder is still obscure.
Vacuous chewing movements in rats are widely accepted as
an animal model of tardive dyskinesia. Oxidative stress and
products of lipid peroxidation are implicated in the
pathophysiology of tardive dyskinesia. Repeated treatment
with reserpine on alternate days for a period of 5 days
significantly induced vacuous chewing movements and tongue
protrusions in rats. Chronic treatment with WS root extract
for a period of 4 weeks to reserpine treated animals
significantly and dose dependently reduced the reserpine-
induced vacuous chewing movements and tongue protrusions.
Oxidative stress might play an important role in the
pathophysiology of reserpine-induced abnormal oral
movements (22). In another study, WS glycowithanolides
(WSG) administered concomitantly with haloperidol for 28
days, inhibited the induction of the neuroleptic TD.
Haloperidol-induced TD was also attenuated by the
antioxidant, vitamin E, but remained unaffected by the GABA-
mimetic antiepileptic agent, sodium valproate, both agents
being administered for 28 days like WSG. Antioxidant effect
of WSG, rather than its GABA-mimetic action reported for the
prevention of haloperidol-induced TD (23). WS significantly
reversed the catalepsy, tardive dyskinesia and 6-
Hydroxydopamine elicited toxic manifestations and may offer
a new therapeutic approach to the treatment of Parkinson's
disease.
Antivenom
Venom hyaluronidases help in rapid spreading of the toxins by
destroying the integrity of the extra-cellular matrix of the
tissues in the victims. A hyaluronidase inhibitor (WSG) is
purified from WS. The glycoprotein inhibited the
hyaluronidase activity of cobra (Naja naja) and viper (Daboia
russelii) venoms, which was demonstrated by zymogram assay
and staining of the skin tissues for differential activity. WSG
completely inhibited the activity of the enzyme at a
concentration of 1:1 w/w of venom to WSG. External
application of the plant extract as an antidote in rural parts
of India to snakebite victims appears to have a scientific basis
(24). In a study by Lizano et al (25) antitoxin-PLA2
glycoprotein isolated from WS neutralized the PLA2 activity of
the Naja naja venom. The implications of these new groups
of PLA2 toxin inhibitors in snake biology as well as in the
development of novel therapeutic reagents in the treatment
of snake envenomations (25).
Antiinflammatory properties
The effects of WS, as antiinflammatory in a variety of
rheumatologic conditions, have been studied by several
authors. In a study, WS root extract (1 g/kg, oral) reduced
Freund’s complete adjuvant induced inflammation in rats;
phenylbutazone was given as a positive control. The α2-
glycoprotein found only in inflamed rat serum was decreased
to undetectable levels in the WS group. Phenylbutazone, on
the other hand, caused a considerable increase in the α2-
glycoprotein in both arthritic and healthy rats (26). In
another study, WS caused dose-dependent suppression of α2-
macroglobulin (an indicator for antiinflammatory drugs) in the
serum of rats inflamed by sub-plantar injection of
carrageenan suspension (27). WS root powder also decreased
air pouch granuloma induced by carrageenan on the dorsum
of rats. WS decreased the glycosaminoglycans content in the
granuloma tissue more than hydrocortisone treatment. WS
also uncoupled the oxidative phosphorylation by significantly
reducing the ADP/O ratio in mitochondria of granuloma tissue
(28). In a different study, WS root extract (1000 mg/ kg,
orally daily for 15 days) caused significant reduction in both
paw swelling and bony degenerative changes in Freund’s
adjuvant-induced arthritis in rats as observed by radiological
examination. The reductions were better than those
produced by the reference drug, hydrocortisone (29). A study
by al Hindawi et al (30) found WS inhibited the granuloma
formation in cotton-pellet implantation in rats and the effect
was comparable to hydrocortisone sodium succinate (5
mg/kg) treatment. In a double blind, placebo-controlled
cross-over study, herbal formula significantly reduced the
severity of pain and disability scores of patients with
osteoarthritis (31). Few studies have been conducted on the
mechanism of action for the antiinflammatory properties of
WS. In one study, rats injected with formaline in the hind leg
footpad showed a decrease in absorption of 14C-glucose in rat
jejunum (32). Glucose absorption was maintained at the
normal level by both WS and the cyclooxygenase inhibitor
oxyphenbutazone. Both drugs produced antiinflammatory
effects. Similar results were obtained in parallel experiments
using 14C-leucine absorption from the jejunum (33). These
studies suggest cyclooxygenase inhibition may be involved in
the mechanism of action of WS.
