Biomedicine & Pharmacotherapy: Withania Somnifera (L.) Dunal (Ashwagandha) : A Comprehensive Review On

Biomedicine & Pharmacotherapy 143 (2021) 112175
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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha
Withania somnifera (L.) Dunal (Ashwagandha): A comprehensive review on

ethnopharmacology, pharmacotherapeutics, biomedicinal and
toxicological aspects
Subhabrata Paul a, 1, Shreya Chakraborty b, 1, Uttpal Anand c, 1, Swarnali Dey d,
Samapika Nandy b, Mimosa Ghorai b, Suchismita Chatterjee Saha e, Manoj Tukaram Patil f,
Ramesh Kandimalla g, h, Jarosław Proćków i, *, Abhijit Dey b, *
a
School of Biotechnology, Presidency University (2nd Campus), Kolkata 700156, West Bengal, India
b
Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, West Bengal, India
c
Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
d
Department of Botany, University of Calcutta, Kolkata 700019, West Bengal, India
e
Department of Zoology, Nabadwip Vidyasagar College (Affiliated to the University of Kalyani), Nabadwip 741302, West Bengal, India
f
Post Graduate Department of Botany, SNJB’s KKHA Arts, SMGL Commerce and SPHJ Science College (Affiliated to Savitribai Phule Pune University), Chandwad,
Nashik 423101, Maharashtra, India
g
CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana, India
h
Department of Biochemistry, Kakatiya Medical College, Warangal-506007, Telangana, India
i
Department of Plant Biology, Institute of Environmental Biology, Wrocław University of Environmental and Life Sciences, Kożuchowska 5b, 51–631 Wrocław, Poland
A R T I C L E I N F O A B S T R A C T
Keywords: Withania somnifera (L.) Dunal (Solanaceae) has been used as a traditional Rasayana herb for a long time.
Ashwagandha Traditional uses of this plant indicate its ameliorative properties against a plethora of human medical conditions,
Ethnobotany viz. hypertension, stress, diabetes, asthma, cancer etc. This review presents a comprehensive summary of the
Phytochemistry
geographical distribution, traditional use, phytochemistry, and pharmacological activities of W. somnifera and its
Pharmacology
Toxicology
active constituents. In addition, it presents a detailed account of its presence as an active constituent in many
Withanolides commercial preparations with curative properties and health benefits. Clinical studies and toxicological con
Withania somnifera siderations of its extracts and constituents are also elucidated. Comparative analysis of relevant in-vitro, in-vivo,
and clinical investigations indicated potent bioactivity of W. somnifera extracts and phytochemicals as anti-
cancer, anti-inflammatory, apoptotic, immunomodulatory, antimicrobial, anti-diabetic, hepatoprotective,
hypoglycaemic, hypolipidemic, cardio-protective and spermatogenic agents. W. somnifera was found to be
especially active against many neurological and psychological conditions like Parkinson’s disease, Alzheimer’s
disease, Huntington’s disease, ischemic stroke, sleep deprivation, amyotrophic lateral sclerosis, attention deficit
hyperactivity disorder, bipolar disorder, anxiety, depression, schizophrenia and obsessive-compulsive disorder.
The probable mechanism of action that imparts the pharmacological potential has also been explored. However,
in-depth studies are needed on the clinical use of W. somnifera against human diseases. Besides, detailed toxi
cological analysis is also to be performed for its safe and efficacious use in preclinical and clinical studies and as a
health-promoting herb.
1. Introduction extensively implemented as herbal medicine. An evergreen woody shrub

of the Solanaceae family, W. somnifera has been assigned several names
Since its inception in 6000 B.C., Withania somnifera (L.) Dunal (Sol with distinct meanings such as “Indian winter cherry” or “Indian
anaceae), popularly known as Ashwagandha in Sanskrit, has been ginseng” in English, “Punir” or “Asgandh” in Hindi and “Asgand” in
* Corresponding authors.
E-mail addresses: jaroslaw.prockow@upwr.edu.pl (J. Proćków), abhijit.dbs@presiuniv.ac.in (A. Dey).
1
Equal contribution.
https://doi.org/10.1016/j.biopha.2021.112175
Received 18 June 2021; Received in revised form 3 September 2021; Accepted 7 September 2021
Available online 27 September 2021
0753-3322/© 2021 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
S. Paul et al. Biomedicine & Pharmacotherapy 143 (2021) 112175
Urdu [12]. The species name has been ascribed as ‘somnifera’, which glabrous, green elliptic leaves and small, green, bell-shaped flowers.
means “sleep-inducer” in Latin, owing to its prodigious anti-stress About 1–7 inconspicuous bisexual flowers appear at the leaf nodes. The
characteristics; ‘Ashwagandha’ (“ashwa” means horse and “gandha” 5-lobed calyx is nearly 5 mm long and in the fruit, it is 20 mm long,
means smell) as the roots possess a characteristic ‘wet horse’ smell and spherical or urn-shaped, membranous, 5–10 ribbed. Narrowly
Indian ginseng due to its familiarity with pharmacologic effects and campanulate corolla is 5 lobed, 5–8 mm long, and light yellow to yellow-
traditional uses of Korean ginseng tea [76]. Designated as the “Sattvic green. The 5 stamens are protruded and yellow-orange. The fruit is a
Kapha Rasayana” in Ayurveda, Ashwagandha has been tremendously hairless spherical berry enclosed in an inflated and membranous
used as astringent, anti-carbuncle, anti-stress, tonic, narcotic, diuretic persistent calyx, 5–8 mm in diameter and orange-red to red when ripe.
and against worms, piles, goitre, leucoderma, nervous breakdown, The fruit has numerous seeds that are pale brown, kidney-shaped, and
insomnia and constipation [6,192]. Withania as “Asgand” also finds its compressed to a rough, netted surface. Roots are stout, fleshy, bearing
mention in the Unani medicine system in Kitab-al-Hashaish written by fiber-like secondary branches arising from the main root having a strong
Dioscorides in 78 A.D. W. somnifera has found its mention as an official odour and bitter, acrid taste [75] (Fig. 1A, B).
drug in Indian Pharmacopoeia-1985 [377]. It is the roots of the plant
that have been extensively used in Unani and Ayurvedic systems of 1.2. Distribution and traditional uses
medicine. Roots are reported to contain 0.13–0.31% alkaloids, volatile
oils, starch, amino acids, glycosides, reducing sugars, and steroids [199]. WS is the most widespread species in the genus. It occurs naturally in
Besides, the root, leaves are useful to cure fever and swellings, flowers drier regions extending from the Mediterranean through tropical Africa
have been used as astringent, diuretics, fruits are used to treat skin ul through South Africa and from the Canary and Cape Verde Islands to the
cers, tumors, carbuncles and seeds are effective in increasing sperm Middle East and Arabia, Afghanistan, Baluchistan, Pakistan, Sri Lanka,
count as well as in testicular growth [345]. This review encompasses the China, Nepal and India. In the warmer parts of Europe, it is cultivated in
various pharmacological activities of W. somnifera (WS) that have been gardens and has become a naturalized weed in South Australia and New
reported in the last two decades with notes on its traditional use, South Wales. In India, however, it is grown as a medicinal crop mainly
phytochemistry, clinical and toxicological aspects. for its fleshy roots that possess a plethora of bioactive compounds having
several pharmacological implications [191,215,377]. In India, the plant
1.1. Botanical/taxonomic description is widely distributed in the drier parts, especially in Punjab, Gujarat,
Uttar Pradesh, Maharashtra, West Bengal and Rajasthan [169]. The
WS is an evergreen, xerophytic, woody, short, tender, perineal shrub various ethnomedical uses of WS are presented in Table 1, whereas
that grows about 2 m tall and 1 m wide. It has tomentose branches Table 2 depicts the popular use of this plant in Ayurvedic and herbal
covered with short fine, silver-gray hairs that extend radially from a commercial formulations.
central stem. The stems are brownish, prostate to erect. Leaves are
alternate (opposite to flowering shoots), almost hairless and green at the
upper surface and densely hairy underneath. It has dulled, simple,
Fig. 1. (A). Withania somnifera plant habit and roots; attribution: Piouswatson [Public domain] (B).Fruits and seeds; attribution: Muséum de Toulouse [CC BY-SA 3.0
(https://creativecommons.org/licenses/by-sa/3.0)], (C). Chemical structures of the withanolides: withanolide A, D, E, F, and L (adapted www.ChemSpider.com).
2
Table 1
Traditional uses of Withania somnifera.
State - country - Plant Local names Ethnomedicinal use against/ Method of preparation Route of administration/ References
place parts as dose
Andhra Pradesh - Root Penneru Combat anemia; increasing Root powder with equal Oral (twice few days); oral [289]
India - East sperm count sugar; with sugar and ghee (daily once for 40 days)
Godavari
Andhra Pradesh - Root Pannerugadda Astringent, aphrodisiac, – Oral [92]
India - East nervine sedative, narcotic,
Godavari diuretic, tonic, alterative,
aphrodisiac, rheumatic swelling
Andhra Pradesh - Whole Ashwagandha Arthritis, anxiety, insomnia, – Oral [89]
India - Yavatmal plant tumors, tuberculosis, asthma
and chronic liver disease
Assam - India - Root Aswagandha Female infertility Powder with tablet (Dron, Oral [352]
Barpeta Sidhelota, and Slilax) and
Rangajoba juice
Assam - India - Leaves and Achagandha Leprosy Paste Topical [113]
Morigaon roots
Bihar - India - Buxur Root Aswagandha Diuretic Seed decoction Oral [348]
Chhattisgarh - India Root, leaf Aswagandha Sexual and general weakness, Root powder, decoction, Oral, topical [134]
headache, pregnancy care, leaf paste, ash
rheumatism, debility, aging,
gonorrhea, ringworm, bed
sores, hemorrhoids, abscesses
and smallpox
Chhattisgarh - India - Root Aswagandha Male sterility Powdered root with milk Oral, for 7 days [142]
Raigarh
Chhattisgarh - India Root Aswagandha Anti-snake venom Aqueous – [214]
Haryana - India - Stem bark Asgand Menstrual disorder Powder with misri and Oral [397]
Rohtak, Jhajjar, water
Bhiwani, Rewari,
Faridabad,
Sonipat,
Mahendergarh
Haryana - India - Askin Cough – – [255]
Jhajjar
Haryana - India - Seeds and Asgand Hardness of mammary – – [398]
Mahendergarh leaves
Haryana - India - Leaf, root Bambhol Vagina related pain; painful Root powder with sugar and Oral; topical [290]
Jind and fruit swelling, boils and rheumatic milk; warm leaf
pains
Haryana - India Stem bark, Guga Fever, cough asthma, migraine Powder or paste Oral, twice daily for 7 days [396]
-Jhajjar root Twice daily until cure
Himachal Pradesh - Leaves Aswagandha Weight loss Raw leaves Oral, chewed every alternate [325]
India - Solan day for a month
Himachal Pradesh - Seeds Ashwagandha Physical and mental weakness Seed powder Oral, with hot water for 10 [175]
India - Hamirpur days, twice a day
Himachal Pradesh - Leaves and Ashvagandha Diabetes Leaf infusion and root Oral [173]
India - Hamirpur Roots powder
Himachal Pradesh - Roots Ashvagandha, Tonic, hypnotic, diuretic, Powder Oral, 200–500 mg of root [324]
India - Keylong Asgandh narcotic, sedative, powder with one glass of warm
and surroundings abortifacient, rheumatism, milk before sleep for 15 days
cough, delay aging, graying of
hairs, provide physical and
mental strength
Jharkhand - India - Roots Ashvagandha Venomous snake bite Powder, with other plants Oral, 1 mg of the powder is [207]
Latehar given to the victim 7 times at
3 min gap
Jammu and Kashmir Leaves Asgandh Memory enhancer, obesity Fresh leaves Oral, chewing on an empty [45]
- India - Udhampur stomach
Jammu and Kashmir Leaves Asgandh Memory enhancer, obesity Fresh leaves Oral [291]
- India - Kathua
Jammu and Kashmir Stem Asgandh Leucorrhea Dried finally chopped Oral, 1 teaspoon stem with [46]
- India - Udhampur water on an empty stomach
Karnataka - India - Root Ashvagandha Diabetes Powder Oral, with water for 15 days [285]
Shimoga
Karnataka - India - Root Ashvagandha Cardio vascular problems Decoction Oral, with root decoction of [276]
Chikmagalur F. microcarpa
Karnataka - India - Root Ashwagandha Asthma Decoction Oral, with garlic and cow’s [195]
Chikmagalur milk, two to four times a day
Karnataka - India - Root, Ashwagandhi Aphrodisiac, ulcers, swellings Root powder; leaf paste Oral, with root powder of [112]
Gulbarga leaves E. echinatus, mustard and
turmeric; topical, root, leaf
paste
Karnataka - India - Root Ashwagandha Paralysis Root paste with the paste of Oral, paste with hot water [284]
Shimoga E. rives and Shatavari twice a day for 1 month
(continued on next page)
3
Table 1 (continued )
place parts as dose
Karnataka - India - Root Ashwagandha Respiratory problem in children Roots with cardamom seeds, Topical, applied over the [4]
Tumkur kumkum kesari boiled in entire body
cow’s butter
Karnataka - India - Root, Ashwagandha Mental stress, insomnia, 20 g of dried, powdered Oral, twice a day, for 45 days [185]
Bijapur leaves amnesia and anxiety leaves, roots with goat milk
Karnataka - India - Root Ashwagandha Diabetes root powder with water [107]
Koppal
Karnataka - India - Root, Ashwagandha Asthma, cough, dropsy, ulcers, [328]
Mysore, Kumkur, leaves blood disorders; sore eyes
etc.
Karnataka - India - Leaves Ashwagandha Cough with sputum Decoction, young leaves of Oral, twice a day for 3–5 [330]
Gadaga the plants are crushed and weeks
boiled in water
Karnataka - India - Root Ashvagandha General weakness 5 g of the powder in warm Oral, twice daily for 2 weeks [123]
Talacauvery and milk or water with sugar
Kudremukh,
Karnataka - India - Root Ashvagandha Diabetes mellitus 100 g root with 50 g of fresh Oral, 3–4 gm of powder with [387]
Bellary root bark of Gymnema cold water
sylvestre boiled in 500 ml of
goat milk, dried in shade
and dried
Kerala - India - 14 Seed Amukkuram Oligomenorrhoea Pounded and cooked with Oral, at night time [287]
districts rice as a form of porridge
Madhya Pradesh - Root, Asgandh Fever and weakness Whole plant used as a tonic, Oral, daily in the morning [143]
India - Jhabua whole root extract in milk
plant
Madhya Pradesh - Root Ashwagandha, Joint pain Stem juice Oral, mixed with warm water [294]
India - East Nimar Asgandh
region
Madhya Pradesh - Root Ashwagandha Antibacterial, rheumatism, – Oral [193]
India - West Nimar tuberculosis
region
Madhya Pradesh - Root, Asgandh Fever, weakness due to fever Whole plant used as a tonic, Oral, daily in the morning [389]
India - Jhabua whole root extract in milk
plant
Madhya Pradesh - Root Ashwagandha Male sterility, leucorrhoea, Decoction of root Oral [144]
India - Balaghat miscarriage
Madhya Pradesh - Root Ashwagandha Leucorrhoea 5 g root powder with 250 g Oral, once a day [180,350]
India - Sidhi milk
Madhya Pradesh - Leaves Ashwagandha Asthma A teaspoonful of leaf paste Oral, once daily in the [8]
India - Anuppur mixed with a cup of cow’s morning before breakfast for
milk 21 days
Madhya Pradesh - Root Ashwagandha Anti-tumor, arthritis, asthma, – Oral [35]
India - Satna cold and cough, conjunctivitis,
diabetes, diuretic, epilepsy,
insomnia, intestinal infections,
leprosy, nervous disorders,
tubercular glands, tumors, ulcer
Madhya Pradesh - Root Ashwagandha Impotency Sweet balls with dried Oral, one ball daily at night [263]
India - Badwani leaves of P. betle
Maharashtra - India - Root Ashwagandha, A nocturnal emission, weakness 2 spoonfuls of root powder Oral, in the morning for 21 [95]
Buldhana Askand with a cup of cow milk days
Maharashtra - India - Root Askand, Paralysis Paste of root powder, milk, Topical, twice daily for body [262]
Buldhana Ashwagandha white of an egg and some massage
edible oil
Maharashtra - India - Leaf, root Dhorgunj, Askand Cough, sperm count, vigor leaf extract along with Oral [317]
Nanded boiled milk; dried root
powder
Maharashtra - India - Whole Ashwagandha, Dolro Rheumatism/ arthritis Plant powder in one cup of Oral, once a day [150]
Jalgaon plant water
Maharashtra - India - Whole Ashwagandha Arthritis, anxiety, insomnia, – Oral [89]
Yavatmal plant tumors, tuberculosis, asthma,
chronic liver disease
Maharashtra - India - Root tubers Dhor-Gunj Muscular weakness Raw along with dates Oral [103]
Ahmednagar
Maharashtra - India Root Ashwagandha Asthmatic troubles in children 5 g root paste boiled with Topical, oil gently massaged [231]
-Ahmednagar 20 ml of mustard oil. over the chest
Maharashtra - India - Root Aasoodkand Sperm count enhancement, Powder with an equal Oral, one teaspoon with cow [56]
Yavatmal menorrhegia, amenorrhegia amount of Shivlingi seeds; milk twice daily for 6 months;
with freshly collected With betle leaf thrice a day for
Katekomai roots, Penghagra 3 days from the first day of
tubers; with the root of safed menstruation; With water
gunj, ghodkand, Gidhya sag daily at morning for 7 days
bark
Root Ashwagandha Aphrodisiac, impotency Oral [261]
4
place parts as dose
Maharashtra - India - Powder, homogenized in

