Ashwagandha (Withania somnifera): Role in Safeguarding Health, Immunomodulatory
Effects, Combating Infections and Therapeutic Applications: A Review
Shoor Vir Singh
Ashwagandha (Withania somnifera) is a well known herb
possessing several health benefits. The steroidal lactones (withanolides) obtained
from its roots have been implicated in a wide range of therapeutic activities
and maintaining general health: Immunomodulation, combating infectious agents,
anti-cancer and anti-epileptic, memory enhancer, to promote good physical and
mental health, mood elevator, diuretic, general tonic and rejuvenator, stress
reliever, cardiorespiratory endurance enhancer, anti-ageing, anti-oxidant, hypoglycemic,
hypocholesterolemic and in common an effective adaptogen. Steroidal alkaloids
and lactones are the active constituents of the plant. Withanolides as per theory
occupies the receptor sites in the cell membrane thereby preventing the attachment
and subsequent exertion of the effect of actual hormone. Withanolides have got
analgesic and anti-inflammatory activity due to cyclooxygenase-2 inhibition
property. Ashwagandha enhances nitric oxide synthatase activity of the macrophages,
which in turn increases the microbial killing power of these immune cells thereby
enhancing the Cell Mediated Immune (CMI) response. A glycoprotein Glycowithanolides
(WSG) commonly known as W. somnifera glycoprotein is responsible for
antimicrobial activity. Milk supplemented with Ashwagandha has been reported
to increase total proteins and body weight and the plant alone helps in inducing
tolerance and dependence. Its anti-stress and radiosensitization action; beneficial
effects on cardiovascular system and sexual behavior; curative properties against
neurodegenerative diseases and poisoning due to toxins and chemicals (including
snake venom) has made this plant a treasure of nature. Thus the plant is an
important component of many polyherbal preparations. Important for researchers
and scientists is that biotechnologically advanced techniques; novel disciplines
of bioinformatics and genomics can help in identifying and generating bioactive
principles of the plant. All these salient health applications of this herb
in biomedicine and veterinary sciences are discussed in this review focusing
its potent role in maintaining sound health, immunomodulatory effects, combating
infections, therapeutic usages and other beneficial applications.
to cite this article:
Ruchi Tiwari, Sandip Chakraborty, Mani Saminathan, Kuldeep Dhama and Shoor Vir Singh, 2014. Ashwagandha (Withania somnifera): Role in Safeguarding Health, Immunomodulatory
Effects, Combating Infections and Therapeutic Applications: A Review. Journal of Biological Sciences, 14: 77-94.
Received: October 16, 2013;
Accepted: October 31, 2013;
Published: January 11, 2014
Ashwagandha (Withania somnifera) is a well known herb possessing several
health benefits and is an important Rasayana as Sattvic Kapha
Rasayana in Indian Ayurveda, used since centuries for its miraculous advantages
(Mahima et al., 2012). Ashwagandha (Withania
somnifera) is a traditional medicine with growing needs due to its remedial
potentials. Chinese, Unani, Ayurveda and Siddha literatures admire the therapeutic
merits of plant-derived medicines against almost all ailments. Herbal medicines
strongly involve mass appeal being safer and inexpensive. An esteemed Rishi
(sage) Punarvasu Atriya was the first person who gave the teaching regarding
the use of Ashwagandha that extends back over 3000 to 4000 years ago wherein
its use is widely extolled as a tonic particularly for emaciation in all age
group of people. This causes enhancement of the reproductive function of both
men as well as women (Mathur and Velpandian, 2009;
Verma and Kumar, 2011; Mahima
et al., 2012; Dhama et al., 2013a).
Ashwagandha is generally available in form of fine powder that can be used
with water, ghee or honey (Gupta et al., 2006).
The Nagori variety is the best among all Ashwagandha varieties. The health products
made up of Ashwagandha (W. somnifera, Apocynaceae) are becoming popular
as commonly used medicinal plants. The steroidal lactones (withanolides) obtained
from its roots have been implicated in a wide range of therapeutic activities
and maintaining general health like immunomodulation, combating infectious agents,
anti-cancer, anti-epileptic, memory enhancer, to promote good physical and mental
health, mood elevator, diuretic, rejuvenator, stress reliever, cardio-respiratory
endurance enhancer, anti-ageing, anti-oxidant, hypoglycemic, hypocholesterolemic
and in common an effective adaptogen (Scarfiotti et
al., 1997; Adallu and Radhika, 2000; Hemalatha
et al., 2006; Naidu et al., 2006;
Mahima et al., 2012; Dhama
et al., 2013a). Such alkaloids (withanolides) also work as marker
compounds/agents for chemical standardization of Ashwagandha-based products
(Dhuley, 2000; Shenoy et al.,
Ashwagandha improves the memory by enhancing the brain and nervous function;
promotes vigour and vitality along with cheerful sexual life and reproductive
equilibrium; augments the body's pliability to stress being a powerful adaptogen;
shows anxiolytic effect, has hepato-protective property, raises hemoglobin level
and red blood cell count, improves energy levels, maintains mitochondrial health;
has potent antioxidant properties so as to protect cellular damage caused by
free radicals and improves the body's resistance against various ailments by
improving the cell-mediated immunity (Scarfiotti et
al., 1997; Bhattacharya and Muruganandam, 2003;
Arora et al., 2004; Kuboyama
et al., 2005; Harikrishnan et al., 2008;
Sandhu et al., 2010). Ashwagandha is a potent
adaptogen or vitalizer and has powerful antioxidant and detoxifying properties.
Multiple actions of this miracle herb include anti-inflammatory, analgesic,
anti-stress, immunomodulatory, ant-microbial, cytoprotective, bettering anabolic
activities, active against air-pollution and anti-cancer effects (Mishra
et al., 2000; Kushwaha et al., 2012;
Mahima et al., 2012, 2013a,
b; Dhama et al., 2013a).