Immunomodulation and hematopoiesis
The role of WS as immunomodulator has been extensively
studied. In a mouse study, WS root extract enhanced total
white blood cell count. In addition, this extract inhibited
delayed-type hypersensitivity reactions and enhanced
phagocytic activity of macrophages when compared to a
control group (34). Recent research suggests a possible
mechanism behind the increased cytotoxic effect of
macrophages exposed to WS extracts. Nitric oxide has been
determined to have a significant effect on macrophage
cytotoxicity against microorganisms and tumor cells. Iuvone
et al demonstrated WS increased NO production in mouse
macrophages in a concentration-dependent manner. This
effect was attributed to increased production of inducible
nitric oxide synthase, an enzyme generated in response to
inflammatory mediators and known to inhibit the growth of
many pathogens (35). In another study, Glycowithanolides
and a mixture of sitoindosides IX and X isolated from WS, both
produced statistically significant mobilization and activation
of peritoneal macrophages, phagocytosis, and increased
activity of the lysosomal enzymes. Root extract of WS was
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tested for immunomodulatory effects in three
myelosuppression models in mice: cyclophosphamide,
azathioprin, or prednisolone (36).
Significant increases in hemoglobin concentration, red blood
cell count, white blood cell count, platelet count, and body
weight were observed in WS-treated mice compared to
untreated control mice. The authors also reported significant
increases in hemolytic antibody responses toward human
erythrocytes which indicated immunostimulatory activity.
The effect of WS was also studied on the functions of
macrophages obtained from mice treated with the carcinogen
ochratoxin A (OTA). OTA treatment of mice for 17 weeks
significantly decreased the chemotactic activity of the
macrophages. Interleukin-1 (IL- 1) and tumor necrosis factor
alpha (TNF-α) production was also markedly decreased (37).
In different study with the aqueous suspension of WS root
powder was investigated for their in vivo and in vitro
immunomodulatory properties. WS showed potent inhibitory
activity towards the complement system, mitogen induced
lymphocyte proliferation and delayed-type hypersensitivity
reaction. Administration of WS root powder did not have a
significant effect on humoral immune response in rats.
Authors reported that immunosuppressive effect of WS root
powder could be a candidate for developing as an
immunosuppressive drug for the inflammatory diseases (38).
In a study of Gautam et al (39) Immunopotentiation on oral
feeding of standardized aqueous extract of WS was evaluated
in laboratory animals immunized with DPT (Diphtheria,
Pertussis, Tetanus) vaccine. Treatment of immunized animals
with test material for 15 days resulted in significant increase
of antibody titers to B. pertussis. Immunized animals
(treated and untreated) were challenged with B. pertussis
18,323 strain and the animals were observed for 14 days.
Treated animals showed significant increase in antibody titers
as compared to untreated animals after challenge.
Immunoprotection against intracerebral challenge of live B.
pertussis cells was evaluated based on degree of sickness,
paralysis and subsequent death.
Reduced mortality accompanied with overall improved health
status was observed in treated animals after intracerebral
challenge of B. pertussis indicating development of protective
immune response. In another study, WS also stimulated
immunological activity in Balb/c mice. Treatment with five
doses of WS was found to enhance the total WBC count on
10th day. Bone marrow cellularity as well as alpha-esterase
positive cell number also increased significantly. Treatment
with WS along with the antigen (SRBC) produced an
enhancement in the circulating antibody titre and the number
of plaque forming cells (PFC) in the spleen. Maximum number
of PFC (985 PFC/10(6) spleen cells) was obtained on the
fourth day. WS inhibited delayed type hypersensitivity
reaction in mice (Mantoux test). Administration of WS also
showed an enhancement in phagocytic activity of peritoneal
macrophages when compared to control in mice. These
results confirm the immunomodulatory activity of WS extract
in indigenous medicine (40).