Buldhana honey or milk
Maharashtra - India - Root Askand Weakness in animals Powder with seed oil of Oral, with fodder [83]
Jalna M. indica
Maharashtra - India - Whole Askand Menstruation Powder 5–10 g with warm water twice [82]
Pune plant a day
Maharashtra - India - Root tuber Ashwagandha Skin cancers – – [353]
Amravati
Orissa - India - Root Ashwagandha Piles, cough and fever – Oral [297]
Mayurbhanj
Orissa - India - Bark Ashwagandha Piles Decoction Oral [227]
Balasore
Orissa - India - Root Ashwagandha Asthma Burnt root powder with Oral, every day early morning [41]
Kandhamal butter
Orissa - India - – Ajagandha, Kanaje Arthritis, general debility, – Oral [87]
Koraput diabetes, hypertension
Orissa - India - Root, leaf Ashwagandha Piles, cough, and fever; Asthma; Root paste, root powder; Oral; every morning [202]
Sundargarh cold and cough; constipation, leaf tea; root powder with
infertility cow’s milk
Orissa - India - Root Ashwagandha Sperm count With the bark of Oral, 15 g daily for 15days [347]
Mayurbhanj area C. paniculatus, crystal sugar
and clove
Orissa - India - Jajpur Root Ashwagandha Paralysis, dysuria, piles, cough Root paste Oral, on an empty stomach [249]
and fever
Orissa - India - Root, Ashwagandha Adenopathy, asthma, The root powder boiled with Oral [225]
Dhenkanal leaves hypertension, tuberculosis cow milk
Orissa - India - Root Ashwagandha To prevent the evil eye of others – – [224]
Dhenkanal
Tamilnadu - India - Root Ashwakantha Ulcers, inflammatory Root paste Topical [205]
Cuddalore conditions and scabies
Tamilnadu - India - Root, Amukramkizhangu Anthelmintic Leaves decoction, root Oral [15]
Salem leaves powder mixed with black
pepper
Tamilnadu - India - Root Amukera Sexual vigor Root powder (20 g) with hot Oral [280]
Kaniyakumari water
Tamilnadu - India - Tuber Amukara Kizhangu Tumors Paste Topical [151]
Salem
Tamilnadu - India - Root Asvakantha Anti-inflammatory; ulcers and Paste; powder with honey Topical, oral [16]
Dindigul scabies
Tamilnadu - India - Leave, root Amukkira Knee pains and joint pains Dried leaves and root paste Topical [382]
Salem
Tamilnadu - India - Root Amukkira Rheumatism, painful swelling Root paste Topical [146]
Kanyakumari
Tamilnadu - India - Leaves Amukkuran Diabetes Leaf juice Oral [1]
Virudhunagar
Tamilnadu - India - Root Ashwagandha Antimicrobial activity – – [307]
Vellore
Tamilnadu - India - Rhizome Amukkaramkizang Nervous disorders Decoction Oral [385]
Coimbatore
Tamilnadu - India - Tuber Amukira kilangu Rheumatism Paste Oral [139]
Coimbatore
Tamilnadu - India - Root, Amukkara Restorative tonic, stress, nerves – Oral [363]
Vellore leaves disorder, aphrodisiac
Tamilnadu - India - Root, Amukkara Diuretic, sedative, and pain – Oral [360]
Dindigul seeds, reliever
leaves
Tamilnadu - India - Whole Ashwagandha Antimicrobial activity, asthma Leaf paste in cow’s milk Oral [84]
Vellore plant
Tamilnadu - India - Rhizome Ashwagandha Pain due to vitiated vata humor, 50 gm powder with 10 gm Topical, powder with warm [101]
Virudhunagar pain in the joints, pain in the powder of seeds of B. juncea, water once a day for three
neck roots cooked in milk, sun- days; oral, 2–3 g mixture with
dried, powdered and mixed milk twice a day, until the cure
with the powder of
M. pruriens
Telangana - India - Root Domma dolu gadda Boils, blisters, wounds, fertility – – [358]
Nalgonda,
Warangal
Telangana - India - Leaves Ashwagandha Backache With root bark of Oral, one pill with goat milk [163]
Adilabad H. suffruticosus to make once a day for 3–4 days
small pills
Telangana - India - Root Dommadolu gadda Boils, blisters, wounds, fertility – – [221]
Adilabad
Telangana - India - Roots Aswagandha, Impotency; back ache and Root powder, 20 g with one Oral, before sleep at night [361]
Vikarabad Panneru gadda, muscular pains; fitness; obesity; glass of cow milk; 10 g with daily for 30 days, once daily
Dommadolu gadda tumors honey; 10 g with goat milk;
5
place parts as dose
roots are fried with ghee; for 15 days, daily for two
green leaves heated with weeks
castor oil Topical, on the affected part
Telengana - India - Tuber Aswagandha heading woods Paste with water once daily for 3–4 days Topical
Mahabubnagar
[288]
Tripura - India Root bark Ashwagandha Leucorrhoea 5 gm with A. berbadensis Oral, 2 teaspoonsful with [81]
juice (5 gm), white Shilajit water, twice post-meal for 3–5
(1 g), Isapgula husk (1 g) days
Uttar Pradesh - India Root Ashwagandha Aphrodisiacs, diuretics, – Oral, topical [342]
- Chandauli memory loss; fertility
Uttar Pradesh - India Root Ashwagandha, Weakness of sexual organs, Root powder Oral, 15 gm with 5 ml honey [155]
- Aligarh and Asgandh premature ejaculation and 200 ml cow milk twice a
surroundings day
Uttar Pradesh - India Root, Ashwagandha Aphrodisiac, sedative, chronic Extract Oral [177]
- Hathras leaves, fatigue, bone weakness,
seeds debility; hypnotic, asthma,
anticancer, antioxidant activity;
diuretic
Uttar Pradesh - India Leaves Ashwagandha Body pain, inflammation Paste of leaves mixed with Topical, [321]
- Shahjahanpur Boerhavia leaves
Uttar Pradesh - India Root Ashwagandha Arthritis Root powder Oral, with goat milk for 2 [370]
- Meerut months
Uttar Pradesh - India Root Ashwagandha Wrinkles Root powder with leaf Oral, with cow milk twice a [157]
- Aligarh and extract of E. prostrata day for 3 months
surroundings
Uttar Pradesh - India Leaves Ashwagandha Tuberculosis, fever, rheumatic Decoction Oral [349]
- Vindhya region pain
Uttar Pradesh - India Root Ashwagandha Sex diseases – Oral [343]
- Firozabad
Uttar Pradesh - India Stem Ashwagandha Menstruation Stem bark extract Oral, on empty stomach in [218]
- Sitapur morning
Uttar Pradesh - India Root, berry Ashwagandha Arthritis, anxiety, hiccups, – Oral [298]
- different regions insomnia, tumors, tuberculosis,
asthma, leukoderma,
bronchitis, backache,
fibromyalgia, menstrual
problems, and chronic liver
disease
Uttar Pradesh - India Root Asgandh, Fever, rheumatic pain, Root powder Oral [344]
- Sonebhadra Ashwagandha; respiratory troubles and
tuberculosis; aphrodisiac, nerve
tonic and rejuvenator
Uttarakhand - India Root, Ashwagandha Urinary disorders, fever, Leaf juice, root powder Oral [48]
–- Dehradun Leaves, insomnia
Uttarakhand - India - Leaves, Talwaada Boils Paste burned leaves and Topical [323]
Haridwar, stem stem mixed with mustard oil
Dehradun and
Pauri
Uttarakhand - India - Leaf, root Asgandha Intestinal worm infestation; Decoction of the leaf; root Oral [250]
Bageshwar rheumatic swellings powder mixed with black
pepper
Uttarakhand - India - Root Talwaada Ear problems Infusion – [110]
Garhwal
Uttarakhand - India - Leaf, root Ashwagandha Urinary disorders, fever, Juice, powder Oral [49]
Kedarnath valley insomnia, Scrofula
Uttarakhand - India - Root Ashwagandha Fatigue, appetite – Oral [296]
Garhwal
Uttarakhand - India Root, Ashwagandha Urinary disorders, fever, Leaf juice, root powder Oral [275]
leaves Insomnia.
Uttarakhand - India - Root Ashwagandha Leucorrhea Roots with A. racemosus, Oral, 3 gm mixture with milk [66]
Garhwal M. pruriens seeds, trifala in twice daily
equal proportion
West Bengal - India - Leaves Ashwagandha Wound and burn – Topical [132]
Paschim
Medinipur
West Bengal - India - Root Ashwagandha Menstrual disorders Extract with an equal Oral, mixture for 15 days [201]
Bankura amount of leaf extract of
C. roseus
West Bengal - India - Root Ashwagandha Impotency Powder Oral, 4 gm powder twice daily [85]
Cooch Behar, with milk
Jalpaiguri
West Bengal - India - Root Ashwagandha Snakebite Root decoction Oral [308]
Paschim
Medinipur
6
place parts as dose
West Bengal - India - Root Ashwagandha Convulsive seizures Root juice Oral [252]
Jhargram
West Bengal - India - Whole Ashwagandha Tonic – Oral [55]
Darjeeling plant
Abbottabad, Root Askan Mastitis 200 g fresh roots are Topical, for 1 week [2]
Haripur, and crushed to make a paste
Mansehra -
Pakistan
Attok, Mianwali, Salt Root Asghand, Aksin Dysentery of animals; Itching, Roots mixed with flour; Oral [235]
range, Sind and allergy, leprosy; dresser and decoction of leaves; fresh of
Heripur - Pakistan astringent fried leaves
Bhimber - Samahni Roots, Asgandh Stop blood flow from the uterus Leaf extract; root powder; Oral, one cup thrice a day [230]
valley - Pakistan leaves, after delivery, power; whole plant decoction
whole hydrocele, leucorrhoea, mixed with A. officinalis
plant menorrhagia, fertility root, P. mungo seeds and
silajeet stone
Bunar - Pakistan Fruits, Ketelal Diuretic, tuberculosis Powder Oral [145]
-Valley Chinglai leaves
Bahawalpur – Root, Asgandh Aphrodisiac, tonic, – Oral [241]
Pakistan leaves, anthelmintic, diabetes,
green inflammations, psoriasis,
berries and bronchitis, asthma, ulcers,
seeds scabies, insomnia, senile
debility, arthritis, general
debility and hypertension
Battagram - Pakistan Leave, Asghand Swellings and diuretic Poultice Topical; oral [128]
roots, seeds
Chakwal - Pakistan Roots Asgandh Rheumatism, painful swellings, Root paste; burnt root Topical; oral, every day early [281]
ulcers and bleeding wounds; powder with butter morning
asthma, cough, uterine disease,
expel phlegm, aphrodisiac,
puerperal tonic; debility
Chitral - Pakistan Roots, Kotilal Sterility in women; as a tonic, Root decoction; root and Oral [327]
leaves, aphrodisiac; rheumatic leaf decoction; leaf and
flowers swellings, general debility flower decoction
Dera Ismail Khan – Root Rutkan, Isgand Rheumatism and general body Dried roots are ground to Oral, 1 gm powder with water [209]
Pakistan pain make powder twice a day
Fata - Pakistan - FR Leaves, Shapyange Indigestion, stomach pain, Fresh crushed leaves as Topical; oral [379]
Tank fruits swelling joint, pain relieve wraps, fruits
Gujrat - Pakistan - Whole Aak san Asthma, constipation, eye – Oral [259]
Mangowal Plant infections, rheumatic disorders,
and ulcers
Hafizabad - Pakistan Roots, Asgandh Malaria, nightmare, Leaf powder, paste and Oral, topical and as snuff [380]
- Kaleke Mandi, leaves, stomachache, asthma, breast decoction; root powder;
Head Qadirabad, flowers. cancer, diabetes, wounds, whole plant powder, fruit
Hafizabad Fruit, menstrual flow and flower powder
city, Sukhakee, whole
Pindi Bhattian and plant
Jalalpur
Hafizabad, Mandi All parts Asgandh Malaria, nightmare, Leaf powder, paste and Oral, topical and as snuff [381]
etc. - Pakistan stomachache, asthma, breast decoction; root powder;
cancer, diabetes, wounds, whole plant powder, fruit
menstrual flow and flower powder
Gujrat - Pakistan Whole Ashghand Asthma, rheumatic disorders, – Oral [198]
Plant insomnia, fever, constipation,
eye disease, painful welling,
ulcer
Gujranwala Root, Aksn Sexual illness, diarrhea, Root powder with milk; Oral [196]
-Pakistan Whole dysentery Whole plant decoction
plant
Hangu - Pakistan Leave, Kapyanga Kidney problems Decoction of leaves Oral [158]
roots, and
seeds
Karak - Pakistan - Leave, fruit Kwatilola Abdominal pain, urinary tract – Oral [233]
Banda Daud Shah inflammation
Karak and Mianwali - Whole Asgandh Diuretic, astringent, Plant extract; crushed leaves Oral; topical [312]
Pakistan - plant diaphoretic, aphrodisiac and along with berries in water;
Makerwal and tonic, rheumatism, easy birth, root powder; poultice of
Gulla Khel infertility, burns leaves
Khushab - Pakistan - Whole Asghand Spermatorrhoea, general Roots powder mixed with Oral, In the early morning [282]
Kadhi Plant, root, debility, backache, as an sugar; whole plant powder; before breakfast
fruits aphrodisiac, swelling of the fruits soaked in water
testis, kidney stones, diabetes
Kohat - Pakistan Leaves Khapyangaea Stomach problems and arthritis – Oral [329]
Shahpiangay Carminative 2–3 seeds/ fruits in water Oral [5]
7
place parts as dose
Khyber Fruits,
Pakhtunkhwa - seeds
Pakistan - FR
Bannu
Khushab - Pakistan - Fruit Asgand Vomiting and fever Decoction Oral, 1 glass twice a day [314]
Soon Valley
Lodhran - Pakistan - Whole Ak San Asthma, Rheumatic disorders, – Oral [137]
Lodhran, Dunya Plant insomnia, fever, constipation
Pur and Kahror and eye diseases, painful
Pacca swellings and ulcer
Muzaffargarh - Aerial parts Akri boty Anthelmintics 250–500 g as feedstuff Oral [138]
Pakistan
Mandi Bahaudin - Whole Ak San Various ailments – Oral [240]
Pakistan Plant
Punjab - Pakistan Root, Aksin Cough, asthma, gastritis Decoction of roots; Poultice Oral; topical [30]
leaves problems, dysentery; itching, from leaves
allergy,
Peshawar valley - Root Azkand Body pain, pregnancy, night Powder Oral [34]
Pakistan discharge and back pain, sexual
disorder of male, gynecological
Swat - Pakistan - Whole Kotilal Aphrodisiac – Oral [14]
Miandam Plant
Thal desert - Pakistan Leave, Digestive problems, Paste, powder, poultice Oral, topical [316]
fruits, root inflammation, diabetes, sexual
problems
Vehari - Pakistan All parts Aksen Diabetes, diarrohea, fever, flu, Decoction, juice, infusion, Oral [11]
narcotics and sedative tea, and with oil
Bangladesh All parts Arshwagandha Constipation, insomnia, tissue- – Oral [131]
building, nervous breakdown
Chiittagong - Whole Ashwagandha Stimulant, Juice Oral [60]
Bangladesh plant,
Chiittagong - Root Ashwagandha Snakebite Paste Topical [147]
Bangladesh
Chiittagong - Root Ashwagondha Rheumatism Decoction Oral, one cup daily [228]
Bangladesh - hill
tracks
Dinajpur - Whole Ashwagandha Anal bleeding, bleeding With C. dactylon, E. crassipes Oral, 2–3 times daily [315]
Bangladesh – plant through the penis and fruits of P. nigrum
Kaliaganj
Dhaka - Bangladesh Root Orshogondha Energy tonic Root powder Oral [378]
Tangail - Bangladesh Root, leaf Ashwagandha Sexual desire; ulcer, cancer, Powdered root with milk; Oral [136]
- Madhupur epilepsy leaf juice
1.3. Phytochemistry (DOXP), shikimic acid and phenylpropanoid, squalene and tocopherol
were also reported in the fruits of WS [44].
A myriad of phytochemicals has been isolated from WS with the aid According to reports, more than 12 alkaloids, 40 withanolides, and
of separation techniques like column chromatography (size exclusion, several sitoindosides were among the numerous constituents found in
reverse phase), thin-layer chromatography (TLC), high-performance several parts of WS by different phytochemical analyses. Among this
liquid chromatography (HPLC), analysis of methanolic extracts of wide spectrum of pharmacologically active principles, only a few are the
different plant parts (leaves, twigs etc.). Withaferin A [394], viscosa key players in exhibiting pharmacological attributes. Withanolides are
lactone B [266], 27-deoxywithaferin A [43], pubesenolide [301], an ergostane type of steroidal compounds with a δ-lactone functionality
jaborosalactone D [384], 4b,27-dihydroxy-L-oxo-22R-witha-2,5,24-tri present between the C-22 and C-26 atoms and an oxidized C-1 position.
enolide [242], 2,3-dihydrowithaferin A-3b-O-sulfate [394], withanolide Withanolides are marker compounds as they are characteristically pre
A [239], and 27- hydroxywithanolide B [26] are worthy mentions in sent in Solanaceae members, especially in the Withania genus. The
them. dominant withanolides are withanolide D and withaferin A. Besides
Chlorinated withanolides, deduced by using an ethyl acetate-soluble having antitumor, anti-inflammatory, and immunosuppressant charac
fraction of the crude extract had been subjected to repeated column ters, they are potent antioxidants implicated in the neuroprotection
chromatography. Finally, the structures were confirmed through single- ability of the plant extract [63,106]. Under in vitro conditions, with
crystal X-ray diffraction experiments. The absolute configuration was anolide A and withanosides IV and VI were found to have a role in the
confirmed based on anomalous scattering of the chlorine atoms in the extension of axons and dendrites [165]. Withanolide A can reconstruct
crystal and was established as 6a-chloro-5b,17a-dihydroxy withaferin A. neuronal networks as well [166]. Besides, withanolides possess the
Other chlorinated compounds were also confirmed with Nuclear mag ability to inhibit acetylcholinesterase and promote the formation of
netic resonance (NMR) studies [372]. In the extract of WS fruits made in dendrites in human neuroblastoma cells [369,404]. Figs. 1C and 2
n-hexane, aqueous methanol, and water, a combination of NMR and Gas represent the various classes of phytochemicals present in the plant.
chromatography Mass spectroscopy (GC-MS) identified chemically Fig. 3 represents the chemical structures of the phytoconstituents
diverse metabolites including organic acids, fatty acids, aliphatic and retrieved from ChemSpider. Major phytochemicals based on their
aromatic amino acids, phenolic acids, withanamides, polyols, sugars, occurrence in WS are listed in Table 3. The organ-specific distribution of
sterols and tocopherols. The primary and secondary metabolites phytochemicals in WS is presented in Table 4.
including mevalonic acid (MVA), 1-deoxy-D-xylulose-5-phosphate
8
Table 2 Table 2 (continued )