The present review describes Ashwagandha (W. somnifera) and its active
compounds, mechanism of action and biological chemistry and classical beneficial
applications of Ashwagandha in biomedicine and veterinary sciences viz., immunomodulatory
effects, activity against microbes and infection and usefulness as an alternative,
chemotherapeutic agent, general health benefits, promoting vigour and vitality,
stress reliever antidepressant, anti-inflammatory and adaptogenic property,
effects on cardiovascular system, role in treating sexual disability, diseases
and disorders, potent anti-cancer effects, reducing poisoning due to toxins/chemicals/drugs,
anti-aging activities, memory enhancer, treating neurodegenerative disorders,
role in development of drug tolerance and dependence.
Ashwagandha (Withania somnifera)
Popular/common name: Indian ginseng/winter cherry: Ashwagandha is an exceedingly
valuable medicinal plant with valuable and wide therapeutic benefits in the
conventional system of medicine. The plant grows in form of shrub with branching,
height reaches to around 150 cm, leaves are up to 10 cm long; flowers present
greenish or lurid yellow color, fruits/berries when mature are orange colored
and its seeds are sown mostly during month of June or July (Khanna
et al., 2006a; Dasgupta et al., 2008).
Yield as well as quality of plant and its metabolites are affected by seasonal
temperature, method of sowing, duration of light and dark period, depth of tillage,
time of harvesting, concentration of fertilizers i.e., nitrogen, phosphorus,
potassium application, effect of manure and field space present in between crops
or density of plant population etc. (Kothari et al.,
2003; Agarwal et al., 2004; Patel
et al., 2004; Sreerekha et al., 2004;
Ajay et al., 2005; Panchbhai
et al., 2006).
Active constituents/compound/principle: The root of Withania somnifera
has more than 35 chemical constituents (Rastogi and Mehrotra,
1998). Steroidal alkaloids and lactones (Withanolides, Withaferins): Anaferine
alkaloid, anahygrine, isopelletierine, cuseohygrine, Ashwagandhanolide (dimeric
thiowithanolide), chlorogenic acid, beta-Sisterol, fruit cysteine, iron, scopoletin,
somniferinine, somniferiene, tropanol, withananine, withanoside IV, withanolides
A-Y (Steroidal lactones) and saponins sitoindosides and acylsterylglucosides.
The sitoindosides VII-X and withaferin-A are anti-stress agents which support
immunomodulatory actions and have antifungal properties also (Abraham
et al., 1975; Choudhary et al., 1995;
Singh et al., 2006). Most of the pharmacological
activities of Ashwaganda have been attributed to two main withanolides, withaferin
A and withanolide D (Singh et al., 2010). Five-dehydroxy
withanolide-R and withasomniferin-A are obtained from the aerial parts of
W. somnifera and effect of withaferin-A has been also seen on human blood
lymphocytes. Withania somnifera is a rich source of iron (Davis
and Kuttan, 2000a; Kuboyama et al., 2006;
Subbaraju et al., 2006; Mirjalili
et al., 2009).
Ethnopharmacological aspects: The pharmacological as well as metabolic
effects of ashwagandha reveals that it has both herbal tonic as well as health
food. In rats the swimming time is increased by Ashwagandha as determined by
physical working capacity test (swimming endurance test). By employing such
test it has been found that the weight of the heart increases relatively and
the content of glycogen in myocardium increased significantly (Dhuley,
Two major classes of compounds viz., steroidal alkaloids and steroidal lactones
are responsible for the wide range of beneficial effects of Ashwagandha. Withanolides
are a class of compound included in the group of steroidal lactones and are
responsible for antioxidant properties as well as free radical scavenging activities.
Till date at least 12 alkaloids and 35 withanolides have been studied. Several
studies have also revealed the antimicrobial properties of ashwagandha along
with antibacterial activity against potentially dangerous like Salmonella
(food poisoning causing organism). The ability of macrophage and immune cells
to eat pathogens is enhanced by the root extract of Ashwagandha in comparison
to macrophages (in control group) that have not received ashwagandha (Davis
and Kuttan, 2000b; Anonymous, 2004; Govindarajan
et al., 2005; Owais et al., 2005).
Treatment with Ashwagandha affords resistance of heart muscle of frog towards
the toxic action of strophanthin-K and the duration of contractility is increased.
The coagulation time is significantly increased by ashwagandha treatment resulting
in attainment of normalcy after 7 days of cessation of treatment. In the blood
serum of rats there is no any significant change in biochemical parameters.
On the basis of such observations adaptogenic, cardioprotective as well as anticoagulant
properties of ashwagandha are well understood (Dhuley, 2000).
Mechanism of action: Due to the property of helping in regulation of
important physiologic processes Ashwagandha is assumed to be amphoteric. As
per requirement withanolides act as important hormone precursors that has got
the capability to convert into human physiologic hormones. The plant-based hormone
precursor as per theory occupies the receptor sites in the cell membrane thereby
preventing the attachment and subsequent exertion of the effect of actual hormone.
Small effect is exerted by the plant-based hormone if the level of original
hormone is low (Misra, 2004). The anti-stress effect
of ashwagandha was due to stimulation of respiratory function causing relaxation
of smooth muscle along with stimulation of thyroid synthesis and secretion.
Increase in dopamine receptors in the corpus callosum of brain induced by stress
is suppressed by ashwagandha. Stress-induced increase in corticosterone in plasma
along with blood urea nitrogen as well as blood nitric acid is also reduced.
Anxiolytic effect of ashwagandha is exerted by acting as a gamma-aminobutyric
acid (GABA) mimetic agent. The anticonvulsant activity by virtue of attachment
to the GABA receptor is also a special feature of Ashwagandha (www.amazondiscovery.com).