Antitumor properties
The chemopreventive effect was demonstrated in a study of
WS root extract on induced skin cancer in mice given WS
before and during exposure to the skin cancer causing agent
7,12-dimethylbenz[a]anthracene. A significant decrease in
incidence and average number of skin lesions was
demonstrated compared to the control group. Additionally,
levels of reduced glutathione, SOD, CAT, and GPX in the
exposed tissue returned to near normal values following
administration of the extract. The chemopreventive activity
is thought to be due in part to the antioxidant/ free radical
scavenging activity of the extract (41). An in vitro study
showed withanolides from WS inhibited growth in human
breast, central nervous system, lung, and colon cancer cell
lines comparable to doxorubicin. Withaferin A more
effectively inhibited growth of breast and colon cancer cell
lines than did doxorubicin. These results suggest WS extracts
may prevent or inhibit tumor growth in cancer patients and
suggest a potential for development of new chemotherapeutic
agents (42). In another study WS was evaluated for its
antitumor effect in urethane-induced lung adenomas in adult
male albino mice. Simultaneous administration of WS (200
mg/kg daily orally for seven months) and urethane (125
mg/kg biweekly for seven months) reduced tumor incidence
significantly. The histological appearance of the lungs of
animals protected by WS was similar to those observed in the
lungs of control animals. WS treatment also reversed the
adverse effects of urethane on total leukocyte count,
lymphocyte count, body weight, and mortality (43).
WS is widely used in the Ayurvedic system of medicine to
treat tumors, inflammation, arthritis, asthma, and
hypertension. Chemical investigation of the roots and leaves
of this plant has yielded bioactive withanolides. Earlier
studies showed that withanolides inhibit cyclooxygenase
enzymes, lipid peroxidation, and proliferation of tumor cells.
Several genes that regulate cellular proliferation,
carcinogenesis, metastasis and inflammation are regulated by
activation of nuclear factor-kappaB (NF-kappaB).
Withanolides suppressed NF-kappaB activation induced by a
variety of inflammatory and carcinogenic agents, including
tumor necrosis factor (TNF), interleukin-1beta, doxorubicin,
and cigarette smoke condensate. Suppression was not cell
type specific, as both inducible and constitutive NF-kappaB
activation was blocked by withanolides. The suppression
occurred through the inhibition of inhibitory subunit of
IkappaB alpha kinase activation, IkappaB alpha
phosphorylation, IkappaB alpha degradation, p65
phosphorylation, and subsequent p65 nuclear translocation.
NF-kappaB-dependent reporter gene expression activated by
TNF, TNF receptor (TNFR) 1, TNFR-associated death domain,
TNFR-associated factor 2, and IkappaB alpha kinase was also
suppressed. Consequently, withanolide suppressed the
expression of TNF-induced NF-kappaB-regulated antiapoptotic
(inhibitor of apoptosis protein 1, Bfl-1/A1, and FADD-like
interleukin-1beta-converting enzyme-inhibitory protein) and
metastatic (cyclooxygenase-2 and intercellular adhesion
molecule-1) gene products enhanced the apoptosis induced by
TNF and chemotherapeutic agents, and suppressed cellular
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TNF-induced invasion and receptor activator of NF-kappaB
ligand-induced osteoclastogenesis. Overall, it is suggested
that withanolides inhibit activation of NF-kappaB and NF-
kappaB-regulated gene expression, which may explain the
ability of withanolides to enhance apoptosis and inhibit
invasion and osteoclastogenesis (44). In different study, the
antiproliferative activity was screened against human
laryngeal carcinoma (Hep2) cells by microculture tetrazolium
assay (MTT). Two extracts (WS and WS-chloroform) and three
fractions negatively affected Hep2 viability at the
concentration and these were further investigated
pharmacologically. Flow cytometry revealed cell cycle block
and accumulation of hypoploid (sub G1) cells as the mode of
antiproliferative activity. Their antiangiogenic potential was
investigated by a chickchorio-allantoic membrane (CAM)
wherein a significant inhibition of vascular endothelium
growth factor (VEGF), induced neovascularization was
recorded. The effect was confirmed in vivo by mouse sponge
implantation method. These findings suggest that the roots
of WS possess cell cycle disruption and antiangiogenic
activity, which may be a critical mediator for its anticancer
action (45). In a study of Senthilnathan et al (46)
benzo(a)pyrene induced cancer animals were treated with WS
extract for 30 days significantly alters the levels of
immunocompetent cells, immune complexes and
immunoglobulins. Based on the data, the carcinogen as well
as the paclitaxel affects the immune system, the toxic side
effects on the immune system is more reversible and more
controllable by WS (47). In another study, a significant
increase in the life span and a decrease in the cancer cell
number and tumour weight were noted in the tumour-induced
mice after treatment with WS. The hematological
parameters were also corrected by WS in tumour-induced
mice. These observations are suggestive of the protective
effect of WS in Dalton's Ascitic Lymphoma (48). In different
study with WS enhanced the proliferation of lymphocytes,
bone marrow cells and thymocytes in responses to mitogens.