Use of Withania somnifera in Ayurvedic and herbal commercial formulations. Manufacturer Product Ingredients Used as/against
Manufacturer Product Ingredients Used as/against
Guduchi (Tinospora
Himalaya Ashvagandha Ashvagandha Long-term stress cordifolia), Amalaki
Drug Capsule (Withania (Phyllanthus
Company somnifera) emblica), Shatavari
Mentat Syrup Madhukaparni Enhancing (Asparagus
(Centella asiatica), memory and racemosus),
Brahmi (Bacopa learning capacity Ashwagandha
monnieri), (Withania
Ashvagandha somnifera)
(Withania Pallrywyn Forte Jaiphal (Myristica Fertility
somnifera) Tablet fragrans),
Tentex Forte Tablets Cowhage (Mucuna Sexual Akkalkara
pruriens), Shilajeet, dysfunction (Anacyclus
Gokshura (Tribulus pyrethrum),
terrestris), Ashwagandha
Ashvagandha (Withania
(Withania somnifera),
somnifera) Kapikachchhu
Quista PRO Ashvagandha Adult nutrition (Mucuna pruriens),
(Withania Lavang (Syzygium
somnifera), Hadjod aromaticum),
(Cissus Amalaki
quadrangularis), (Phyllanthus
Pomegranate emblica), Gokshur
(Punica granatum), (Tribulus terrestris)
Taurine, Vitamin B Vigomax Forte Ashwagandha Fertility
complex, Vitamin Tablet (Withania
E, Vitamin C somnifera),
Stress Relief Country Mallow Stress relief Kapikachchhu
Massage Oil (Sida cordifolia), (Mucuna pruriens),
Ashvagandha Gokshur (Tribulus
(Withania terrestris), Salep,
somnifera), Indian Safed musli
Tinospora (Chlorophytum
(Tinospora borivilianum),
cordifolia), Indian Erandmula (Ricinus
Madder (Rubia communis)
cordifolia) Endotone Capsules Musta (Cyperus Endometriosis
Charak Manoll Nutra Syrup Ashwagandha Stress relief, rotundus), Haridra related pain
Pharma and capsule (Withania promote (Curcuma longa), control
somnifera), Amalaki immunity Lodhra (Symplocos
(Emblica officinalis), racemosa),
Yastimadhu Ashwagandha
(Glycyrrhiza glabra), (Withania
Guduchi (Tinospora somnifera), Twak
cordifolia) (Cinnamomum
Zoazest Nutra Kapikachu Fertility, sperm cassia), Shunthi
Tablets (Mucuna pruriens), health (Zingiber officinale)
Ashwagandha M2 Tone Syrup and Ashwagandha Menstrual cycle
(Withania Tablet (Withania
somnifera), Amalaki somnifera),
(Emblica officinalis), Shatavari
Carnitine, (Asparagus
Lycopene, N-Acetyl racemosus),
Cysteine, C0- Jatamansi
enzyme Q-10, (Nardostachys
Selenium, Zinc, jatamansi),
Vitamin A, Folic Devadaru (Cedrus
acid, Vitamin B 12 deodara), Lodhra
Gynelth nutra Twak (cinnamon), Menstrual health (Symplocos
Tablets Ashwagandha racemose),
(Withania Nagakeshar (Mesua
somnifera), Guggul ferrea), Ashoka
(Commiphora (Saraca asoca),
wightii), Shunth Suddha Kasis
(Zingiber Evanova Capsule Soya (Glycine Insomnia,
officinale), Zinc, N- max), Osteophoresis
Acetylcysteine, Ashwagandha
Folic acid, B (Withania
vitamins, somnifera), Brahmi
Magnesium, Iron, (Bacopa monnieri),
Calcium, Folic acid. Jyotishmati
Addyzoa Capsule Shilajit, Fertility, sperm (Celastrus
Kapikachchhu health paniculatus),
(Mucuna pruriens), Jatamansi
(Nardostachys
9
Table 2 (continued ) Table 2 (continued )

Manufacturer Product Ingredients Used as/against Manufacturer Product Ingredients Used as/against
jatamansi), Arjun Carom

(Terminalia arjuna), (Trachyspermum
Abhrak Bhasma, ammi)
Kukkutandatwak Divya Vatari Ginger (Zingiber Gastric problems
Bhasma Churna officinale), Kutki
Sumenta Tablet Ashwagandha Neuroprotective (Picrorrhiza kurroa),
(Withania action Fenugreek
somnifera), Brahmi (Trigonella foenum-
(Bacopa monnieri), graecum),
Jyotishmati Ashwagandha
(Celastrus (Withania
paniculatus), Tagar somnifera),
(Tabernaemontana Suranjana
divaricate), (Colchicum luteum)
Jatamansi Glucoshakti Glucose, Energy booster
(Nardostachys Ashwagandha
jatamansi), (Withania
Cognium Tablet and Ashwagandha Cognitive somnifera), Satavar
syrup (Withania functions (Asparagus
somnifera), Brahmi racemosus), Aloe
(Bacopa monnieri), (Aloe verai)
Arjun (Terminalia Ashvashila Capsule Shilajit, Sexual wellness
arjuna), Ashwagandha
Shankhapushpi (Withania
(Convolvulus somnifera)
pluricaulis), Muniyal Geriton Leha Tonic Kantakari (Solanum Chronic
Jyotishmati Ayurveda virginianum), respiratory
(Celastrus Hareetakee problems,
paniculatus) (Terminalia constipation, and
ZZOWIN Tablets Ashwagandha Anxiety, chebula), loss of appetite
(Withania relaxation, sleep Ashwagandha
somnifera), Tagar deprivation (Withania
(Tabernaemontana somnifera), Pippali
divaricata), (Piper longum),
Yashtimadhu Abhraka Bhasma
(Glycyrrhiza glabra), Munipayn Tablets Guggulu Rheumatism and
Jatamansi (Commiphora arthritis
(Nardostachys wightii),
jatamansi), Ashwagandha
Mandukparni (Withania
(Centella asiatica), somnifera), Rasna
Pippali (Piper (Alpinia galanga),
longum) Bala (Sida
Chropaxe tablet Ashwagandha Chronic pain cordifolia), Guduchi
(Withania (Tinospora
somnifera), Tagar cordifolia),
(Tabernaemontana Shatavari
divaricata), (Asparagus
Gokshura (Tribulus racemosus)
terrestris), Shunthi Muniprajna Tablets Brahmi (Bacopa Neuroprotection
(Zingiber officinale), monnieri),
Shyonak (Oroxylum Shankhapushpi
indicum) (Convolvulus
Patanjali Ashwagandha Ashwagandha Stress reliever puricaulis),
Churna and Capsule (Withania Jyotishmati
somnifera) (Celastrus
Spirulina Capsule Shaivaal (Spirulina Superfood paniculate),
with Ashwagandha sp.), Ashwagandha Ashwagandha
(Withania (Withania
somnifera) somnifera), Rajata
Peedantak Kwath Peeplamul (Piper Pain reliever Bhasma
longum), Nirgundi Muniojus Tablets Ashwagandha Anti-viral (HIV)
(Vitex negundo), (Withania
Ashwagandha somnifera), Nimba
(Withania (Azadirachta
somnifera), Rasna indica), Shuddha
(Alpinia galanga), Shilajatu, Dhataki
Nagarmotha (Woodfordia
(Cyperus rotundus), fruticosa)
Arendmul (Ricinus Muneks Tablets Kanchanara Anti-cancer
communis), Aaunth, (Bauhinia
Nagkesar (Mesua variegata),
ferrea), Gajpeepal Shuddha Guggulu
(Scinadapsus (Commiphora
officinalis), Jasmine Mukul),
(Jasminum sp.) Ashwagandha
10

(Withania Patra
somnifera) (Cinnamomum
Heartogen Tablets Shuddha Shilajith, Cardioprotective tamala), Elaichi
Ashwagandha (Elettaria
(Withania cardamomum),
somnifera), Bala Lavang (Syzygium
(Sida cordifolia), aromaticum), Sunth
Shuddha Guggulu (Zingiber officinale),
(Commiphora Kababchini (Piper
Mukul), Arjuna cubeba),
(Terminalia arjuna), Pimplimool (Piper
Pravala Bhasma longum), Taj
Herbsforever Ashwagandha Ashwagandha Anti-stress and Shardardaghna Goudanti Bhasma, Migraine
Capsules (Withania energy Praval Pish,
somnifera) Shringa Bhasma,
Ashwagandha Bala Ashwagandha Nerves, skin, Jatamansi ghan
Shatavari Oil (Withania muscles and (Nardostachys
somnifera), Bala bones jatamansi), Brahmi
(Sida cordifolia), strengthening. (Bacopa monnieri),
Shatavari Ashvagandha
(Asparagus (Withania
racemosus) somnifera),
Ashwagandha Ashwagandha Anti-stress and Nagarmotha ghan
Powder (Withania energy (Cyperus rotundus),
somnifera) Khurasni ghan
Veria Id His 60 Tablets Ashwagandha Man health (Hyoscyamus niger)
(Withania Baidyanath Leukonil Tablets Ashwagandha Leucorrhoea
somnifera), (Withania
Fenugreek somnifera), Vidhara
(Trigonella foenum- (Argyreia speciosa),
graecum), Badi Elaichi
Gokhshura (Amomum
(Tribulus terrestris), subulatum),
Atmagupta Majuphal (Quercus
(Mucuna pruriens), infectorial)
Bhunimba Rhuma Gel, oil, Blue gum Pain relief
(Andrographis spray, capsule (Eucalyptus
paniculata), Musli globulus),
(Chlorophytum Ashwagandha
borivillianum) (Withania
Dr. Vaidya’s Herbobuild powder Ashwagandha Bodybuilding somnifera), Satavar
(Withania (Asparagus
somnifera), Safed recemosus), Amada
musli (Curcuma amada),
(Chlorophytum Til (Sesame
borivilianum), indicum).
Shatavari Rumartho Gold and Guggul Rheumatoid
(Asparagus Gold plus Capsules, (Commiphora arthritis and osteo
racemosus) wightii), arthritis
Herbo 24 Turbo Kamal Gota Men stamina Ashwagandha
capsules (Nelumbo nucifera), (Withania
Mastaki (Pistacia somnifera), Iron
lentiscus), Kesar Powder, Bishop’s
(Crocus sativus), Weed (Aegopodium
Jayfal (Myristica podagraria), Gold
fragrans), Baidyanath Vita-Ex Kaunch Beej Men energy,
Ashwagandha Gold and Gold plus (Mucuna pruriens), vigor, and
(Withania capsules Shodhit Shilajit, stamina
somnifera), Shudh Safed Musli
Shilajit, Shatavari (Chlorophytum
(Asparagus borivilianum),
racemosus), Vidari Ashwagandha
Kand (Pueraria (Withania
tuberosa), Sweet somnifera), Purified
Museli Kuchla (Strychnos
(Chlorophytum nux-vomica),
borivilianum), Dalchini
Salam Panja (Cinnamomum
(Dactylorhiza verum), Samudra
hatagirea), Amla Sokh, Salam Mishri,
ghan (Emblica Vang Bhasm,
officinalis), Gokhru Abhrak Bhasm,
(Tribulus terrestris), Jaiphal (Myristica
Akalkara fragrans), Javitri
(Anacyclus (Myristica fragrans),
pyrethrum), Tej Akarkara
11

(Anacyclus serrata), Rose Hip

pyrethrum), Laung and Curcumin
(Syzygium Male mate Gokhru (Tribulus Vitality and vigor
aromaticum), Kant terrestris), Cowhage
Lauh Bhasm, Kesar (Mucuna pruriens)
(Crocus sativus), and Safed musli
Swarna Bhasm (Chlorophytum
Vita-Ex Massage Oil Velvet Bean Aphrodisiac and borivilianum),
(Mucuna pruriens), sexual wellness Ashwagandha
Ashwagandha (Withania
(Withania somnifera)
somnifera), Nutmeg Mood Elixir Ashwagandha Mood
(Myristica fragrans), (Withania management
Swarna Bhasma somnifera),
Dabur Ashwagandha Ashwagandha Stamina and Anantmool
Churna (Withania energy (Hemidesmus
somnifera) indicus), Bramhi
Stresscom Capsule Ashwagandha Anxiety, stress (Bacopa monnieri)
and Syrup (Withania and fatigue Stress Shield Ashwagandha Anxiety and stress
somnifera) root (Withania support
powder somnifera), Brahmi
Dabur Shila-X Oil Shuddha Shilajatu, Weakness of local (Bacopa monnieri),
Nutmeg oil muscular and Jatamansi
(Myristica fragrans), nervous tissues (Nardostachys
Clove Oil (Syzygium jatamansi)
aromaticum), Man Matters Perform Vitality Ashwagandha Energy and
Shatavari Tablets (Withania Vigour
(Asparagus somnifera), Safed
racemosus), musli
Amalaki (Emblica (Chlorophytum
officinalis), borivilianum), L-
Ashwagandha arginine
(Withania Seniority Performance Ashwagandha Men Sexual
somnifera), Bala Capsules (Withania Wellness
(Sida cordifolia), somnifera), Safed
Shveta Chandana musli
(Santalum album), (Chlorophytum
Jivanti (Leptadenia borivilianum), Kali
reticulata), Yashti Musli (Curculigo
(Glycyrrhiza glabra), orchioides), Koch
Kumkuma (Crocus Beej (Mucuna
sativus), Kamala pruriens)
(Nelumbo nucifera), Maharishi Ashwagandha Ashwagandha Semen disorders,
Utpala (Nymphaea Ayurveda Churna (Withania Oligospermia,
stellata), somnifera) Premature
Sukshmaila ejaculation,
(Elettaria Prameha.
cardamomum) Amar Sahi Veerya Gokshura (Tribulus Erectile
Ashwagandharishta Ashwagandha Depression, Healthcare Paushtik churan terrestris), dysfunction
(Withania Anxiety and Ashvagandha
somnifera), Mushali Stress (Withania
(Chlorophytum somnifera), Tal
borivilianum), Makhana (Euryale
Manjishtha (Rubia ferox), Koch Beej
Cordifolia), Haritaki (Mucuna pruriens)
(Terminalia Protex Powder Ashwagandha Anemia,
chebula), Nisha (Withania weakness, fatigue
(Curcuma longa) somnifera),
Dashmularishta Dashmula, Post-delivery Shatavari
Ashwagandha weakness. (Asparagus
(Withania racemosus), Mukta
somnifera), Sukhti Pisti, Loh
Manjishta (Rubia Bhasma, Soya, Milk
Cordifolia) Draksha Trankula Capsules Brahmi (Bacopa Hyper tension
(Vitis vinifera) and Tonorex Syrup monnieri),
Cureveda Debility Elixir Dashmula, Paralysis Ashvagandha
(Withania somnifera),
somnifera), Shankhapushpi
Shatavari (Convolvulus
(Asparagus pluricaulis)
racemosus) Avestia Ashwagandha Root Ashvagandha Stress relief
Joyful Joints Ashwagandha Joint support and Pharma Extract Capsule (Withania
(Withania flexibility somnifera)
somnifera), Salai Morpheme Ashwagandha Stress relief
guggul (Boswellia Remedies Capsule
12