Toxicological properties: Acute toxicity studies of ashwagandholine
(total alkaloids from the roots of Withania somnifera) in 10% propylene
glycol on the central nervous system. The acute LD50 has been found
to be a bit higher in rats (465 mg kg-1) than in mice (432 mg kg-1)
(Mishra et al., 2000). Sharada
et al. (1993) tested acute (24 h) toxicity of alcohol extract from
the roots of ashwaganda in swiss albino mice and subacute toxicity (30 days)
in wistar rats. Single intraperitoneal injection of 1100 mg kg-1
of the extract in mice did not produce any deaths within 24 h, but small increases
in dose led to mortality. LD50 value was calculated as 1260 mg kg-1
b.wt. Repeated injections of ashwagandha extract at a dose of 100 mg kg-1
b.wt. for 30 days in either sex of wistar rats for subacute toxicity studies
did not produce any mortality and no change in peripheral blood constituents.
But, significant reductions in the weights of spleen, thymus and adrenals were
observed in male rats at the end of the experiment. The acid phosphatase content
of peripheral blood in both sexes showed a significant increase from control
whereas other biochemical parameters were in the normal range.
Acute toxicity studies of Withania somnifera (L.) Dunal, WSF did not
reveal any mortality and clinical signs of toxicity up to 2000 mg kg-1
b.wt. Chronic administration of WSF did not cause any clinical signs of toxicity
up to 1000 mg kg-1 b.wt. Genotoxic study of WSF did not showed increase
in percentage abnormal metaphases up to 1000 mg kg-1 b.wt. Moreover,
WSF was found to increase immunological response against antigenic stimuli (Sharma,
Dose-related tolerability, safety and activity of Withania somnifera
formulation in normal individuals were evaluated in eighteen apparently healthy
volunteers (12 male and 6 female) ageing about 18-30 years. The volunteers were
treated with WS capsules (aqueous extract, 8:1) daily in two divided doses with
increase in daily dosage every 10 days for 30 days (750, 1000 and 1250 mg day-1x10
days). Except one volunteer, all tolerated WS without any adverse effects. One
volunteer showed increased appetite, libido and hallucinogenic effects with
vertigo at the lowest dose and was withdrawn from study. In six volunteers,
improvement in quality of sleep was noticed. Reduction in total and LDL cholesterol,
normal values in organ function tests, reduction in total body fat percentage
and increase of strength of muscle activity was significant (Raut
et al., 2012).
Biological chemistry of Withania sominifera: Withanolide obtained
from the plant possess analgesic and anti-inflammatory activity due to its cyclooxygenase-2
inhibition property (Nair and Jayaprakasam, 2007). Peroxidases
enzyme have been purified from this herb. Withanolides I-III and IV-V isolated
from W. somnifera inhibited cholinesterase, acetylcholinesterase and
butyrylcholinesterase, toxic phospholipase enzymes and therefore, are under
consideration to be among the potent therapeutic candidate for treatment of
Alzheimers disease (Choudhary et al., 2004,
2005; Johri et al., 2005;
Kambizi et al., 2006). Important constituent
withanolides can be isolated and purified by various techniques mainly by High
Performance Liquid Chromatography (HPLC) and spectrometry (Khajuria
et al., 2004; Sharada et al., 2007).
Classical applications of ashwagandha: Ashwagandha attains the special
name as the root smells like horse (Ashwa) and it is believed
that on guzzling it provides power of a horse. Different parts of Ashwagandha
have significant therapeutic potency either as a whole plant extract or as separate
constituents (Bhatt et al., 2006; Gupta
and Rana, 2007). Utmost benefits comes out when fresh powder from the plant
The root of Ashwagandha is very useful due to properties of being effective
narcotic, diuretic, tonic, aphrodisiac, anthelmintic, astringent, antiangiogenic
in case of tumor, antimutagenic, thermogenic and stimulant (Mohan
et al., 2004; Khanam and Devi, 2005a; Khanna
et al., 2006b; Mahima et al., 2012).
Roots are equally effective against emaciation, constipation, debility, goiter,
rheumatism, vitiated conditions of leucoderma, insomnia and nervine disorders,
lead-induced DNA damage etc (Sharma et al., 1985;
Khanam and Devi, 2005b).
The paste of roots prepared with water effectively reduces the incidences of
asthma, arthritis, rheumatoid, osteoarthritis, carbuncles, ulcers, leucorrhoea,
boils, pimples, flatulent colic, piles and painful swellings as anti-arthritic
agent when applied locally (Rasool and Varalakshmi, 2006b;
Salve et al., 2006).
The root in conjunction with other drugs is prescribed for snake venom as well
as in scorpion-sting. Glycoprotein obtained from W. somnifera hampers
activity of hyaluronidase and neurotoxic phospholipase A(2) and counteract the
toxicity (Machiah and Gowda, 2006; Machiah
et al., 2006).
Studies demonstrated that root extract upregulates Th1-dominant polarization
due to the presence of withanolide-A and hence supports the humoral immunity
(HI) and Cell-mediated Immune (CMI) responses in BALB/c mice (Bani
et al., 2006; Malik et al., 2007).
The leaves are bitter and recommended in fever and tender swellings (Kaur
et al., 2004).
It also shows phenomenon of cytomixis (Datta et al.,
2005; Kaul et al., 2005).
The flowers are useful as astringent, depurative, diuretic and aphrodisiac
(Singh et al., 2011).
Fruits of Withania have potent inhibitory effect on peroxidation of lipid (Jayaprakasam
et al., 2004).
The seeds on one side have anthelmintic property to expel the worms from the
body and on another hand they are capable of increasing the sperm count and
testicular growth (Abdel-Magied et al., 2001).
Aqueous extract of plant can modulate the immune response of vaccine, such
as DPT vaccine (Guatam et al., 2004).
Ashwagandharishta prepared from seeds is used against conditions of hysteria,
anxiety, memory loss etc. It also acts as a potent stimulant (Dadkar
et al., 1987).