Both PHA and Con A mitogens along with Withania treated
splenocytes, bone marrow cells and thymocytes could
stimulate proliferation twice greater than the normal.
Withania treated splenocytes along with the mitogen LPS
could stimulate the lymphocyte proliferation six times more
than the normal. Natural killer cell activity (NK) was
enhanced significantly in both the normal and the tumour-
bearing group. Antibody dependent cellular cytotoxicity
(ADCC) was enhanced in the Withania treated group on the
9th day. An early Antibody dependent complement mediated
cytotoxicity (ACC) was observed in the WS treated group on
day 13 (34). In a study of Gupta et al (48) after paclitaxel
administration significant fall in total WBC and absolute
neutrophil count was observed on day 3 and day 5. WS per se
produced significant increase in neutrophil counts. WS when
administered for 4 days before paclitaxel treatment and
continued for 12 days caused significant reversal of
neutropenia of paclitaxel. WS may be used as an adjuvant
during cancer chemotherapy for the prevention of bone
marrow depression associated with anticancer drugs.
Hypolipidemic effect
WS root powder decreased total lipids, cholesterol and
triglycerides in hypercholesteremic animals. On the other
hand, significantly increased plasma HDL-cholesterol levels,
HMG-CoA reductase activity and bile acid content of liver. A
similar trend also reported in bile acid, cholesterol and
neutral sterol excretion in the hypercholesteremic animals
with WS administration. Further, a significant decrease in
lipid-peroxidation occurred in WS administered
hypercholesteremic animals when compared to their normal
counterparts. However, WS root powder was also effective in
normal subjects for decreasing lipid profiles (49). In another
study with aqueous extract of fruits of Withania coagulans to
high fat diet induced hyperlipidemic rats for 7 weeks,
significantly reduced elevated serum cholesterol, triglycerides
and lipoprotein levels. This drug also showed hypolipidemic
activity in triton-induced hypercholesterolemia. The
histopathological examination of liver tissues of treated
hyperlipidemic rats showed comparatively lesser degenerative
changes compared with hyperlipidemic controls. The
hypolipidemic effect of Withania coagulans fruits reported to
be comparable to that of an Ayurvedic product containing
Commiphora mukkul (50). In another study, hypoglycemic,
diuretic and hypocholesterolemic effects of roots of WS were
assessed on human subjects. Six mild NIDDM subjects and six
mild hypercholesterolemic subjects were treated with the
powder of roots of WS for 30 days. Suitable parameters were
studied in the blood and urine samples of the subjects along
with dietary pattern before and at the end of treatment
period. Decrease in blood glucose was comparable to that of
an oral hypoglycemic drug. Significant increase in urine
sodium, urine volume, significant decrease in serum
cholesterol, triglycerides, LDL (low density lipoproteins) and
VLDL (very low density lipoproteins) cholesterol were
observed indicating that root of WS is a potential source of
hypoglycemic, diuretic and hypocholesterolemic agents (51).
Sexual behaviour
Methanolic root extract of WS were orally administered at
dose 3000 mg/kg/day of 7 days in rats. Their sexual
behaviour was evaluated 7 days prior to treatment, day 3 and
7 of treatment, and day 7, 14 and 30 post-treatment by
pairing each male with a receptive female. The WS root
extract induced a marked impairment in libido, sexual
performance, sexual vigour, and penile erectile dysfunction.
These effects were partly reversible on cessation of
treatment. This antimasculine effect was not due to changes
in testosterone levels but attributed to hyperprolactinemic,
GABAergic, serotonergic or sedative activities of the extract.
WS roots may be detrimental to male sexual competence
(52).