Ashvagandha Jatamansi
(Withania (Nardostachys
somnifera) jatamansi),
Green Ashvagandha Weight Mandukparni
Coffee+ Capsules (Withania management (Centella asiatica),
somnifera), Malabar Shankpushpi
tamarind (Garcinia (Evolvulus
cambogia), Green alsinoides),
tea, Green coffee Yastimadhu
beans (Glycyrrhiza glabra),
Hair Vital Glow Bhringraj (Eclipta Healthy Hair Ashwagandha
alba), Amla (Withania
(Emblica officinalis), somnifera), Vacha
Shikakai (Acacia (Acorus calamus)
concinna), Brahmi Stress Suppress Ashwagandha Stress
(Bacopa monnieri), Capsule (Withania management
Ashwagandha somnifera), Tagara
(Withania (Valeriana
somnifera), wallichii), Brahmi
Shankhpushpi (Bacopa monnieri),
(Convolvulus Jatamansi
pluricaulis) (Nardostachys
Kohinoor Gold Plus Ashwagandha Strength, Power, jatamansi)
(Withania and Stamina. MemoCare Plus Brahmi (Bacopa Mental alertness
somnifera), Safed monnieri),
Musli (Asparagus Ashwagandha
adscendens), Shilajit (Withania
(asphaltum), somnifera), Vacha
Gokshura (Tribulus (Acorus calamus),
terrestris), Licorice
Kapikachhu (Glycyrrhiza glabra),
(Mucuna pruriens), Indian Sandalwood
Vidarikand (Santalum album),
(Pueraria tuberosa), Shankhpushpi
Akarkara (Convolvulus
(Anacyclus pluricaulis)
pyrethrum), Dr. William Ashwagandha Ashwagandha General
Jatiphala (nutmeg) Schwabe mother tincture and (Withania weakness,
and Shatavari tonic somnifera) sterility,
(Asparagus leucorrhoea,
racemosus). menstrual
Arthritis Support Shallaki (Boswellia Joint and muscle disorder,
serrata), Guggul support hemorrhage in
(Commiphora women
mukul), Nirgundi SBL Withania somnifera Ashwagandha Depression,
(Vitex negundo), Mother Tincture (Withania arthritis and
Guduchi (Tinospora somnifera) rheumatic pains
cordifolia), Ginger Dr. Reckeweg Ashwagandha Ashwagandha Stress
(Zingiber officinale), Mother Tincture (Withania management
Ashwagandha somnifera)
(Withania ADEL Ashwagandha Ashwagandha Reducing stress,
somnifera) Mother Tincture (Withania strain and fatigue.
Arthcare Pain Relief Camphor Body and joint somnifera)
Oil (Cinnamomum pain Livestamin Ashwagandha Ashwagandha Fertility, stress,
camphora), Capsules (Withania muscle growth
Peppermint somnifera) with 7% etc.
(Mentha piperita), withanolides
Shuddha guggulu Allens Drug Ashwagandha Tonic Ashwagandha 6X, Systematic and
(Commiphora Avena sativa 3X, metabolic
mukul), Garlic Damiana 12, Salix corrective,
(Allium sativum), Nig. 6X, Nat. Phos. increases.
Ajwain 12X, Calc. Phos. Appetite,
(Trachyspermum 12X digestion and
ammi), Nirgundi assimilation
(Vitex negundo), Zandu Vigorex SF Tablets Kauncha (Mucuna Non – hormonal
Rasna (Pluchea pruriens), restorative tonic
lanceolata), Ashwagandha and vitalizer
(Withania somnifera), Shilajit,
somnifera) Chandroday
Mind Plus Capsules Jyotishmati Memory, focus (Suvarna ghatit
(Celastrus and clarity` Makardhwaj,
paniculatus), Musali [white]
Brahmi (Bacopa (Chlorophytum
monnieri) Extract arundinaceum),
(100 mg), Guduchi (Tinospora
13

cordifolia), Marica (Piper

Gokshurak (Tribulus nigrum), Sunthi
terrestris), Amalak (Zingiber officinale),
(Emblica Jatiphala (Myristica
officianalis), Abhrak fragrans), Tvak
Bhasma, (Cinnamomum
Vishtinduk zeylanicum),
(Strychnos nux Tejapatra
vomica), Praval (Cinnamomum
Bhasma, Manikya tamala), Pippali
Bhasma, Kanta (Piper longum),
Loha Bhasma, Goksura (Tribulus
Manikya Rasa, terrestris),
Jatiphala (Myristica Nagakesara (Mesua
fragrans) ferrea), Musali
Brento Forte Tablets Shankhpushpi General mental (Chlorophytum
(Convolvulus debility, Mental borivilianum),
microphyllus), retardation, Vidanga (Embelia
Bramhi (Bacopa Senile dementia, ribes) Atmagupta
monnieri), age-related (Mucuna pruriens),
Mandukparni memory Bala (Sida
(Centella asiatica), impairment cordifolia), Vamsa
Ashwagandha (Vanshlochan),
(Withania Godanti bhasma,
somnifera), Mukta Sukti pisti,
Jyotishmati Abhraka bhasma,
(Celastrus Yasada bhasma,
paniculata) Ghrta, Iksu
Brento Tablets and Shankhpushpi General mental (Sarkara)
Syrup (Convolvulus debility, cognitive Zandu Diabrishta- Amalaki (Emblica Sugar level
microhyllus), dysfunction, 21 Tonic officinalis), Methi management
Brahmi (Bacopa decreased (Trigonella foenum-
monnieri), vigilance, lack of graecum),
Ashwagandha concentration, Aswagandha
(Withania loss of memory (Withania
somnifera), somnifera), Tvak
Yashtimadhu (Cinnamomum
(Glycyrrhiza glabra), zeylanicum),
Kath (Saussurea Haridra (Curcuma
lappa), Vacha longa), Karavallaka
(Acorus calamus), (Momordica
Sarpagandha charantia), Guduchi
(Rauwolfia (Tinospora
serpentina), cordifolia), Jambu
Jatiphala (Myristica (Syzygium cuminii),
fragrans), Nimba (Azadirachta
Chandroday indica), Mesasrngi
(Suvarna ghatit (Gymnema
Makradhwaj) sylvestre),
Alpitone syrup Ashwagandha Anorexia, Raktapunarnava
(Withania nutritional (Boerhaavia
somnifera), Bala deficiencies, diffusa), Kalmegh
(Sida cordifolia), general debility, (Andrographis
Shatavari fatigue, stress, paniculata),
(Asparagus convalescence Goksura (Tribulus
racemosus), Chitrak terrestris),
(Plumbago Tvakapatra
zeylanica), Gokshur (Cinnamomum
(Tribulus terrestris), tamala), Lavanga
5 Rasna (Pluchea (Syzygium
lanceolata), aromaticum), Sunthi
Draksha (Vitis (Zingiber officinale),
vinifera), Amruta Marica (Piper
(Tinospora nigrum), Yavani
cordifolia), Sunthi (Trachyspermum
(Zingiber officinale) ammi), Draksha
Kesari Jivan Amalaki (Emblica Health (Vitis vinifera),
officinalis), supplement Madhuka (Madhuca
Kunkuma (Saffron), indica), Dhataki
Asvagandha (Woodfordia
(Withania fruticose),
somnifera), Kanyasara
Suksmaila (Elettaria Concentrate (Aloe
cardamomum, barbadensis)
Lavanga (Syzygium AyurSip Stress Aswagandha Physical and
aromaticum), Control (Withania mental stress
14
Table 2 (continued ) depicts several reports both in vivo and in vitro elucidating the bio
Manufacturer Product Ingredients Used as/against activities of the various parts of this plant. Table 5 represents the diverse
pharmacological properties of WS extracts and their active constituents
somnifera), Brahmi
(Bacopa monnieri),
alone or in combinations.
Yasti (Glycyrrhiza
glabra), Vaca 1.5. Anti-cancer and apoptotic activities
(Bauhinia forficate),
Saunf (Foeniculum
Both chemotherapy and radiation therapy cause severe side effects
vulgare), Amalaki
(Emblica officinalis), such as vomiting, nausea, alopecia, pulmonary fibrosis, mucosal ulcer
Vidarikand ation, hepatic and cardiac toxicity, etc. Drugs that can eliminate these
(Pueraria tuberosa), side effects can be a boon for cancer therapy. Aqueous root extracts of
Jaiphal (Myristica
WS (0.05–0.4 mg/ml) can modulate peripheral blood mononuclear cell
fragrans),
Mandukparni
(PBMC) and leukemic THP-1 cell viability, increase oxidant scavenging
(Centella asiatica), and caspase (8, 9, 3/7) activities, at the same time decrease tumor ne
Lavanga (Syzygium crosis factor-alpha (TNF-α), interleukin (IL)− 10 and Glutathione (GSH)
aromaticum), levels [238]. Withanolide D reportedly decreases anti-apoptotic genes
Arjuna (Terminalia
(TERT, Bcl-2, Puma) in the Leukemic Murine mouse model [114]. Novel
arjuna)
protein fraction isolated from WS roots could promote
mitochondria-mediated apoptosis in triple-negative breast cancer cells
1.4. Pharmacological properties of plant extracts and phytochemicals (MDA-MB-231) at an IC50 dose of 92 µg/ml by the virtue of excessive
ROS production, dysregulation of Bax/Bcl-2 expression, and simulta
Usage of WS has been authenticated after a large number of pre neous disruption of mitochondrial membrane potential (ΔΨm). Cas
clinical trials and pharmacological investigations. The following section pase3 activation along with G2/M cell cycle arrest and cleavage of
Fig. 2. Different classes of phytochemicals present in Withania somnifera.
15
Fig. 3. Chemical structures of phytochemicals from Withania somnifera (from www.ChemSpider.com).
very promising anti-cancer activities in both in vitro and in vivo con

Table 3
ditions, still no approved drug candidates are available till now. Per
Major phytochemicals present in Withania somnifera (based on the degree of
forming clinical trials with WS phytochemicals/ formulations is the need
occurrence).
of the hour to find new anti-cancer drugs.
Sl. No. Compounds Formula Pubchem CID Mol. Wt.
1. Withanolide C28H38O6 53477765 470.6 1.6. Anti-inflammatory activity

2. Withanolide A C28H38O6 11294368 470.6
3. Withanolide D C28H38O6 161671 470.6
WS has been known to deliver remarkable anti-inflammatory activ
4. Withanolide E C28H38O7 301751 486.6
5. Withanolide F C28H38O6 44562999 470.6 ities in various disease models. Rectal gel application of WS root extracts
6. Withanolide L C28H38O5 179575 452.6 (500 µg/ml and 1000 mg/kg b.w.) were documented to exhibit muco-
7. Withanone C28H38O6 21679027 470.6 restorative and anti-inflammatory activities by reducing neutrophil
8. Quercetin C15H10O7 5280343 302.23 infiltration, necrosis, and edema in trinitrobenzene sulfonic acid
9. Kaempferol C15H10O6 5280863 286.24
(TNBS)-induced inflammatory bowel disease [265]. Antioxidative
properties of the extract (NO scavenging, H2O2 scavenging, lipid per
nuclear lamin proteins were also reported [77]. Moreover, the crude oxidation inhibition) are comparable with that of ascorbic acid and
water extract (0.5%) of WS altered the signaling pathway involving curcumin. Oral administration of WS root extract powder (500 and
pro-apoptotic and tumor-promoting proteins that helped to suppress 1000 mg/kg body weight) was found to be effective against systemic
tumor growth. Thus exhibiting a pleiotropic anti-glioma phenomenon in lupus erythematosus like symptoms (nephritis, proteinuria, autoanti
both in vitro and in vivo systems by inhibiting proteins involved in cell body production), reducing pro-inflammatory cytokines (IL-6), Tumor
survival [(Nuclear factor-kappa B (NFκB), Phospho-Akt (p-Akt), B-cell necrosis factor (TNF)-α, reactive oxygen species (ROS) and nitric oxide
lymphoma-extra large (Bcl-xl) and Heat shock protein 70 (HSP70)], (NO) in female Balb/c mouse models [212,213]. Withaferin-A extracted
proliferation (cyclin D1), angiogenesis [Vascular endothelial growth from WS (1.882 µg per mouse) could inhibit phorbol-12-myristate
factor (VEGF)], invasion [Matrix metallopeptidases (MMPs), Neural cell 13-acetate (PMA)-induced [Endothelial protein C receptor (EPCR)]
adhesion molecule (NCAM) and polysialylated neuronal cell adhesion shedding by the inhibition of TNF-α and Interleukine (IL)− 1b in Human
molecule (PSA-NCAM)] of glioma cells [153]. The methanolic root Umbilical Vein Endothelial Cell lines (HUVECs) by inactivating tumor
extract also promotes attenuation of proliferative, metastatic, and necrosis factor-α converting enzyme (TACE). Additionally, withaferin-A
angiogenic signals mediated by interleukin-8 and cyclooxygenase-2 attenuated phosphorylation of p38 by stimulating Extracellular
expression and cell cycle arrest in the G2/M phase in prostate cancer signal-regulated kinase (ERK)− 1/2, PMA, and c-Jun N-terminal kinase
PC3 cells with an IC50 dose of 10 µg/ml [36]. Stable isotope labeling by (JNK) [164]. Withaferin-A protected the integrity of the vascular barrier
amino acids in cell culture (SILAC) based proteomic analysis of with of HUVECs in mice, which was induced by High Mobility Group Box 1
aferin A treated prostate cancer cells, (22Rv1, DU-145, and LNCaP) (HMGB1) by inhibiting the expression of Calmodulin (CAMs), inflicting
reveal upregulation of proteins involved in stress response [179]. hyperpermeability, migration, and adhesion of leukocytes, production
Ethanolic extract of WS is cytotoxic (99.7 µg/ml), an inducer of of TNF-α, IL-6 and activation of nuclear factor of j-light polypeptide gene
apoptosis, and an inhibitor of cell migration and angiogenesis [271]. enhancer in B-cells (NFκB) [186]. Withaferin-A from the extracts (2 µM
Withaferin-A derivative, 2,3-dihydro-3β-methoxy withaferin-A has been in vitro) prevented Iκb kinase activation and phosphorylation, which
found to increase the circadian rhythm in Sarcoma 180 cancer cells in a further blocked the translocation of NFκB, binding of NFκB and DNA,
dose-dependent way [371]. Though several formulations of WS showed and transcription in murine fibrosarcoma L929sA cells [148]. Addi
tionally, it inhibited TNFα induced expression of ICAM-1 and VCAM-1
16
Table 4 immunostimulatory preparations or Rasayanas that are popularly used