Immunomodulatory effects: Extract of W. somnifera has been shown
to significantly increase the Cell Mediated Immunity (CMI) in normal mice. Root
extract enhances the level of interferon gamma (IFN-γ), interlukin-2 (IL-2)
and granulocyte macrophage colony stimulating factor (GM-CSF) in mice, suggestive
of an immunopotentiating and myeloprotective effect. Ashwagandha enhances nitric
oxide synthatase activity of the macrophages, which in turn increases the microbial
killing power of these immune cells (Iuvone et al.,
2003). It activates and mobilizes macrophages for rendering increased phagocytic
activity, potentiates activity of lysosomal enzymes and acts as an anti-stress
molecule and anti-inflammatory agent in mice and rat (Rasool
and Varalakshmi, 2006a). Immune enhancement with Ahswagandha has also been
observed in mice with myelosuppression induced by cyclophosphamide, azathioprin
and prednisolone. Root extract of W. somnifera has been reported to induce
helper T-lymphocyte (Th1) polarised cell mediated immune response in BALB/c
mice (Davis and Kuttan, 1998; Iqbal
and Datta, 2006; Malik et al., 2007). Both
immunostimulatory and immunosuppressive properties are present in Ashwagandha.
It induces inhibition of delayed hypersensitivities (Auddy
et al., 2008; Verma et al., 2012).
Powdered root extract from Ashwagandha has profound effect on production of
healthy white blood cells thereby it is an effective immunoregulator as well
as chemoprotective agent in mice. The delayed type of hypersensitivity is also
inhibited by this extract along with enhancement of phagocytic activities of
macrophages while comparing with a control group. It has been found that the
nitric oxide activities of the macrophages are enhanced by W. somnifera
via induction of nitric oxide synthase enzyme activity. The plant is also responsible
to cause down regulation of the senescence-specific beta-galactosidase activity
(Choudhary et al., 2004; Kiefer,
2006; Singh et al., 2010; Widodo
et al., 2009).
Active against microbes and infection: Due to rapid emergence of antibiotic
resistant strains of bacteria, treatment of infectious diseases is becoming
challenging day by day and at the same time rapidly developing bacterial resistance
is growing as a matter of global concern (Tiwari et al.,
2013a). This alarming health concern particularly due to the continuous
increase of immunocompromised patients demands various alternative therapeutic
modalities such as bacteriophage, panchgavya, cytokine, herbal therapy and others
(Tiwari and Hirpurkar, 2011; Mahima
et al., 2012; Dhama et al., 2013b,
c, d; Tiwari
et al., 2013b, c, d).
Herbal therapy is an ancient revered therapy which is again gaining the momentum
in lieu of need of alternative novel therapies and with least or no side effects
this therapy is rapidly speeding the steps (Mahima et
al., 2012; Dhama et al., 2013b). Though
morphological, biochemical, functional and genetic variation exist but as a
whole variety of herbs form a bouquet of safe, sound and easily available medicine
(Dhar et al., 2006; Bandyopadhyay
et al., 2007; Kumar et al., 2007;
Mahima et al., 2012). In regards to Ashwagandha
besides other biological health promoting effects, the herb has also been found
to illustrate antibacterial, antifungal and anti-viral effects.
A glycoprotein Glycowithanolides (WSG), commonly known as Withania somnifera
glycoprotein, 28 kDa isolated from the W. somnifera root has demonstrated
potent antimicrobial activity against the pathogenic fungi and bacteria. WSG
protein put forth fungistatic effect in terms of inhibiting fungal spore germination
and reduction of hyphal growth of Fusarium oxysporum, F. verticilloides
and Aspergillus flavus. Antibacterial effect has also been seen against
Clvibacter michiganensis subsp. Michiganensis bacteria. In
vitro antibacterial property of Withania plant in laboratory plant
cell culture is also on hand. These findings persuade further studies to explore
wide horizons of WSG as a budding therapeutic agent against various fungi and
bacteria (Girish et al., 2006; Jamil
et al., 2007; Kulkarni et al., 2007).
W. somnifera plant has potent antibacterial property even against multidrug
resistant (MDR) strains of microbes as withaferin and withanolides are the chief
compounds. Withania has been found to be effective in inhibiting the
growth of several bacteria viz., Neisseria gonorrhoea, Escherichia
coli, Salmonella, Pseudomonas fluorescens, P. aeruginosa,
Bacillus subtilis, Listeria monocytogenes, Staphylococcus aureus
and methicillin-resistant Staphylococcus aureus or Oxacillin resistant
S. aureus (MRSA or ORSA) (Akinyemi et al.,
2004; Owais et al., 2005; Kambizi
and Afolayan, 2008; Mehrotra et al., 2011;
Sundaram et al., 2011; El-Boshy
et al., 2013). Ashwagandha has been shown to provide immunoprotection
against Escherichia coli infection in Guinea pigs, Listeria monocytogenes
infection in mice and Bordetella pertussis infection in animals (Teixeira
et al., 2006). It is a potent inducer of inhibiting Delayed Type
of Hypersensitivities (DTH). Clinical health benefits of Ashwagandha have been
reported in groups of Human Immunodeficiency Virus (HIV) infected patients and
to treat the cases of genital herpes occurring due to herpes simplex virus type
1 and 2 (HSV1 and-2) (Kambizi et al., 2007).
Ashwagandha is a potent antidepressant with the property to strengthen immunity
against cold, flu and other common infections. Recently, ashwagandha has been
found to ameliorate the effects of chicken infectious anaemia virus induced
clinical parameters (haematological changes), pathology and pathogenesis in
virus infected chicks, indicating protective potential of this herb in immunosuppressive
viral disease of poultry (Latheef et al., 2013a,
General health benefits: Milk supplemented with Ashwagandha has been
reported to increase total proteins and body weight (Venkataraghavan
et al., 1980). It has a rejuvenative effect on the body mainly on
the reproductive and nervous systems and is used to improve vitality and aid
in recovery after chronic illness (Bhattacharya et al.,
1987). Aphale et al. (1998) reported that
the combination of Asgand (Withania somnifera) and Ginseng (Panax ginseng)
was significantly increased the body weight, food consumption, liver weight
and improved haematopoiesis when administered orally for 90 days using three
doses in rats.