Antibacterial effect
Both aqueous as well as alcoholic extracts of the plant (root
as well as leaves) were found to possess strong antibacterial
activity against a range of bacteria, as revealed by in vitro
Agar Well Diffusion Method. The methanolic extract was
further subfractionated using various solvents and the
butanolic sub-fraction was possessed maximum inhibitory
activity against a spectrum of bacteria including Salmonella
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typhimurium. Moreover, in contrast to the synthetic
antibiotic (viz. chloramphenicol), these extracts did not
induce lysis on incubation with human erythrocytes,
advocating their safety to the living cells. Oral administration
of the aqueous extracts successfully obliterated salmonella
infection in Balb/C mice as revealed by increased survival
rate as well as less bacterial load in various vital organs of the
treated animals (53). In another study, the methanol, hexane
and diethyl ether extracts from both leaves and roots of WS
were evaluated for the antibacterial/synergistic activity by
agar plate disc-diffusion assay against Salmonella
typhimurium and Escherichia coli. Different concentrations
of Tibrim, a combination of rifampicin and isoniazid, were
tested to find out the minimum inhibitory concentration
(MIC), which came out to be 0.1 mg/ml for S. typhimurium
and E. coli. From the six extracts tested, only methanol and
hexane extracts of both leaves and roots showed potent
antibacterial activity. A synergistic increase in the
antibacterial effect of Tibrim was noticed when MIC of Tibrim
was supplemented with these extracts (54).
Cardiovascular protection
WS may be useful as a general tonic, due in part to its
beneficial effects on the cardiopulmonary system, as reported
in the following studies. The effect of WS was studied on the
cardiovascular and respiratory systems in dogs and frogs (55).
The alkaloids had a prolonged hypotensive, bradycardiac, and
respiratory-stimulant action in dogs. The study found that
the hypotensive effect was mainly due to autonomic ganglion
blocking action and that a depressant action on the higher
cerebral centers also contributed to the hypotension. The
alkaloids stimulated the vasomotor and respiratory centers in
the brain stem of dogs. The cardio-inhibitory action in dogs
appeared to be due to ganglion blocking and direct cardio-
depressant actions. The alkaloids produced immediate
predominant but short-lived cardio-depressant effects and a
weak but prolonged cardiotonic effect in isolated normal and
hypodynamic frog hearts. In another study, Left ventricular
dysfunction was seen as a decrease in heart rate, left
ventricular rate of peak positive and negative pressure change
and elevated left ventricular end-diastolic pressure in the
control group was recorded. WS showed strong
cardioprotective effect in the experimental model of
isoprenaline-induced myonecrosis in rats. Augmentation of
endogenous antioxidants, maintenance of the myocardial
antioxidant status and significant restoration of most of the
altered haemodynamic parameters may contribute to its
cardioprotective effect (56).
Tolerance and dependence
Drug addiction, is one of the world's major health problem,
with large direct health costs. Chronic treatment with
benzodiazepine, ethanol or opioids induced tolerance and
withdrawal signs. Benzodiazepine, ethanol and opioids
induced tolerance and withdrawal also have blocked by a
polyherbal preparation, BR-16A (Mentat), which has WS as a
one of its ingredient (57-59). Interestingly, repeated
administration of WS for 9 days attenuated the development
of tolerance to the analgesic effect of morphine. WS also
suppressed morphine-withdrawal jumps, a sign of the
development of dependence to opiate as assessed by
naloxone precipitation withdrawal on day 10 of testing (60).
The studies revealed that the chronic administration of the
WS did not exhibit any dependence-liability of its own, even
upon an abrupt cessation. These findings may have clinical
implications without producing tolerance and withdrawal
effects on long-term use.
CONCLUSION
The extensive survey of literature revealed that WS is an
important source of many pharmacologically and medicinally
important chemicals, such as withaferins, sitoindosides and
various useful alkaloids. In Indian variety thirteen
Dragendroff positive alkaloids have been reported. The
withanolides are the most searched chemical constituents of
WS and till date around 138 withanolides with both β and α
side chain has been reported apart from various amino acid
and other normal plant constituents. The plant has also been
widely studied for their various pharmacological activities like
antioxidant, anxiolytic, adaptogen, memory enhancing,
antiparkinsonian, antivenom, antiinflammatory, antitumor
properties. Various other effects like immunomodulation,
hypolipidemic, antibacterial, cardiovascular protection,
sexual behaviour, tolerance and dependence have also been
studied. Although the results from this review are quite
promising for the use of WS as a multi-purpose medicinal
agent, several limitations currently exist in the current
literature. While WS has been used successfully in Ayurvedic
medicine for centuries, more clinical trials should be
conducted to support its therapeutic use. It is also important
to recognize that WS extracts may be effective not only on
isolation, but may actually have a modulating effect when
given in combination with other herbs or drugs.
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