Organ-specific distribution of phytochemicals in Withania somnifera. in the indigenous system of medicine. Cytoprotection against lead
Plant part Phytochemicals References toxicity (25–400 µM) in C6 cells was found by pretreatment with 0.1%
WS extract [174]. Moreover, a 20 mg/dose/animal of 70% methanolic
Roots and Withaferin-A [88]
leaves Withanone root extract increased the WBC count, circulating antibody titer and
Withastramonolide antibody-forming cells, stimulation of the weight of spleen and thymus,
27-hydroxywithanone and phagocytosis of macrophages. Besides, it could further inhibit the
Physagulin Delayed type hypersensitivity [80]. Dose-dependent immunomodula
Withanolide-A
Fruits Fatty acids [44]
tory activity of WS (20, 50, 100 mg/Kg) was seen in Erhlich ascites
Sterols tumor (EAT) bearing mice [211].
Tocopherols
Hydrocarbons (squalene) 1.8. Anti-diabetic activity
Leaves 5b,6b-epoxy-4b-hydroxy-1-oxo-witha-2,16,24- [216]
trienolide
6a,7a-epoxy-3b,5a,17a-trihydroxy-1-oxo-witha-24- Many ancient polyherbal formulations such as Dianix and Trasina of
enolide Indian medicine showed potent antidiabetic activity in humans [50,51,
27-acetoxy-3-oxo-witha-1,4,24-trienolide 111,236]. Patients administered with root powder of WS (3 g/day to
5a,17a-dihydroxy-6a,7a-epoxy-1-oxo-3b-O- [372] each human subject for 30 days) were observed to have a stabilized
sulfatewitha-24-enolide
17-hydroxy withaferin A
blood glucose concentration that could be compared to the effect of an
6a-Chloro-5b,17a-dihydroxywithaferin A oral hypoglycemic drug Daonil [24] with no adverse effects. In addition
6a-chloro-5b-hydroxywithaferin A to that, WS treatment could significantly improve the insulin sensitivity
2,3-dihydrowithaferin A [394] index in non-insulin-dependent diabetes mellitus (NIDDM) rats [27].
3-methoxy-2,3-dihydrowithaferin A
Aqueous extracts of WS (200, 400 mg/kg for 5 days) were found to be
withanoside IV
withanoside X effective in decreasing blood glucose, HbA1c, and insulin levels. Based
viscosalactone B [266] on these reports, WS root and leaf extracts appear to be beneficial in
27-deoxywithaferin A [43] improving glucose uptake in adipocytes and skeletal myotubes. How
27- hydroxywithanolide B [26] ever, the leaf extract was found to demonstrate a more pronounced ef
Pubesenolide [301]
Jaborosalactone D [384]
fect than that of the root [116]. Root and leaf extracts (200 and
4b,27-dihydroxy-L-oxo-22R-witha-2,5,24-trienolide [242] 400 mg/kg b.wt./day for 8 weeks) significantly normalized the glucose
2,3-didehydrosomnifericin [183] levels in urine, blood, tissue glycogen, and glucose-6-phosphatase levels
6achloro-5b-hydroxywithaferin A [242] in alloxan-induced diabetic rats. In addition to that, attenuated im
(22R)- 5b-formyl-6b,27-dihydroxyl-1-oxo-4- [243]
provements of the enzymatic and nonenzymatic antioxidant defenses
norwith-24-enolide
Roots 16b-Acetoxy-6,7a-epoxy-5a–hydroxy-1- [217] were also documented [375,376]. Phenolics and flavonoids present in
oxowitha2,17(20),24-trienolide the extracts were supposed to be responsible for the anti-diabetic ac
5,7a-Epoxy-6a,20a-dihydroxy-1-oxowitha-2,24- tivity. In addition, withaferin-A from WS could block the inflammatory
dienolide responses caused due to cytokine-induced damage to the islets of
Ariel parts 3α-(uracil-1-yl)− 2,3-dihydrowithaferin A [395]
3β-(adenin-9-yl)− 2,3-dihydrowithaferin A
Langerhans in vitro after transplantation and it exhibited potential
2,3-dihydrowithaferin A-3β-O-sulfate anti-glycating activity [33,357].
3β-OButyl-2,3-dihydrowithaferin A
3β-(uracil1-yl)− 2,3-dihydrowithaferin A 1.9. Cardio-protective activity
WS is known to possess cardioprotective and cardiotropic properties

by inactivating AKT, ERK, and NFκB in U937 pulmonary epithelial cells
in animal models when administered at 30, 60, and 90 mg/kg/day as a
of humans resulting in loss of adhesion with A549 lung cancer cells
polyherbal combination containing 50 mg/capsule of WS tuber for 60
[244]. In addition to that, withaferin-A could block the NFκB activation
days (orally) [246,277]. Polyherbal formulations which contained WS
by specifically targeting cysteine 179 in the catalytic site of the inhibitor
(50, 75, and 100 mg/ml, in vitro) also provides cardio-protection
of nuclear factor kappa-B (IKK-b) [130]. In cellular models of cystic
(doxorubicin-induced) in animals ([220,367]) by activating a tran
fibrosis, withaferin-A (3 µM/ml in vitro) led to inhibition of IL-8 and
scription factor known as nuclear factor-erythroid-2(Nrf)− 2, which
NFκB in cellular models (HEK293) of cystic fibrosis [197]. WS extract
stimulates phase-II detoxification enzymes, thereby evading apoptosis in
(500 mg/kg/day) along with Ricinus communis extract (250 mg/kg/day)
an Nrf-2-dependent manner in HL-1 cardiomyocytes [295]. In addition
showed a reduction in tissue inflammation in methotrexate (3 mg/kg
to that, ginseng with WS in the 10:1 ratio improved haematopoiesis in
twice a week) induced arthritis in Wistar rats [135]. Body weight and
albino rats (Haffkine stain) [28]. Treatment with WS (50 mg/kg b.w. for
organ indices were restored along with a decrease in oxidative stress and
30 days) in wister rats significantly restored the balance between
arthritic score.
myocardial oxidant and antioxidant [31,119,222], anti-apoptotic and
pro-apoptotic effects, and further reduced histopathologic deterioration
1.7. Immunomodulatory activity of myocardium and triphosphate nick-end labeling (TUNEL) positivity
(apoptosis) in rat models [223]. Furthermore, standardized WS extracts
Ashwagandha extracts in Swiss albino mice caused suppression of (1.5% withanolides) at a dose of 300 mg/kg prevented cardiotoxicity
cyclophosphamide-induced potentiation of Delayed type hypersensi induced by doxorubicin and restored several biochemical changes like
tivity (DTH) reaction, a significant increase in white blood cell counts, reduction in elevated malondialdehyde level, catalase, superoxide dis
platelet counts, and Immunoglobulin E-mediated anaphylaxis as a mutase activity, calcium content, Bcl-2 protein levels [127].
reduction of ovalbumin-induced edema [6]. Extracts of WS were found
to be effective in animals treated with cyclophosphamide to reduce 1.10. Antimicrobial activity
DTH. Activity against cyclophosphamide-induced myelosuppression
and immunosuppression was also observed with a significant increase in WS has been used for ages against infections even without proper
platelet, WBC counts, and hemagglutinating, hemolytic antibody re scientific explanation. Methanolic leaf extract (2 mg/ml,100 µl per well
sponses. Similar results were also reported for herbal in agar well diffusion assay) of the plant has shown remarkable
17
Table 5
Pharmacological properties of Withania somnifera extracts and active constituents.
Pharmacological Extract/ Experiment (dose or Type of assay, animal Allied or related assays Underlying References
activity fraction/plant concentration) models or cell line conducted mechanisms/observed
parts parameters
Anti-cancer and Ethanol extract of (0.2–0.4 mg/ml) in vitro; PBMC, THP-1 Cell viability assay Modulate PBMC viability [238]
apoptotic activities roots decreased PBMC viability
(0.05–0.4 mg/ml) Quantification of cytokines Modulate THP-1 viability
decreased THP-1 viability
(0.05–0.4 mg/ml) Oxidant The GSH assay Oxidant scavenging
scavenging activity was activity was increased
increased Caspase and ATP assays TNF-α and IL-10 levels
were decreased
GSH levels were decreased
caspase (− 8, − 9, − 3/7)
activities were increased
Withaferin A EC50 in the range of in vitro and in vivo; Cell proliferation and Withaferin A targets the
1.92–3.6 mM against DLBCL, MINO, Ramos survival assays functional activity of the
Diffuse large B-cell and Balb/c mice Hsp90 chaperone complex
lymphoma (DLBCL) resulting in degradation of
EC50 (1.92–3.6 mM) Cell apoptosis analysis client proteins that include
against Mammary critical pro-survival
intraepithelial neoplasia kinases, cell cycle
outgrowths MINO regulators, pro-survival
EC50 of 0.45 mM against Cell cycle analysis factors, and B cell receptor
Ramos NF-kb nuclear translocation signaling components
assay
In-vivo tumor inhibition
study
Withaferin A 0.99 μM against A549 in vitro; A549, CL141, Cytotoxicity and Withaferin A is an effective [133]
H441, CL97, H1975, Sulforhodamine B assay agent for inhibiting Cancer
0.46 μM against CL141 CL152, H1299 ROS detection in living cells stem cell (CSC) growth by
0.57 μM against H441 In Situ proximity ligation affecting multiple targets
assay of the mammalian target of
1.49 μM against CL97 Side population assay rapamycin/ Signal
0.35 μM against H1975 Spheroid formation assay transducer and activator of
0.50 μM against CL152 Western blot analysis transcription 3 (mTOR/
0.60 μM against H1299 Combined drug analysis STAT3) pathway in Non-
Small Cell Lung Cancer
Root novel IC50 92 μg/ml against in vitro; MDA-MB-231, Mitochondrial membrane Withania somnifera [77]
protein fraction MDA-MB-231 MCF-7, T47D, MBA- potential loss analysis protein fraction (WSPF)
MB-435, A549, HCT- promotes mitochondria-
116 MCF-10A mediated apoptosis in
MDA-MB-231 cells by
dysregulation of Bax/Bcl-2
expression and
simultaneous disruption of
ΔΨm
Expression analysis of WSPF induced cell toxicity
apoptosis-associated and reduction in cell
proteins viability through G2/M
phase cell cycle arrest
Flow cytometry WSPF induced ΔΨm loss in
cancer cells was found to
be associated with a dose-
dependent generation of
intracellular ROS
Withaferin A 5 mg/kg in vivo; PC-3 Cell viability and apoptotic PAR4-dependent apoptosis [359]
Xenograft in nude assays
mice Western blot analysis
Reverse transcription-PCR
analysis
Transient transfection and
luciferase assays
Xenograft studies
Immunocytochemical
analysis
Fluorometry for caspase-3
activation
Withaferin A 4–8 mg/kg in vivo; PC-3 Nucleophilic susceptibility Inhibition of proteasome [400]
Xenograft in nude analysis system
mice Caspase-3 (or − 7) activity
assay
Human prostate tumor
xenograft experiments
18
parts parameters
Proteasome inhibition and

apoptosis assays using tumor
tissue samples
Withaferin A 4 mg/kg in vivo; MDA-MB 231 Cell culture and cell viability FOXO3a and Bim [335]
Xenograft in nude assay dependent apoptosis
mice Determination of apoptosis
Immunoblotting
RNA interference
Xenograft studies
H and E staining and
immunohistochemical
analysis of PCNA expression
Detection of apoptotic
bodies by terminal
deoxynucleotidyl
transferase-mediated dUTP
nick-end labeling
Withaferin A 4 mg/kg in vivo; MDA-MB 231 MTS assay Activation of ERK/RSK and [401]
Xenograft in nude Apoptosis study CHOP/Elk1, upregulation
mice Withaferin A-biotin pull- of DR5
down assay
ATP-sepharose binding
assay
Co-immunoprecipitation
and western blotting assay
Real-time PCR assay
Pancreatic tumor xenograft
Withaferin A 3.6 mg/kg in vivo; Panc-1 Western blot analysis HSP90 inhibition and [302]
Xenograft in nude Xenograft tumor model and degradation of Akt and
mice WA administration Cdk4
Calcitonin enzyme-linked
immunosorbent assay
(ELISA) for serum evaluation
Withaferin A 8 mg/kg in vivo; DRO81–1 Cell proliferation assay Inhibition of RET proto- [232]
Xenograft in nude oncogene phosphorylation
mice and activation
CaSki xenograft in Annexin V/propidium Downregulation of HPV16
nude mice iodide assay for apoptosis E6 and E7, increasing p53
Cell cycle analysis by flow protein levels
cytometry
Protein extraction and
western blot analysis
Coimmunoprecipitation
Messenger RNA stability and
quantitative real-time
polymerase chain reaction
Withaferin A 4 mg/kg 4T1 spontaneous Cytotoxicity assay Phosphorylation and [365]
mouse mammary In-vitro wound migration disassembly of Vimentin
carcinoma model assay
Matrigel invasion assay
Synthesis of Withaferin A
analogs
Western blotting
Confocal imaging
Real-time PCR
Withaferin A WA 2 mg/kg, Doxorubicin A2780 xenograft in Cell proliferation assay Induction of ROS and [303]
1 mg/kg nude mice Autophagy
8 mg/kg, 12 mg/kg 92.1 xenograft in SCID Colony formation assay Inhibition of AKT,
mice Cell migration assay inhibition of c-MET
Assessment of apoptosis by activation
annexin V/propidium iodide
Withaferin A 100 μg MMTV-neu mice Mammosphere formation Suppression of glycolysis [161]
assay and Tricarboxylic acid
Flow cytometric analysis of (TCA) cycle. Inhibition of
aldehyde dehydrogenase 1 self-renewal of cancer stem
(ALDH1) activity and cells
CD44high/CD24low/
epithelial-specific antigen-
positive (ESA+) population
Real-time quantitative PCR,
RT2 profiler PCR array,
Withaferin A WA 2 mg/kg, Cisplatin A2780 xenograft in Immunohistochemical [124]
6 mg/kg nude mice analysis and Terminal
19
parts parameters
Deoxynucleotidyl Inhibition of Notch-1,

Transferase-Mediated downregulation of cancer
Deoxyuridine-5′ - TUNEL stem cells
assay
Two-Dimensional Metabolomics
Gel
Electrophoresis
and Mass
Spectrometry
(MS)
Withaferin A 2 mg/kg HCT116 xenograft in Cell viability assay Inhibition of STAT3 [72]
nude mice Wound-healing assay phosphorylation and
Signal transducer and activation
activator of transcription 3
(STAT3) transcription factor
assay
Tumor xenograft models
Withaferin A 20 μg TPA skin cancer model Determination of Withaferin Suppression of AP-1 and, [405]
A in skin tissue samples by inhibition of transcription
HPLC of ACC1 gene
Antibody microarray
analysis
Western blot analysis
ACC1 siRNA transfections
RNA extraction and Real-
Time PCR
Withaferin A WA 3 mg/kg, Oxaliplatin Panc-1 xenografts in Cell viability assay Mitochondrial [187]
10 mg/kg nude mice Colony formation assay dysfunction, induction of
Apoptosis assay ROS, inactivation of PI3K/
Mitochondrial AKT pathway
transmembrane potential
assessment
Detection of intracellular
reactive oxygen species
Protein isolation and
Immunofluorescence
Immunohistochemistry and
TUNEL analysis
MDA assay
Withaferin A WA 2 mg/kg, DOXIL A270 intraperitoneal Cell migration boyden Targeting cancer stem cells [149]
2 mg/kg tumors in nude mice chamber assays
Protein isolation and
Withaferin A 10 mg/kg 4 T1 spontaneous/ Western blot analysis Inhibition of Ras-Mnk and [293]
orthotopic mouse Cap (7 m-GTP) pull-down PI3-AKT-mTOR, inhibition
mammary carcinoma assay of eIF4E phosphorylation
model Polysome analysis and protein translation,
Immunocytochemistry downregulation of c-FLIP
Matrigel invasion assay
Cell scatter assay
Invadopodia fluorescent
gelatin degradation assay
Gelatin zymography
Flow cytometric cell cycle
analysis
In-vivo anticancer activity of
3-AWA against Ehrlich
ascites carcinoma (EAC)
In vivo anti-metastasis and
anti-tumor efficacy studies
Withaferin A 12 mg/kg A20 allograft in Balb/c Cell proliferation and HSP90 inhibition [210]
mice survival assays
Cell apoptosis analysis
NF-κb nuclear translocation
assay
Withaferin A WA 10 mg/kg, DBZ Notch1-mutant T-ALL Microarray gene expression eIF2A-dependent [304]
10 mg/kg xenograft in NRG mice profile analysis translation inhibition
Leaf extract in 140 mg/kg/day C6 glioma cell line Immunostaining Alteration of the signaling [153]
distilled water pathway involving
proapoptotic and tumor-
promoting proteins to
20
parts parameters
suppress the tumor growth