Anti-stress agent: Aswagandha is a potent anti-stress agent. It checks
stress induced changes in adrenal function and augments protein synthesis. Ashawagandha
with anti-stress activity is effective in increasing the physical endurance,
plasma corticosterone level, sexual vigour, more sperm count, phagocytic index,
cardiac activity, augmenting level of Th-1 cytokines, rising T lymphocytes proliferation
and preventing stress induced ulcer, carbon tetrachloride (CCl4)
induced hepatotoxicity and mortality (Ilayperuma et
al., 2002; Tomi et al., 2005; Khan
et al., 2006; Al-Qirim et al., 2007).
Experimental studies in rats and mice showed same aforesaid effects when pre-treated
with the crude form of Ashawagandha. Several studies have indicate the potent
clinical and beneficial use of Ashwagandha (W. somnifera) in various
health related issues viz., in the prevention and treatment of cyclophosphamide
induced urotoxicity, protection of gonads in case of carbendazim toxicity, many
stress induced diseases like arteriosclerosis, early ageing, arthritis, diabetes,
hypertension and malignancy due to its potent anti-stress, vitalizing and rejuvenating
properties (Scarfiotti et al., 1997; Davis
and Kuttan, 2000b; Bhattacharya and Muruganandam, 2003;
Singh et al., 2011).
Rodents received a mild electric shock to their feet for a period of 21 days,
resulting in stress induced effects like hyperglycemia, increase in plasma corticosterone
levels, glucose intolerance, gastric ulcerations, male sexual dysfunction, immunosuppression
and mental depression. Ashwagandha was given to the animals one hour before
the electric shock and it is effectively reduces chronic stress in rodents (Bhattacharya
and Muruganandam, 2003). The anti-anxiety effect of Ashwagandha was due
to GABA-like activity, inhibitory neurotransmitter in the brain. It decreases
the neuron activity and inhibits nerve cells from over firing, results in calming
effect (Mehta et al., 1991).
Ashwagandha has been used to stabilize mood in patients with behavioural disturbances.
It has an anti-depressant and anti-anxiety effect in rodents when compared to
the anti-depressant drug imipramine and the anti-anxiety drug lorazepam (Ativan)
(Archana and Namasivayam, 1999). Ashwagandha is one
of the most widespread tranquillizers used in India (Singh
et al., 2010). Bhattacharya and Muruganandam (2003)
compared the ability of Withania somnifera and Panax ginseng to
relieve chronic stress syndrome in a rat model. They showed that both Ashwagandha
and Panax ginseng decreased the frequency and severity of stress-induced
ulcers, reversed stress-induced immunosuppression, reversed stress-induced inhibition
of male sexual behaviour and inhibited the effects of chronic stress on retention
of learned tasks, but only the Withania extract increased peritoneal
Anti-oxidant activity: Root powder of W. somnifera has been reported
to prevent Cadmium-induced oxidative stress in chicken and lead-induced oxidative
damage in mouse (Chaurasia et al., 2000; Mahadik
et al., 2008; Bharavi et al., 2010).
Plant extract protects myocardial cells from adverse effect of infarction or
cardiac necrosis and stroke in rats which has molecular basis and high regeneration
power as well (Arya et al., 2004; Gupta
et al., 2004; Mohanty et al., 2004;
Sivanesan, 2007). Withania has showed antiulcer
property and antioxidant activity also in rats along with improved calcification
of bone in calcium-deficient ovariectomized rats (Sisodia
and Bhatnagar, 2004; Bhatnagar et al., 2005;
Nagareddy and Lakshmana, 2006; Sumantran
et al., 2007a).
Withania somnifera has powerful antioxidants. It increases the levels
of three natural antioxidant enzymes like superoxide dismutase, catalase and
glutathione peroxidise in the brain of rats (Dhuley, 2000).
Active principles of Withania somnifera root have antioxidant effects
like anti-stress, cognition-facilitating, anti-inflammatory and anti-aging effects
Anti-inflammatory effects: Ashwagandha acts as an effective anti-inflammatory
agent and relives the symptoms of arthritis and variety of rheumatologic conditions.
Naturally, it has much higher steroidal content than that of hydrocortisone
(Anbalagan and Sadique, 1981). Begum
and Sadique (1988) demonstrated that rats treated with powder of Withania
somnifera root orally for 3 days, 1 h before injection of inflammatory agent
produced anti-inflammatory responses comparable to that of hydrocortisone sodium
Effect on cardiovascular system: In humans, assessment of the hypoglycemic
as well as diuretic and hypocholesterolemic effects of Ashwagandha root revealed
that the treatment of subjects suffering from type 2 diabetes and mildly hypercholesterolemic
can be initiated for a period of 30 days with a powder extract which results
in a decrease in the glucose level in blood, comparable to that of an oral hypoglycemic
drug. Significant increase in volume and sodium content in urine and decrease
in cholesterol as well as triglycerides and low density lipoproteins in serum
have also been observed (Bhattacharya and Muruganandam, 2003).
Hepatoprotective activity: Withaferin A has significant hepatoprotective
effect in Ccl4-induced hepatotoxicity in rats at a dose of 10 mg
kg-1 b.wt. (Rastogi and Mehrotra, 1998; Khare,
Hypothyroid activity: An aqueous extract of dried Ashwaganda root was
administered to mice daily for 20 days to test thyroid activity. Significant
increase in serum T4 levels indicates the stimulating effect at the glandular
level via its effect on cellular antioxidant systems. These results indicate
ashwaganda is a useful treating agent for hypothyroidism (Panda
and Kar, 1998).
Anti-hyperglycaemic effect: Transina is a commercial preparation, which
contains active ingredient of Ashwaganda and other components. It decreases
streptozocin (STZ) induced hyperglycaemia in rats due to its pancreatic islet
free radical scavenging activity (Bhattacharya et al.,
Musculotropic activity: Alkaloids of Ashwaganda have muscle relaxant
and antispasmodic effects against several spasmogens on bronchial, blood vascular,
intestinal, uterine and tracheal muscles. This smooth muscle relaxant activity
of the alkaloids was similar to that of papaverine which is a direct musculotropic
agent (Anonymous, 1982).