of glioma cells
Wistar strain male Cell cycle analysis Exhibition of a pleiotropic
albino rats Annexin–fluorescein anti-glioma phenomenon
isothiocyanate apoptosis by inhibiting proteins
assay involved in survival (NFκB,
Matrix metalloproteinase p-Akt, Bcl-xl, HSP70),
zymography proliferation (cyclin D1),
Western blot analysis angiogenesis (VEGF), or
RNA isolation and invasion (MMPs, NCAM,
semiquantitative RT-PCR PSA-NCAM) of glioma cells
Plasmid transfection
Crude water IC50–24 hr is 350 μg/ml in vivo; A375 cells Fluorescence microscopic [125]
extract observations
IC50–48hr is 250 μg/m DNA fragmentation study
IC50–200 μg/ml for 72 hr Electrospray ionization mass
spectrometry (ESI-MS)
Methanolic root IC50–10 µg/ml in vitro; PC3 MTT assay Attenuation of [36]
extract Lactate dehydrogenase proliferative, metastatic
(LDH) assay and angiogenic signals
Cell morphology assessment mediated by IL-8 and
using phase-contrast Cyclooxygenase-2
imaging expression and by
Quantitative Real arresting cell cycle in G2/
Time-PCR studies M phase
Antioxidant activity Water extract 5.0 mg/ml HepG2cells Cytotoxicity analysis by Antioxidant activities [13]
MTT assay and examination increased; they were
of cell viability compared with the control
untreated cells
Assessment of antioxidant TNF-α level significantly
activity decreased
Assessment of Fas-ligand levels and
concentrations of FAS-ligand caspase-3, − 8, and − 9
and TNF-α activities significantly
increased
Assessment of caspase-3, Binding between cyclin D1
caspase-8, and caspase-9 and Ashwagandha
activity
Molecular modeling and Significant accumulation
docking study of ASH-WX-treated HepG2
cells in the G0/G1 and G2/
M phases
Immunomodulatory Coded WS2 at doses of 150 and Swiss albino mice IgE-mediated anaphylaxis cyclophosphamide- [6]
activity Ashwagandha 300 mg/kg (Haffkine strain) study induced potentiation of
extracts, labeled DTH reaction was
as WST and WS2 suppressed
WST at a dose of 1000 mg/ Delayed type A significant increase in
kg and WS2 at a dose of hypersensitivity study white blood cell counts and
300 mg/kg platelet counts
CP+WST - 20 + 1000 mg/ IgE-mediated anaphylaxis
kg as reduction of ovalbumin-
CP+WS2–20 + 300 mg/ induced paw edema
kg
70% methanolic 20 mg/dose/animal Balb/c mice Mantoux test Increases the circulating [80]
root extract antibody titer and
antibody-forming cells
Stimulation of the weight
of spleen and thymus
Stimulation of the
phagocytosis of
macrophages
Inhibition of the delayed-
type hypersensitivity
Anti-inflammatory Ethanolic extract 76.4 mg/kg Inbred albino male Cotton-pellet granuloma
activity of Ariel plant Wistar rats assay
parts
Root extract 500 lg/ml and 1000 mg/ TNBS-induced Anti-lipid peroxidation Mucorestorative and anti- [265]
kg b.wt. (rectal route) inflammatory bowel activity assay inflammatory, neutrophil
disease in rats NO scavenging activity infiltration, resolved
Hydrogen peroxide edema and necrosis
scavenging activity
Evaluation of the reducing
power
21
parts parameters
Microscopic assessment of
colitis
500 and 1000 mg/kg b.wt. Mouse model of lupus NO assay Inhibited proteinuria, TNF- [212]
(orally) IL-6 and tumor necrosis α, nephritis, ROS and NO
factor-α
ROS in serum and/or ascitic
fluid
Withaferin-A 1.882 μg per mouse (I.V.) Human umbilical vein – Inhibited TNF-α and IL-1b [164]
endothelial cells
2 lM In-vitro Murine fibrosarcoma Biological IL-6 assay Attenuated p38, ERK-1/2, [148]
Reporter gene analysis C jun JNK
Electrophoretic Mobility
Shift Assay (EMSA)
Zymosan-induced inflamed
paw model
Determination of systemic
IL-6 levels in blood
In-vitro kinase Assay
3 lM/ml In-vitro Cellular models of Titer Glo luminescent cell Inhibited IL-8 and Ijb [197]
Cystic Fibrosis viability assay phosphorylation and
inflammation (KKLEB degradation by blocking
cells) NFj-b translocation
Activity against post- Water–ethanol 500 mg/kg Male Wistar rats Induction of SPS model Antagonizes hippocampal [18]
traumatic stress (7:3) root extract oxidative stress
disorder (PTSD) The radial arm water maze Prevents changes of major
(RAWM) procedure oxidative stress
Animal’s decapitation and biomarkers
brain dissection
Biochemical analysis
Ultra high-performance
liquid chromatography
(UHPLC) analysis
Anxiolyticand Aqueous 20 and 50 mg/kg Inbred Charles Foster Elevated plus-maze test GABA-mimetic effect [52]
antidepressant concentrate of strain male rats Social interaction test
activities WSroots Rotarod test
Novelty-suppressed feeding
latency test
Rat brain tribulin activity
Forced swim-induced
’behavioral despair’ test
’Learned helplessness’ test
Adaptogenic activity Aqueous 25 and 50 mg/kg Adult male Wistar Gastric ulceration CS-induced perturbation of [54]
ethanolic root strain rats glucose homeostasis
extract Swim stress-induced Inhibition of the
‘‘behavioral despair" significant increase in
plasma corticosterone
levels induced by CS
Learned ‘‘helplessness’’ test Attenuation of acute stress-
Transfer latency on the induced gastric ulcerations
elevated plus-maze in rats by affecting a
Passive avoidance test reduction in acid – pepsin
Sexual behavior levels and an increase in
Immune function tests gastric mucin activity
Biochemical investigations
Hypoglycemic Methanolic root 50 mg / ml RIN-5 F cells Membrane leakage test Hypoglycemic properties [116]
activity extracts L6 (CRL-1458) skeletal Osmotic potential detection
myoblasts
3T3-LI (CL-173) HPLC
fibroblasts GC–MS
Root extract 3 g/day human subjects Human subject – Stabilized blood glucose [24,27]
(orally) levels
Aqueous extract 200 and 400 mg/kg b.wt./ Non-insulin- Determination of blood Blocked the rise in [375]
day for 5 weeks (orally) dependent diabetes sugar, urine sugar, HbA1C, homeostasis model
mellitus in rats Hb, and liver glycogen assessment of insulin
Determination of tissues resistance and improved
lipids like TG, TC and PL and insulin sensitivity index
serum lipid profile
Determination of tissue and
serum protein
Determination of assay of
serum enzymes like ALT,
AST, ACP and ALP, and liver
G6P
Urine sugar detection [376]
22
parts parameters
Root and leaf 200 mg/kg b.wt. for 8 Alloxan-induced Fasting blood sugar Normalized the blood
extract weeks(orally) diabetes mellitus in detection glucose, urine sugar, tissue
rats Liver glycogen estimation glycogen levels, and
Vitamin C and E estimation glucose-6-phosphatase
SOD activity
Lipid peroxidase (LPO)
activity
CAT, GPx, and GST activity
Cardioprotective hydro-alcoholic 50 mg/kg Wistar albino male rats Effect of Vitamin E on Restoration of LDH and [222]
activity root extract biochemical parameters creatine phosphokinase
activity
Ventricular function Produced myocardial
assessments adaptive changes
(augmentation of
endogenous antioxidants)
Histopathological Restoration of the
assessment of injury antioxidant status of the
myocardium
Biochemical assessment of Protective effect on the
injury myocardium
Male wistar rats aged Protein carbonyl levels were Decrease in GSH activity [356]
9–10 weeks determination and redox ratio (GSH/
GSSG)
ROS assay Lowering of protein
carbonyls and attenuate
ROS generation in the
ipsilateral cortex
GSH, glutathione disulfide Increased SOD, catalase
(GSSG), and redox ratio
determination
High-resolution clear-native The enzymatic activities of
polyacrylamide gel the mitochondrial
electrophoresis (hrCN- complexes-I, II, IV, and
PAGE) and in-gel F1F0 ATPase were found to
histochemical staining be significantly reduced
24 h after reperfusion
injury
Mitochondrial swelling and Reduction in the activity of
membrane potential the cytosolic caspases and
determination reversal of the expression
of Bcl-2 and Bax proteins
Transmission electron Decrease in the swelling
microscopy and restoration of the
Caspase-3 and caspase-9 mitochondrial membrane
activity determination potential and structural
Western blotting integrity
Y-maze test
Mitochondria respiratory
chain enzymes
determination
Whole extract 30, 60 and 90 mg/kg/day Myocardial infarction – Cardiotropic and [246,277]
for 60 days (orally) in rats cardioprotective
50, 75 and 100 mg/ml In- Coronary artery Biochemical studies Activated Nrf2, abrogated [223]
vitro occlusion in rats Determination of the Infarct apoptosis in a Nrf2-
Size dependent manner, and
Ultrastructural Studies by stimulated phase II
transmission electron detoxification enzymes
microscope
Determination of myocardial
apoptosis
50 mg/kg b.wt. for 30 Mice model – Anti-apoptotic/pro- [31]
days (orally) apoptotic effects, and
reduced TUNEL positivity,
and lessened
histopathologic
deterioration of
myocardium
Antibacterial activity Water and 20 mg/ml Female Balb/C mice Keller-Killani test Anti-bacterial activity [248]
alcoholic extract Mayer and Wagner’s reagent
of roots and test
leaves Thin-layer chromatography
Agar well diffusion assay
Methanolic leaf 2 mg/ml In-vitro Agar well diffusion assay Anti-bacterial activity [58]
extract
23
parts parameters
Methicillin- resistant
Staphylococcus aureus
and Enterococcus spp.
Methanolic 0.125–2 mg/ml In-vitro Oral infections by Agar well diffusion assay Inhibited acid production, [253]
extract Streptococcus sobrinus biofilm formation of oral
and Streptococcus bacteria, and acid
mutans tolerance
Withanolides (F5 60 and 15 lg/ml In-vitro Leishmania donovani Scanning electron Apoptosis, externalization [67]
and F6 fractions) microscopy of phosphatidylserine and
In-vitro antileishmanial cell cycle arrest, decreased
activity mitochondrial potential,
Flow cytometric analysis increased ROS, and
Detection of occurrence of DNA nicks,
phosphatidylserine
externalization
Measurement of ROS
Measurement of
mitochondrial membrane
potential
Glycoproteins 20 lg/ml In-vitro Aspergillus flavus, Assay for ribonuclease Inhibiting hyphal growth [115]
Fusarium verticilloides, activity and spore germination
F. oxysporum Assay for deoxyribonuclease
activity
Assay of protease activity
Hemolytic activity assay
Cytotoxicity assay
Stability assays
Protein estimation
Neuroprotective Chloroform- 20 μg/ml Human neuroblastoma In-vitro traumatic injury Enhancement of neuronal [310]
activity methanol root SH-SY5Y cells survival following an In-
extraction vitro injury that mimics TBI
and this involves Bax
downregulation at the
mRNA and protein levels
Immunocytochemistry Decrease in annexin V
LDH activity Decrease in Bax expression
RT-PCR
Western immunoblots
protein antibody arrays
Measurement of neurite
length
Dry leaf powder 35 mg/250 g BW of the Wistar albino young Blood glucose and Reduction of stress levels [203]
animal female rats corticosterone test maybe by targeting key
pathways such as
modulating BDNF
mediated synaptic
plasticity and cell survival
in discrete brain regions,
hence promoting overall
health and vitality
Rotarod test It might prevent memory
Narrow beam walk test loss and neuro-motor
Novel Object Recognition impairments
(NOR) test
Immunohistochemistry
Western blotting
mRNA expression analysis
by RT-PCR
Ethanolic root 100 mg/kg body weight/ Male Swiss albino Y-maze test Learning and memory was [57]
extract day, orally mice found to be significantly
enhanced
Morris water maze test Restoring the level of N-
methyl-D-aspartate
receptor (NMDAR) in BPA
intoxicated mice
Lipid peroxidation assay Significantly reduce the
Catalase and SOD activity level of LPO and increase
Immunoblotting analysis the activities of SOD and
Immunohistochemistry catalase through its free
radical scavenging activity
root extract Synchronized adult Negative geotaxis assay in Diminished oxidative [206]
standard powder Drosophila flies stress
melanogaster flies Determination of lipid Enhanced antioxidant
peroxidation defenses
24
parts parameters
Measurement of ROS Elevated dopamine

generation depletion
Measurement of Reduced cholinergic
hydroperoxide (HP) levels function
Determination of reduced Enhanced survivorship
GSH against ROT
Activities of antioxidant Enhanced GSH levels
enzymes
Activity of Upregulated activity levels
acetylcholinesterase (AChE) of antioxidant
Mitochondrial assays
Analysis of dopamine
concentrations by HPLC
Determination of protein
purified extract of 40 mg/kg BW Adult Swiss albino NADPH-d Histochemistry nNOS inhibition [47]
the root mice ChAT Suppression of
Immunohistochemistry glucocorticoid release
Serotonin estimation Reversal of the reduction
in cholinergic markers
(Ach, Cholineacetyl
transferase)
Upregulation of cortical
muscarinic acetylcholine
receptor expression
Downregulation of
glutamatergic neurons in
the hippocampus
Leaf extract 140 mg/kg Wistar albino female Novel object recognition test Conferred intact [204]
rats recognition memory
Rotarod test Restoration of the
exploratory behavior
Immunohistochemistry Suppression of anxiety-like
behavior
Western blotting Maintenance of motor
coordination functions
Leaf extract Adult zebrafish Lipid peroxidation study Altered the scototaxis [226]
(anxiety-like) behavior
Protein carbonylation assay Restored the reduced GSH
Reduced GSH level
Catalase assay
Histopathological study
Light/dark preference test
Novel tank diving test
Leaf extract and 100, 200 and 300 mg/kg Scopolamine induced RT-PCR and Produced glial and [162]
Withanone b.wt. for 7 days (orally) toxicity in mice immunostaining neuronal protection cells
by activating neuronal
proteins, DNA damage,
and oxidative stress
Root extract 20 mg/kg b.wt. for 30 Immobilization stress Significantly reduced the [141]
days (orally) in albino rats number of degenerating
cells in CA2 and CA3
subareas of the
hippocampus in rats
Withanolide-A, 10 lM/kg/day (orally) Amyloid- b toxicity Quantification of neurite Promoted neurite [167]
withanolidesIV, (rat cortical neurons) outgrowth and outgrowth, dendritic and
Withanoside-VI immunostaining axonal, and synaptic
rejuvenation
Water extract 0.05% and 0.1% In-vitro Glutamate induced Cytotoxicity assays and Reversed glutamate- [152]
excitotoxicity in immunostaining evoked stress response by
IMR32 and C6 cells Protein assay and Western promoting upregulation of
blotting HSP70, reduced kainic
Semi-quantitative RT-PCR acid-induced excitotoxic
damage by mitigating
oxidative stress and
restored neuronal
plasticity
Anti-amyotrophic 11:1 extract from 5 mg of root powder as a Transgenic mice Analysis of clinical Reduced levels of [97,98]
lateral sclerosis the plant root suspension in 200 µl carrying G93A sod1 symptoms misfolded SOD1 species
activity sterile buffered saline mutant Motor performance test Reduce oxidative stress
Immunohistochemistry Induction of production of
Immunoprecipitation for molecular chaperones that
misfolded SOD1 help to refold the
Immunoblot analysis misfolded protein or to
Cytokine array
25
parts parameters
maintain their native

conformation
Anti- neuro- Leaf water extract 5 mg/kg body weight Wistar strain male Elevated plus maze test Inhibition of TLR4- [121]
inflammatory albino rats mediated NFκB, P38, and
properties BV-2 cell line Estimation of pro- SAPK/JNK MAPKs
inflammatory cytokines pathways
levels in serum by ELISA
Expression study of proteins
by western blotting
mRNA expression analysis
by RT-PCR
Iba-1 immunostaining
Nitrite determination
Anti-stroke activity Withanolides – – Selection and retrieval of the Inhibits MMP-2 and MMP- [178]
structure of compounds 9
Drug properties prediction
of compounds
Docking preparation of
gelatinases and compounds
Molecular docking
aqueous root 200 mg/kg Rat Permanent distal middle Prevention of apoptotic [283]
extract pheochromocytoma cerebral artery occlusion neuronal cell death
(PC12) cell line Infarct volume analyses increases the expression
Western blots levels of HO1
300 mg/kg Male Wistar rats Antioxidant activity of Reduced cellular stress [355]
WSextract by DPPH, free
radical scavenging assay
Narrow beam walk test Restored neuronal
functioning
Rotarod treadmill test Decreased time for spatial
recognition
Morris water maze test Enhanced motor learning
Elevated plus maze test Regulate the cortical
cholinergic signal
transduction cascade
AChE activity Enhancing the capacity of
muscarinic receptors
Lipid peroxidation assay Neutralize free-radical-
mediated Cell Mol
Neurobiol 123 MDA
production
Total thiols estimation assay Decreased lipid
peroxidation and increased
LMW-SHs concentration
anti-Alzheimer’s ethanol: water 20 mg/kg PC-12 cell line Acute oral safety study Reduced the increased [251]
disease activity (1:1) root extract levels of pro-inflammatory
mediators TNF-α, IL-1β, IL-
6, and MCP-1
Male Wistar rat Single-trial passive Decrease in enzymatic
avoidance test activity of both β- and γ-
secretase activity
Elevated plus-maze Inhibited Th1 and Th17
Quantification of Amyloid- cytokine expression and
beta in supernatant from non-significantly increased
tissue homogenate the levels of Th2 cytokines
Quantification of IL-1β, TNF-
α, IL-6, and MCP-1
Acetylcholine (ACh) assay
Estimation of β-secretase and
γ-secretase
Measurement of oxidative
stress parameters
Estimation of peripheral
intracellular cytokines
(Methanol: 0.016–0.25 µg / ml SK-N-MC MTT cell viability assay Growth stimulatory effects [181]
Chloroform) (3:1) LDH leakage assay Prevention of cellular
root extract degeneration
Internalization of Aβ 1–42 by Inhibits
congo red staining acetylcholinesterase
DIL staining and spine activity and thus has the
density analysis using potential to modulate the
confocal microscopy cholinergic function
LS-MS analysis
26
parts parameters
(Methanol: 0.016–0.25 µg / ml SK-NMC Analysis of cell death in Ab Protective effects against [182]
Chloroform) (3:1) treated cultures the cytotoxicity
root extract MTT formazan exocytosis Increasing calcium entry
through L-type voltage-
dependent calcium
channels
Acetylcholinesterase
activity
Western blot MAP2 levels reduced
analysis
Alcoholic Leaf i-Extract, 1 μg/ml for C6 C6 (glioblastoma) and LDH-cytotoxicity assay Reduction in H2O2- and [313]
extract and 0.4 μg/ml for IMR32 IMR32 glutamate-induced
(neuroblastoma) cells accumulation of ROS and
γH2AX
withaferin A-0.3 μg/ml for Detection of ROS Increase in GFAP, NF-200,
C6 and 0.2 μg/ml for MAP2 proteins
IMR32
withanone- 5 μg/ml Immunofluorescence
for C6 and 2 μg/ml Immunoblotting
for IMR32
Anti-Parkinson’s Ethanolic root 100 mg/kg body weight Male Swiss albino Hanging test The biomarker for LPO is [273]
disease activity extract mice significantly reduced
Narrow beam walking test Levels of NO were
significantly reduced
Footprinting test Increase in catalase
activity
LPO content Reduction in TH
immunoreactivity in the
SN of MB–PQ exposed
mice
Nitrite estimation Significant restoration in
the number of TH positive
neurons
Catalase activity Enhances the survival of
TH-immunoreactivity dopaminergic neurons
Activity against A standardized 20⋅5 and 49⋅2 µg/ml SK-N-SH cells AChE inhibition assay Inhibition of AChE activity [408]
canine cognitive extract of WS Intracellular ROS level Inhibition of
dysfunction (CCD) determination cholinesterase activity
To induce outgrowth of
axons and dendrites
antimicrobial activity against Gram-positive isolates of Methicillin- donovani-infected mice when compared to only WS-treated L. donova
resistant Staphylococcus aureus (MRSA) and Enterococcus sp. isolated ni-infected mice by increasing the percentage of Clusters of differ
from pus samples [58]. In addition to that, it showed potential antimi entiation-4 + (CD4 +) and CD8 + T cells and Natural killer (NK)
crobial activities against Gram-negative bacteria viz. E. coli, Proteus cell-associated marker NK1 [299]. WS protected the packed cell vol
mirabilis, Salmonella typhi, Pseudomonas aeruginosa, Citrobacter freundii, ume drop effect and reduced parasite load d in malarial mice with a MIC
and Klebsiella pneumoniae [17,346]. Cytotoxicity, immunopotentiation, of 600 mg/kg, leaves and root bark extracts showed 50.43% and 29.13%
and gene silencing help to impart antimicrobial activity [237]. WS parasite inhibition [90]. A 28kDA nontoxic, acidic protease inhibitor
further demonstrated potent antimicrobial properties against Salmonella glycoprotein extracted from WS tubers imparted a fungistatic effect to
typhimurium (32.00 ± 0.75 mm zone of inhibition, minimum inhibitory many phytopathogenic fungi like Fusarium oxysporum, Aspergillus flavus,
concentration 6.25 mg/ml,) in vitro [17]. Additionally, an increase in and Fusarium verticillioides by inhibiting hyphal growth and spore
the rate of survival and reduction in bacterial load in various organs of germination [115]. Moreover, flavonoids from WS extracts were re
Balb/c mice suffering from salmonellosis was reported after adminis ported to be effective against Candida albicans with Minimal Fungicidal
tration of WS leaves and root extracts [248]. WS leaves and root Concentration (MFC) of 0.039 and MIC of 0.039 [345].
(methanolic and hexane) extracts were also reported to increase the
synergistic antibacterial activity of Tibrim (isoniazid and rifampicin) 1.11. Neuroprotective activity
against E. coli and Salmonella typhi [29]. Methanolic extract of WS
(0.125–2 mg/ml) reportedly inhibited acid production, tolerance, and Neuroprotective activities of WS have been well documented by
biofilm production of oral microflora such as Streptococcus sobrinus and many studies. Reports obtained from preclinical researches and clinical
Streptococcus mutans at sub-Minimal inhibitory concentrations (MIC) trials have substantiated the neuroprotective role of WS [94,168,341,
levels in vitro [253]. Withanolides containing ethanolic extracts (60 and 393]. Withanone found in the leaf extract can protect against
15 mg/ml in vitro) isolated from WS could induce apoptosis-like cellular scopolamine-induced toxicity in both glial and neuronal cells in exper
death in Leishmania donovani (in vitro) by inducing DNA nicks, imental animals. Several neuronal cell markers [Microtubule-associated
apoptosis, and cell cycle arrest in dose-dependent and time-dependent protein 2 (MAP-2)], Neurofilament (NF)-H, Growth Associated Protein
manner by increasing Reactive oxygen species (ROS) production and 43 (GAP-43) and postsynaptic density protein 95 (PSD-95)], markers of
decreasing mitochondrial potential [67] probably by blocking the Pro glial cells [glial fibrillary acidic protein (GFAP)] and oxidative stress
tein kinase C (PKC) pathway shown by an in silico study [118]. WS markers of DNA is found to be significantly reduced by WS extracts
showed synergistic protection in the case of cisplatin-treated L. [162]. WS extract could further attenuate the toxicity induced by lead in
27
glial cells by balancing the expression of Heat shock protein 70 (HSP70), 1.11.1. Anti-Parkinson’s disease (PD) activity
NCAM, GFAP, and mortalin [174]. WS-derived glycowithanolides Parkinson’s disease (PD), an age-related progressive neurodegener
showed marked antioxidant activity in the striatum and cortex of the rat ative disease, is caused due to destruction of nigral dopaminergic neu
brain by inducing an increase in superoxide dismutase (SOD), catalase, rons resulting in dopamine depletion in the striatum, accompanied by
and glutathione peroxidase (GPx) activities [50,51]. Oxidative damage oxidative stress and mitochondrial malfunction [7,38,79,368]. PD is
caused by streptozotocin in mice was also attenuated via reducing characterized by resting tremors, postural abnormalities (stooped
oxidative stress by WS extracts [258]. Root powder extract of WS posture), and symptoms like bradykinesia, festinating gait, and akinesia
(20 mg/kg body weight for 30 days) markedly reduced the number of [245]. Loss of neurons of the nigrostriatal tract of the brain and the
degenerating cells in Carbonic Anhydrase (CA)2 and CA3 of rat’s hip existence of Lewy bodies in the surviving neurons are pathological
pocampus subjected to stress [141]. Derivatives of WS root extract hallmarks of the disease [38]. 6-hydroxy dopamine, 1-methyl-4-pheny
promoted neurite outgrowth extension in the cell lines of human neu l-1, 2, 3, 6tetrahydropyridine (MPTP), N, N′ -dimethyl-4,40-bipyridini
roblastoma [404]. Withanolide-A normally extended the axons and um dichloride (paraquat; PQ), cypermethrin, manganese ethylene-
dendrites, whereas withanolides-IV and VI extended only the dendrites. bis-dithiocarbamate (maneb; MB), and rotenone are frequently used as
However, withanoside-IV induced both axons and dendrites and neurotoxins to elicit PD symptoms in animal models [337].
restored synapses in rat cortical neurons that were damaged by MPTP-induced movement impairment in animal models closely mimics
amyloid-b (Ab) (dose: 10 µM/kg/day) [165,167]. WS leaf extract could the clinical symptoms of PD patients and has also been reported to
rescue retinoic acid differentiated IMR-32 and C6 cells from glutamate trigger oxidative stress and mitochondrial dysfunction culminating in
toxicity. Pre-treatment with WS inhibited cell death by glutamate in dopaminergic depletion in the striatum [234]. Once inside the brain,
duction which further induced reversal of glutamate evoked a stress monoamine oxidase (MAO) catalyzes MPTP to its active toxin, 1-meth
response by upregulating HSP70 and restoring neuronal plasticity in yl-4-phenylpyridinium (MPP+) along with the generation of free radi
neural CAMs, and its polysialylated form [152]. WS extract (0.05% and cals. MPTP treated mice exhibits reduced mean hind limb stride length
0.1%, in vitro) could also reduce excitotoxic damage caused by kainic compared to their forelimbs and worse rotarod and hang test perfor
acid by reducing oxidative stress [257]. mance [306]. Oral administration of ethanolic root extract of ashwa
The root extracts of the plant have been found to play a pivotal role gandha led to elevated levels of striatum dopamine that attenuated the
against anxiety, depression, senile dementia, cognitive disorder, and effects of 6-hydroxy dopamine-induced Parkinsonism which further
many other neurodegenerative disorders (such as Alzheimer’s disease validated the potent antioxidative property of ethanolic extract of WS.
and Parkinson’s disease). Among the various constituents present in the 6-Hydroxydopamine (6-OHDA) is a widely used alternative to elicit PD
extract, glycowithanolides are chiefly responsible for neuroprotective clinical conditions [267,278]. 6-OHDA when injected stereotactically
activity owing to their superior lipid peroxidation and inhibition prop into the striatum of the brain or substantia nigra tract, specific degen
erties. Later, further studies have validated the potential of withanolides eration of catecholaminergic neurons occurs. 6-OHDA-induced dopa
and sitoindosides (VII-X) to escalate the activities of catalase and minergic toxicity involves oxidative stress due to the generation of
glutathione peroxidase [176]. The root extract has been reported to hydrogen peroxide (H2O2) and hydroxyl radicals and lowers the reduced
bring down nitric oxide production by inhibiting the activation of GSH content and SOD activity leading to a surge in the striatum’s
stress-induced Nicotinamide adenine dinucleotide phosphate reduced malondialdehyde (MDA) [170,268,300]. Ahmad et al. [9] reported
(NADPH)-diaphorase (NADPH-d) in the brain. This is achieved through dose-dependent reversal of the 6-OHDA induced neurotoxicity mainly
activating choline acetyltransferase and suppressing the release of due to the strong antioxidant properties of WS extract. Contralateral
corticosterone [47]. WS extracts acted as a tonic, energy rejuvenator, rotation in 6-OHDA lesioned rats due to ipsilateral and apomorphine is a
and stimulant due to the presence of an array of amino acids, proteins, hallmark of dopamine (DA) depletion. Treatment with WS extract was
starch, reducing sugar, and steroidal lactones. The antioxidant property found to increase dopaminergic D2 receptor populations in the striatum
is mainly due to the presence of phenolics. Besides, in healthy in and striatal content of DA. Onset and progression of PD are often asso
dividuals, it improved endurance at an intensity of 65% VO2 max ciated with age, genetics, as well as environmental factors such as fun
(maximal oxygen uptake) [305]. The oxygen-carrying capacity of blood gicides, pesticides, and neurotoxins [102,339,340]. Paraquat (PQ), a
was found to be escalated by the extract by improving the hemoglobin herbicide, is known to induce neurotoxicity by generating free radicals
and red blood cell (RBC) count of the blood [326]. A significant hike in that culminate in oxidative stress. PQ can swiftly cross the blood-brain
the levels of antioxidant enzymes such as chloramphenicol acetyl barrier (BBB) and enter the Central nervous system (CNS) via neutral
transferase (CAT), superoxide dismutase, glutathione (GSH), and amino acid transporters [354]. Manganese ethylene-bis-dithiocarbama
glutathione S-transferase (GST) has been recorded when root extract te (MB) is a fungicide that can alter normal mitochondrial function
was applied in animals exposed to lead nitrate [286,322]. The extract generating oxidative stress [402]. Residents of rural farming commu
exhibited the tremendous potential to inhibit lipid peroxidation and nities are at high risk of PD due to uncontrolled use of such pesticides,
revitalize the nerve cells. It could heal severely damaged neurons by herbicides, and fungicides [188]. PQ and MB through their synergistic
regenerating neurites and reconstructing synapses [166]. WS showed an action can lead to neuronal toxicity which causes degeneration of
ability to reverse β-amyloid induced neuropathogenesis. The withano dopaminergic neurons and extensive oxidative stress which resembles
sides and withanolides present in the plant extract could minimize the the pathophysiology of PD [366]. The ethanolic root extract of WS was
accumulation of β-amyloid peptides and oligomers in the brain and reported to restore impaired motor movements, bring down MDA and
transport them to the periphery [181,311]. Certain neuronal receptors NO levels, enhance catalase activity and revive tyrosine hydroxylase
and their activities were up-regulated when treated with WS such as (TH) positive neurons, all of which in turn reduce oxidative stress and
low-density lipoprotein receptor-related protein (LRP), β-amyloid protect dopaminergic neurodegradation elicited by PQ and MB toxicity
peptide-degrading protease neprilysin [311], and dopaminergic D2 re in Swiss albino mice [273]. Faulty regulation of programmed cell death
ceptor [286]. An oral dose of leaf water extract of WS ameliorated LPS (PCD) has also been identified as one of the probable causes for neuro
mediated cognitive impairment and neurodegeneration in male Wistar degenerative diseases and apoptotic damage of nigral dopaminergic
rats [122]. The ethanolic root extract of WS showed neuroprotective neurons [61,336]. PQ-MB model of PD disclosed disruption of apoptotic
activity in bisphenol A (BPA) induced loss of spatial learning and homeostasis due to upregulation of proapoptotic protein Bax and sub
working memory in Swiss albino mice [57]. With mild and transient sequent downregulation of antiapoptotic protein Bcl-2. This condition
adverse effects, 1000 mg of standardized WS extract showed potent inclines to a proapoptotic state that enhances dopaminergic neuro
activity in the treatment of anxiety and depression caused by schizo degradation and accelerates oxidative stress. WS root extract could
phrenia in a human trial [109]. restore the expression level of Bcl-2 and bring down Bax protein, thereby
28
stabilizing the apoptotic homeostasis and providing neuroprotection. drugs are hence used to prevent or cure the occurrence of such lesions
Besides, WS modulates Glial fibrillary acidic protein (GFAP) in the induced by ischemia within the ‘neuroprotective window’. The ‘reper
substantia nigra region of the brain of PD affected mice and decreases fusion’ and ‘neuroprotective’ windows together serve as the so-called
the expression of inducible NOS (iNOS) to help regulate NO production. ‘therapeutic window’ in ischemic stroke [208,279]. Plasminogen acti
High-performance liquid chromatography (HPLC) analysis revealed the vator is the only clinically administered drug in ischemic stroke that
possible role of withaferin-A in the neuroprotective activity of WS root serves only a handful of patients. Several neuroprotective drugs have
extract [274]. been proved to be effective in animal models but failed miserably during
clinical trials, which led us to the present-day scenario where no neu
1.11.2. Anti-Huntington’s disease (HD) activity roprotective drugs are available for clinical use in ischemic stroke.
Huntington’s disease (HD), a rare, progressive neurodegenerative Several studies in animal models have highlighted the fact that pre
disorder, received its eponym in 1872 after George Huntington pre treatment has proved to be much effective than post-onset treatment,
sented an elaborate and detailed description of its clinical manifesta which has brought about the concept of prophylactic neuroprotection
tions. This is an autosomal dominant genetic disorder resulting from [104]. Besides, reoccurrence is very prevalent in patients who have
mutations in the Huntington gene that encodes for the Huntington already experienced one incidence of stroke and a prophylactic
protein, with its onset usually during the fourth decade of life [194]. approach for such patients is of utmost importance. One of the earliest
This disease affects movement and cognition due to the selective loss of reports of WS was used as a chronic treatment in an ischemic model of
neurons in the striatum and cerebral cortex through factors like oxida stroke in rats to determine its prophylactic value in stroke patients who
tive stress, excitotoxicity, and energy impairment [62]. Oxidative stress are at high risk [69]. In this study, adult male Wistar rats were orally
has been pointed as one of the major reasons as degenerated areas of the treated with hydro-alcoholic extract of WS (1 g/kg b.w.) for 15 and 30
HD brain are often being characterized by high levels of heme oxygen days, and on the 16th and 31st day, they were subjected to cerebral
ase, MDA, 3-nitropropionic acid (3-NP), and 8-hydroxyguanosine ischemia induced by occlusion of the middle cerebral artery (MCA) by
(8-Oxoguanosine) [160]. Kumar and Kumar [171] employed 3-nitropro intraluminal suture. Two hours of MCA occlusion followed by reperfu
pionic acid (3-NP), a potent neurotoxin that inhibits succinate dehy sion decreased motor activity of the untreated rats as determined by foot
drogenase (SDH) activity resulting in oxidative stress and striatal fault test, rotarod test, and grip test. MDA levels were also found to be
damage in animals to generate HD symptoms in male Wistar rats under high indicating oxidative stress. While 15 days of oral administration of
laboratory conditions to study the possible neuroprotective effect of WS the hydroalcoholic extract of WS did not improve the symptoms of
root extract against biochemical, behavioral and mitochondrial mal stroke, 30 days of oral treatment restored motor functioning in treated
function. Administration of 3-NP (10 mg/kg body weight) was reported rats. The free radical scavenging activity (by stimulating the antioxidant
to mimic symptoms of HD in rats. The symptoms included weight loss defense system) of some of the active constituents present in WS was
and abnormality of motor movement (decreased rearing and ambula found to be crucial in this respect as high amounts of free radicals
tion) due to lack of proper energy metabolism owing to ATP depletion formed due to ischemia–reperfusion culminates in cell death. Trigu
and striatal lesions. Chronic treatment with root extract of WS sus nayat et al. [374] reported the antagonizing activity of WS root extract
pended in 0.5% carboxymethyl cellulose (0.5 ml/100 g b.w.) was found in ischemia-reperfusion injury due to the rise in Thiobarbituric acid
to increase weight and improve motor movement in 3-NP treated rats reactive substance (TBARS) level and changes in Superoxide dismutase
owing to its anabolic, adaptogenic and anti-oxidant properties that are (SOD) and thyroid-stimulating hormone (T-SH) levels. WS has also
effective in restoring the energy balance. Antioxidant effects of glycol helped to increase the levels of cyclic AMP (cAMP) which generally
withanoloids (an active constituent of WS were reported to reverse the occurs following injury and helps in reversing stroke-induced vasospasm
muscle activity impairments in 3-NP treated rats as depicted in rotarod in central vessels of the brain.
and limb withdrawal tests. Oxidative stress serves as a hallmark for
neurodegenerative disorders including HD. Neurotoxins like 3-NP have 1.11.4. Anti-Alzheimer’s disease (AD) activity
been found to elevate lipid peroxidation and nitrite levels along with Alzheimer’s disease (AD) stands as one of the most prevalent
suppressing the activities of antioxidant enzymes like SOD and catalase. neurodegenerative diseases that is known to affect about 36 million
Several reports have highlighted the free radical scavenging activity of people throughout the world [392]. An intriguing report highlights that
sitoindosides VII–X and withaferin A (glycol-withanolides) present in with the continuation of the current trend and no medical innovation, by
WS [53,306]. [171] validated the same as they presented that root ex 2050, one in 85 people will be affected with AD [272]. The patho
tracts of WS efficiently cut down the lipid peroxidation and nitrite levels physiology of AD is complicated and characterized by progressive loss of
and escalated the activity of the antioxidant enzymes. Besides, the root memory and recognition of objects or persons, inability of task perfor
extract was able to normalize the functioning of mitochondrial enzyme mance, psychological symptoms like depression, mental upset, anxiety,
complexes (I, II, and III) and some other key citric acid cycle enzymes and language deficits mainly due to cholinergic neuronal degradation,
viz. SDH, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and dystrophic neuritis, gliosis, toxic β-amyloid (Aβ) plaques, abnormal
malate dehydrogenase were hampered due to 3-NP treatment. neurofibrillary tangles and deficiency of essential neurochemicals
necessary for normal neuronal transmission [129,403]. Studies have
1.11.3. Anti-Ischemic stroke activity identified Aβ cytotoxicity as the characteristic etiologic feature of AD
Stroke is a type of acute cerebrovascular disease that is the world’s pathology [65,399]. Oxidative stress due to overproduction of ROS
second greatest cause of mortality and a primary source of long-term during the early phase of neuronal death has been recognized as a signal
impairment or permanent disability [19,229]. Transient or permanent to trigger apoptosis [65,247]. Besides, Aβ toxicity has also been found to
cutdown of blood flow owing to occlusion of a cerebral artery due to escalate Hydrogen peroxide (H2O2), one of the typical elicitors of
local thrombosis or embolus results in ischemic stroke, the third most neuronal cell apoptosis [309,391]. The role of aqueous extract of the
leading cause of death in industrialized countries [91]. Ischemic stroke root of WS against H2O2 and Aβ induced toxicity in vitro was investi
is one of the most common causes of physical damage in humans, ac gated by Kumar et al. [172]. Molecular dynamics simulation (MDS)
counting for roughly 87% of all strokes worldwide [42,93,386]. The studies by Pahal et al. [254] showed Isopelletierine and Nicotine from
extent of damage due to stroke depends on two variables: decrease in WS could inhibit Amyloid precursor protein (APP), a significant player
cerebral blood flow (CBF) and the ischemia time. If the blood flow is in AD.
restored within the ‘reperfusion window’, the effects of stroke can be
reversed however ‘delayed lesions’ (pathophysiological changes
persistent even after proper blood flow) may appear. Neuroprotective
29
1.11.5. Anti-amyotrophic lateral sclerosis (ALS)/ Frontotemporal lobar EuMil is also seen to reduce glucose intolerance and normalize male
degeneration (FTLD) activities sexual behavior [407]. Furthermore, glycol-withanolides from WS ex
A root extract of WS reversed transactive response DNA binding tracts were able to normalize perturbations found in oxidative free
protein 43 (TARDBP or TDP-43) proteinopathy in mouse ALS/FTLD. The radical scavenging enzymes and lipid peroxidation in the frontal cortex
extract significantly reversed the cytoplasmic mislocalization of hTDP- of rats and striatum induced by foot-shock stress in rats [53]. T cell
43 when administered in hTDP-43A315T mice orally and was suggested population reduction and Th1 cytokine upregulation in chronically
as a promising therapeutic agent against TDP-43 proteinopathy [96]. stressed mice were corrected by aqueous root extract of WS [156]. It has
Moreover, in the SOD1G93A mouse model of ALS, WS extracts exhibited further been documented to provide significant protection against
protective effects in animals with TDP-43 proteinopathy. WS showed an stress-induced gastric ulcers and other stress-related disorders. Ashwa
immunomodulatory effect by reducing glial activation remarkably, via gandha root extracts (500 mg/kg) in male Wistar rats were even shown
inducing autophagy, and via preventing nuclear factor kappaB (NF-κB) to antagonize hippocampal oxidative stress as documented by [18].
phosphorylation besides changing the expression of multiple cytokine
s/chemokines [98]. 2.1. Withania somnifera against psychological and behavioral disorders
2. Sleep inducing, anxiolytic and antistress properties The patented Compound Herbal Preparation (CHP) that includes
Paeonia alba, W. somnifera, Centella asiatica, Spirulina platensis, Bacopa
Sleep has a crucial role in the maintenance of the physical and monnieri, and Melissa officinalis was found to improve attention, cogni
mental health of the mammalian body. Sleep loss or abatement may tion, and impulse control in children with attention deficit hyperactivity
culminate in an array of physical, metabolic, and cognitive disturbances disorder (ADHD) [154]. In a randomized, double-blind, placebo-con
that in turn initiate stress, anxiety, obesity, and other neurocognitive trolled study among 66 patients, a standardized extract of WS (WSE) was
dysfunctions. Hippocampus and pyriform cortex, two regions of the suggested as a promising adjunctive treatment in patients affected by
brain associated with memory and perception, losses their sleep- recent exacerbations of schizophrenia [71]. WSE also improved
dependent functions owing to complete loss of sleep [64,292,364, auditory-verbal working memory and social cognition in patients of
383]. ‘Somnifera’ means sleep-inducing and thus to validate the role of bipolar disorder with cognitive dysfunction [70]. Furthermore, in a
WS in averting anxiety, motor dysfunction, and cognitive deficits in placebo-controlled study with WS extract, subtle changes in thyroid
sleep-deprived animals, Manchanda et al. [204] used an aqueous extract indices were noted in patients affected by bipolar disorder. Such results
of WS root to elucidate its sleep-inducing potential. In the study, 12 hr open up further research scope in the treatment of subclinical hypo
sleep-deprived rats were found to exhibit neuromotor dysfunction and thyroidism, especially in patients with bipolar and unipolar mood dis
memory impairments, which could be reverted with pretreatment orders [108]. Mamsyadi Kwatha, an Ayurvedic compound formulation
before sleep deprivation with WS extract for 15 days. Pre-treatment was (ingredients: Nardostachys jatamansi, W. somnifera, and Hyoscyamus niger
also found to improve alertness, recognition memory, and explorative in 8:4:1 ratio) exhibited profound antidepressant activity in Swiss albino
nature among rats. A very recent finding of Lopresti et al. [190] showed mice via reversing behavioral despair remarkably and via exhibiting
that daily intake of 240 mg of WS extract can cause a reduction in anti-reserpine activity [332]. WS root extract showed significant pro
Hamilton anxiety rating scale (HAM-A) and stress scale-21 (DASS-21). It tective properties in 30 patients with obsessive-compulsive disorder
was also associated with a reduction in morning cortisol and dehydro (OCD) as evidenced by the Yale-Brown Obsessive-Compulsive Scale
epiandrosterone. An insignificant increase in testosterone in males was (Y-BOCS) [140].
only found associated with this study. Withanolide free root extract of Neuroprotective and psychoactive activities of WS extracts/purified
WS, up to a dose of 10 mg/kg/day in mice can act as triethylene glycol compounds are presented in Table 6. These various activities of extracts/
(TEG) in response to stress-triggered changes. It also protected against formulations/phytochemicals made WS a potent candidate against these
stress-induced changes in blood glucose and insulin levels and acted as ailments.
an antidepressant in higher doses of 33.3 and 100 mg/kg/day [86]. The
methanolic root extract of WS can also significantly suppress ethanol 3. Clinical studies
and morphine stimulation in rats [40]. Oral administration of WS root
powder at a dose of 500 mg/kg/day prevented posttraumatic stress WS along with Terminalia arjuna, Phyllanthus emblica (= Emblica
disorder (PTSD)-induced memory impairment in single prolonged stress officinalis), and Ocimum tenuiflorum (= O. sanctum) in a capsule form
(SPS) rat model [18]. (Cardipro) twice daily improved the condition of coronary artery disease
In addition, 20 and 50 mg/kg of aqueous concentrate of WS roots in (CAD) patients. Following the treatment, a significant reduction of
inbred Charles Foster strain male rats could show its GABA-mimetic systolic and diastolic blood pressure was observed along with decreased
effect hence can act as a potential antidepressant [52]. WS has a serum cholesterol, triglycerides, and increased high-density lipoprotein
remarkable quality to reduce the corticosterone levels in treated mice (HDL) cholesterol without any marked biochemical or clinical side ef
compared to vehicle-treated ones which were subjected to restraint fects [99]. Ethanolic extract of WS was found to be potential anxiolytic
stress for 30 days straight [47]. Standardized ratios of root extract (against ICD-10 anxiety disorders) in A double-blind, placebo-controlled
powder of WS prevented stress-induced neuronal degeneration in the study with no adverse effects compared to the placebo group [25]. Three
hippocampal Cornu Ammonis-2 (CA2) and CA3 areas compared to hundred mg twice a day standardized to 1.5% withanolides from WS
control or nonstressed animals [141]. In addition, the root extract root along with dietary counseling, deep breathing, relaxation tech
powder was also able to significantly mitigate changes in neuronal cell niques, and standard multivitamin significantly improved mental
bodies found in CA2 and CA3 regions of the hippocampus which were health, concentration, vitality, and social function leading to a better
affected by stress (Stresscom from Dabur India Ltd.). In another study, quality of life without any serious adverse effects [74]. Treatment with
involving 60 adults, the plant extract was found to reduce stress WS improved semen quality and sperm motility of infertile males. It
significantly without any side effects compared to the placebo group. reduced oxidative stress, inhibited lipid peroxidation with an increase in
The foresaid effects were concluded to be partly due to effects on the antioxidants [10]. A study by Shukla et al. [334] showed a reduction of
hypothalamus-pituitary-adrenal axis. However, the study lacks merit as ROS and apoptosis along with an increase in essential metal ions (Cu2+,
a small sample was considered [189]. A polyherbal formulation, EuMil, Zn2+, Fe2+, and Au2+) in seminal plasma resulted in improved semen
containing WS as a major component was demonstrated to regulate quality. High-concentration full-spectrum extract of WS root (300 mg
cerebral monoamine levels after they were subjected to chronic capsule for 60 days) significantly reduced serum cortisol and provided
electro-shock stress in rats as documented by Bhattacharya et al. [409]. resistance towards stress in a double-blind, randomized,
30
Table 6
Neuroprotective and psychoactive activities of Withania somnifera extracts/purified compounds: in vitro, in vivo and clinical investigations.
Source Activity Model Mode of action Reference
Glycowithanolides Neuroprotective activity Mice Decrease in lipid peroxidation [176]