Effect on sexual behaviour: Impairment in libido and sexual performance,
sexual vigour as well as dysfunction in penile erection can be corrected by
root extract of W. somnifera. The roots contain Fe, K, Mg and Ni which
plays significant role in the diuretic, aphrodisiac activity and in the treatment
of spermatopathia and seminal depletion. On cessation of treatment, these effects
are partially reversible and are attributed to hyperprolactinemic, Gamma Amino
Butyric Acid (GABA), serotonergic or sedative activities of the extract instead
of changes in levels of testosterone. Male sexual competence is detrimentally
affected by roots of W. somnifera and thereby is contradictory. GABA
mimetic activities of W. somnifera roots as well as serotonergic systems
strongly depresses the libido (Ilayperuma et al.,
Anti-cancer effects: The anti-cancer importance of the Ashwagandha plant
has been well documented in a number of experimental studies and its extracts
have potential use in cancer chemotherapy (Nath et al.,
2005; Winters, 2006; Yang et
al., 2007; Mathew et al., 2010; Dhama
et al., 2013a). Literature reveals that Ashwagandha can be used as
synergizer to support conventional chemo or radiation therapy due to its long
term tumor growth inhibition property. Roots have been found to hamper the cellular
growth and attachment of Chinese Hamster Ovary (CHO) carcinoma cells and thereby
exerting the anti-tumor effect. This plant has also been found effective against
uterine fibroids, dermatosarcoma, prostate cancer in humans, urethane induced
lung-adenoma in mice, neuroblastomas in humans, ascitic lymphoma, benzopyrene
induced lung cancer in male Swiss Albino rat and leukaemia in humans (Singh
et al., 1986; Devi, 1996; Christina
et al., 2004; Senthilnathan et al., 2006a,
b; Winters, 2006; Senthil
et al., 2007; Sumantran et al., 2007b;
Srinivasan et al., 2007; Widodo
et al., 2010; Kataria et al., 2013)
Anti-carcinogenic effects are mainly on account of decreased expression of nuclear
factor-kappa-B, suppression of intercellular Tumor Necrosis Factor (TNF) and
potentiation of apoptotic signaling in cancerous cells of animals or cell lines
(Singh et al., 2010; Dhama
et al., 2013e). Withaferin A is shown to inhibit umbilical vein endothelial
cell (HUVEC) that sprouts in three-dimensional collagen-I matrix at doses relevant
to the inhibitory activity of NF-kappa B. In HUVECS, Withaferin A inhibits proliferation
of cell at significant doses that are lower than those that are required for
cell line of tumor origin via cyclin D1 expression inhibition. On the basis
of these findings, it is proposed that in HUVECS NF-kappa B inhibition by Withaferin
A occurs by interference of proteosome pathway mediated by ubiquitin. This is
evident from the increase in the level of poly-ubiquinated proteins. Moreover,
the finding that a potent anti-angiogenic activity is exerted by Withaferin
A in vivo at lower doses than that required to induce anti-tumor activity
in vivo highlights the use of this natural product obtained from W.
somnifera to treat or prevent cancer (Mohan et al.,
2004; Bargagna-Mohan et al., 2005; Ichikawa
et al., 2006; Rao and Naresh, 2010; Dhama
et al., 2013a).
A study regarding revealing the effect of W. somnifera root extracts
on cell cycle and angiogenesis, as an anti-angiogenic compound showed Withaferin
A and Withanolide D to inhibit growth of cancer (Maitra
et al., 2003; Mathur et al., 2006).
Ashwagandha plant extract inhibited benzo (a) pyrene-induced forestomach papillomagenesis,
carrageenin induced air pouch granuloma and DMBA-induced skin papillomagenesis
with up to 60 and 92% and 45 and 71% inhibition in tumor incidence and multiplicity,
respectively in mice (Padmavathi et al., 2005).
Genesis of papilloma of skin induced by 7, 12-dimethylbennzanthracene is inhibited
by W. somnifera. In mice, however during the study this plant does not
show any toxic effect apparently (Padmavathi et al.,
2005). Sometimes, Ashwagandha (Indian ginseng) may produce interference
in the immunoassay of serum digoxin level measurement (Dasgupta
et al., 2007).
W. somnifera reduces tumor cell proliferation and mitigate undesirable
side effects, hence increases overall animal survival time. It potentially supports
radiation therapy and reduces the side effects produced by chemotherapeutic
agents such as cyclophosphamide and paclitaxel without interfering with the
tumor-reducing actions of the drugs. W. somnifera has been suggested
to act as a novel complementary therapy in the field of oncology (Visavadiya
and Narasimhacharya, 2007).
Recent in vitro studies in India has shown that the extract of the plant
disrupt the ability of cancer cells to reproduce and is a significant step in
fighting cancer. In addition it has been indicated by laboratory analysis that
anti-angiogenic activity of ashwagandha extract against new blood vessels supporting
unbridled growth. Oral administration ashwagandha extract effectively Inhibits
the experimentally induced stomach cancers in laboratory animals. It reduces
the incidence of tumor by 60% and multiplicity of tumor by 92%. Incidence and
multiplicity of tumor are inhibited by 45 and 71%, respectively when study has
been carried out in rodent model of skin cancer (Christina
et al., 2004; Mathur et al., 2004;
Padmavathi et al., 2005).
Anti-cancer activity of Ashwagandha has been attributed to Hypothalamic Pituitary
Adrenal (HPA) axis and the neuroendocrine system. It modulates the activity
of cytotoxic lymphocytes (CTL) for reducing the tumour and cancerous growth.
Augmentation of the Natural Killer (NK) cell activity reduces the tumor growth
and incidences and increases serum T3 and T4 in mice (Panda
and Kar, 1998) Compared to doxorubicin, Ashwagandha showed better efficacy
in arresting growth of breast and colon cancer cell line (Jayaprakasam
et al., 2003). Extracts of Ashwagandha also possess potent antioxidant
and detoxifying properties (Rasool and Varalakshmi, 2007).
Withaferin A stoutly exerts I kappa B kinase beta hyperphosphorylation for inhibition
of its kinase action thereby causing death of cancerous cells (Kaileh
et al., 2007; Wang et al., 2012).
Radiosensitization action and activities: Studies have revealed that
a good natural source of a potent and relatively safe radio sensitizer/chemotherapeutic
agent is Ashwagandha. The radiosensitizing effect of W. somnifera has
been studied in vivo on the B16F1 mouse melanoma. Volume doubling time
(the time required for a quantity to double in size) and growth delay in dose
dependent manner has been observed by treating 100 mm3 tumors with
intraperitonial injection of 10-60 mg kg-1 of Withaferin A. On the
other hand, there has been a significant enhancement in tumor response due to
gamma irradiation locally followed by injection of Withaferin A at the rate
of 30-50 mg kg-1. Such study has shown that the plant extract (Withaferin
A) is effective mostly when injected intraperitonially 1 h prior to irradiation
and thereby Withaferin A significantly enhance the radiation response of melanoma
(Uma et al., 2000; Diwanay
et al., 2004; Rao and Naresh, 2010).
Reducer of poisoning due to toxins and chemicals/drugs: Cancer is likely
induced by chemotherapeutic agents like cyclophosphamide and cadmium and the
side effects produced by chemotherapy as well as radiotherapy are sometimes
more hazardous than the disease proper. Significant reduction in cyclophosphamide
induced leucopenia has been observed due to administration of W. somnifera.
When W. somnifera and cyclophosphamide together are used for treatment
purposes, cellulairty of bone marrow increases significantly compared to cyclophophamide
treatment alone. Alpha-esterase positive cells increase in number in the bone
marrow of animals treated with cyclophosphamide due to administration of Ashwagandha
because of stem cell proliferation (Kumar et al.,
2011; Rahal et al., 2013). As per studies
so far, toxicity induced by cadmium has not been reported to be regulated by
any plant. But lipid peroxidation based results indicate that cadmium induced
toxicity can be reduced by Ashwagandha, thereby indicating the potential of
this plant to regulate metal induced toxicity (Panda et
al., 1997). Ashwagandha is also known to significantly reduce the ochratoxin
A induced suppression of chemotactic activity as well as interleukin IL-1 and
TNFalpha along with Asparagus racemosus (Satavari), Tinospora
cordofolia and Picrorhiza kurroa (Katuki) (Mahima
et al., 2012; Chakraborty and Pal, 2012;
Dhama et al., 2013e). Tissue venom like hyaluronidase
destroys the integrity of extracellular matrix thereby helping to spread toxin.
It is an interesting finding that W. somnifera is a source of a hyaluronidase
inhibitor, glycowithanolide (WSG) glycoprotein inhibits the hyaluronidase activity
completely at a concentration of 1:1 w/w of snake venom to WSG, which could
be help provide protection in case of Cobra (Naja naja) and Viper (Daboia
russelii) bites. It is a scientific approach to use the Ashwagandha plant
extract externally as an antidote to victims of snake bite in rural India. The
Naja naja venom has got phospholipase A2 (PL-A2) activity which can be
neutralized by glycoprotein isolated from W. somnifera known as antitoxin-PLA2.
This has got implications in novel therapeutic reagent development as well as
for treating snake evenomations along with implication in snake biology (Machiah
et al., 2006).
Anti-aging activities: Double-blind clinical trial was conducted to
test the anti-aging properties of Ashwagandha in a group of 101 healthy males,
ageing about 50-59 years were given at a dosage of 3 g daily for one year. The
volunteers showed significant improvement in hemoglobin, red blood cell count,
hair melanin, seated stature, improvement in sexual performance, decrease in
serum cholesterol and nail calcium was preserved (Bone, 1996;
Ilayperuma et al., 2002).
Role against neurodegenerative disorders: Ashwagandha can be used as
neuro-regenerative agent to treat Alzheimer's, Parkinson's, Huntington's and
other neurodegenerative diseases at any stage of the disease as it can significantly
reverse the neuritic atrophy and synaptic loss, along with GABA mediated anticonvulsant
effect, GABA mimetic effect and promoting formation of dendrites due to therapeutic
activity of glycowithanolides withaferin-A and sitoindosides VII-X present in
the roots of Ashwagandha (Schliebs et al., 1997;
Abbas et al., 2004, 2005;
Ahmad et al., 2005). Ashwagandha enhances regeneration
of the neurons along with reconstruction of synapse thereby acting as memory
enhancer. The expression of Brain Derived Neurotropic Factor (BDNF) as well
as Glial Fibrillary Acidic Protein (GFAP) is reversed by treatment with extract
of Ashwagandha (Konar et al., 2011).
Alkaloids from the roots of Ashwagandha showed prolonged hypotensive, bradycardiac
and respiratory stimulant activities in dogs. Hypotensive effect was mainly
due to autonomic ganglion blocking action and was augmented by the depressant
action on higher cerebral centres. In experimental animals, total alkaloids
produced a taming and a mild depressant effect like tranquillizer-sedative type
on the CNS (Rastogi and Mehrotra, 1998). Systemic administration
of Ashwagandha root extract led to slightly enhanced acetylcholinesterase (ACHE)
activity in the lateral septum and globus pallidus. Ashwagandha root extract
affects mainly in the cortical and basal forebrain cholinergic signal transduction
cascade. It increases cortical muscarinic acetylcholine receptor capacity leads
to cognition-enhancing and memory-improving effects in animals and humans (Schliebs
et al., 1997).
Anticonvulsant activity: Ashwagandha root extract significantly reduces
the jerks in 70% animals and clonus in 10% animals caused by pentylene tetrazole
(PTZ) induced convulsions when administered with dose of 100 mg kg-1
and it was evident from EEG wave pattern (Kulkarni and
George 1996). It also showed reduction in severity of motor seizures induced
by electrical stimulation in right basilateral amygdaloid nuclear complex through
bipolar electrodes. The protective effect was due to GABAergic mediation of
Ashwagandha (Kulkarni et al., 1993).
Role of Ashwagandha in development of drug tolerance and dependence:
Drug addiction has become a major health problem worldwide and is a very costly
affair to be managed. In drug addict individuals, tolerance as well as withdrawal
signs are observed due to chronic treatment with benzodiazepine as well as ethanol
or opioids that can be blocked by BR-16A (Mentat) which contains W. somnifera
as one of its important ingredient. The morphine induced analgesic effect is
significantly attenuated when the Ashwagandha plant extract is administered
repeatedly for a period of 9 days. As per assessment by naloxone precipitation,
withdrawal signs of development of dependence to opiate viz., morphine withdrawal
jumps can be suppressed by W. somnifera. Studies have revealed that there
is no dependence liability of the plant even upon cessation abruptly which have
got clinical implications without production of long-term tolerance and withdrawal
effect (Kulkarni and Sharma, 1994; Kulkarni
and Ninan, 1997; Kest et al., 2002).
Biotechnological techniques as a stand-pillar in upliftment of herbal therapy:
Medicinal plants are broadly used to deal with an array of health problems.
The major impediments in the study of therapeutic herbal plants consist of erroneous
identification and less yield of active principles such as medicinally important
withanolides in case of Ashwagandha. Biotechnological advance techniques such
as deoxyribonucleotide (DNA) based techniques like Polymerase Chain Reaction
(PCR), stochastic algebraic modelling language (SAMPL), Restriction Fragment
Length Polymorphism (RFLP), Amplified Fragment Length Polymorphism (AFLP), Random
Amplified Polymorphic DNA (Rapd), High Performance Liquid Chromatography (HPLC),
molecular cloning and sequencing of any target gene can help to resolve uncertainties
in identification of appropriate plants and their constituents (Sharma
et al., 2007). The novel disciplines of bioinformatics and genomics
involving recombinant DNA techniques, in vitro organ and tissue/cell
culture methods can be employed to produce bioactive alkaloids such as withanolides
under definite conditions (Patra et al., 2004;
Jha et al., 2005; Negi et
al., 2006; Supe et al., 2006; Wadegaonkar
et al., 2006; Titanji et al., 2007).
Commercial preparations: Ashwagandha is the principal component of many
polyherbal preparations viz., Immu-21, Amrit®, Su-Ruksh®,
Ashwgandha® and ImmuPlus® etc (Sangwan
et al., 2004). Immu-PlusR has been reported to stimulate
blastogenic capacity of T and B cells and increases antibody titer in dogs.
Polyherbal preparations like Ashwagandharist act as a nervine tonic and Himalaya
ashwagandha is a monoherbal extract used for management of stress. Stresswin
is used for reduction of anxiety, strain as well as stress. Stresscom is a monoherbal
extract that relieves anxiety. Himalaya massage oil is a polyherbal preparation
used for relaxation of body along with relief from stress. It is a good immunopotentiating
agent when used along with vaccines, like in pups it improves immune stimulation
when used in conjunction with parvovirus and rabies virus vaccines (Chauhan,
1999). Similar beneficial immunomodulatory effects have been observed in
poultry birds while using with infectious bursal disease and Newcastle disease
vaccines (Dhote et al., 2005). Not only this
but in few fishes also such as Labeo rohita, famous as Indian major carp,
'ImmuPlus' has helped in increasing immunity and providing enhanced resistance
against the diseases at different growth stages of fish life (Kumari
et al., 2007). Immunomodulatory effects of Immu-21R have
been reflected in modest improvements in conditions of HIV patients (Singh
et al., 2001).
The uses of botanical medicines continue to grow with the expansion of modern
medicine. The revered herb (Ashwagandha) potentiates the immune functions, enhances
the longevity and facilitates the restoration of homeostasis by reducing the
stress. Along with these, the role of Withania to exert beneficial effect
against anxiety as well as cognitive and neurological disorders, inflammation
and Parkinsons disease are quiet
noteworthy. Ashwagandha is a potent stress reliever and antidepressant with
the property to strengthen immunity against cold, flu and other common infections.
Root powder is useful in treatment of acute rheumatoid arthritis. The roots
are used as potent diuretic and aphrodisiac, increases sexual performance and
help to maintain vigour and vitality. The plant is also a good anti-inflammatory
agent and is useful in graft-vs-host reaction. Ashwagandha extract supports
antioxidant and immunomodulant activities. Withaferin A has powerful antitumor
effects. It possesses metastatic and angiogenetic properties of decresing order.
Withania increases the bodys
ability to withstand stress of all types signifying anti-stressor adaptogenic
property. Roots and leaves of Withania exhibit marked antibacterial activity
against S. aureus, Neisseria gonorrhoea and anti-fungal activity
against Candida albicans. These facts indicate that W. somnifera
can be regarded as a fine natural source of a potent and relatively safe radiosensitizer/chemotherapeutic
agent. However the aforesaid benefits are documented in the literature but still
multi-disciplinary evaluation is required with systematic approach before large
scale commercialization of this miraculous herb. Proper caution should be taken
while using this plant along with drugs that have anectodal effect (importantly
barbiturates). The dose regimen should be given equal importance as in large
dosage the plant extract causes gastrointestinal upset as well as diarrhea and
vomition and may also have abortifacient effect (so better to avoid during pregnancy).
Working hand-in-hand with oncologists as experienced natural medicine practitioners
can effectively increase the therapeutic efficiency of Ashwagandha as well as
decrease the side effects of W. somnifera when used for conventional
treatments. In order to determine whether W. somnifera can duplicate
the immunomodulatory and haematopietic activities in humans, optimal dosage
for achieving these effects must be determined for which more research works
are mandatory. Because of its wide pharmacological activities, Ashwagandha is
considered as an important component of various polyherbal preparations. Thus
the plant has got immense practical applicability in biomedicine as well as
veterinary medicine focusing its potent role in the maintenance of sound health.
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