Withanolides and sitoindosides Neuroprotective activity Mice Increase in catalase, GPx [176]
Root extract Reduce NO production Mice Decrease in NADPH-d [47]
Standardized root extracts Serves as a tonic, energy rejuvenator, and Human Increase in phenols, amino acids, proteins, starch, [305]
stimulant reducing sugar and steroidal lactones
Extract capsules Improves oxygen-carrying capacity of the Human Increase in hemoglobin and RBC count [326]
blood
Hydromethanolic root extracts Potent anti-oxidant Male Swiss Albino mice Increase in CAT, SOD, GSH, and GST [166,286,
Inhibit lipid peroxidation 322]
Methanol extract Revitalize nerve cells SH-SY5Y cells Regenerates neurites and reconstruct synapses [166]
Methanolic chloroform root Prevent β-amyloid induced SK-N-MC cells Decrease in accumulation of Aβ and transport them [181,311]
extract neuropathogenesis to the periphery
Semi purified root extract Enhanced activity neuronal receptors APP/PS1 Alzheimer’s Trigger expression of Neuronal receptors such as [286,311]
transgenic mice, PD mouse LRP, D2 receptors
Glycowithanolides Manage stroke and post-stroke syndromes Charles-Foster (CF) male Decrease in reperfusion, hypoperfusion induced [374]
albino rats changes in mice
Leaf water extract Neurodegeneration Wistar rats Decrease in cognitive and motor coordination [122]
impairments
Ethanolic root extract Parkinsonism Mice Increase in striatum dopamine [306]
WS extract Dose-dependent reversal of 6-OHDA Rats Increase in strong antioxidant property, [9]
induced neurotoxicity dopaminergic D2 receptor
Ethanolic root extract Dopaminergic neurodegradation Swiss albino mice Decrease in MDA, NO levels, increase in TH [273]
protection
Root extract Neuroprotection Swiss albino mice Decrease in Bcl-2, increase in Bax [274]
WS root extract Neuroprotective activity Mice Decrease in iNOS [274]
Root extract in 0.5% carboxy Anti HD activity 3 NP treated wister mice Increase in weight, motor movements [171]
methyl cellulose
Withaferin A 3-NP induced HD Rats Increase in free radical scavenging activity [53,306]
Root extract 3-NP induced HD Rats Decrease in lipid peroxidation and nitrite levels, [171]
increase in antioxidant enzymes
Hydro-alcoholic extract MCA induced cerebral ischemia Male Wistar rats Increase in motor functioning [69]
Root extract Stroke induced vasospasm Rats Increase in cAMP [374]
Aqueous extract of root H2O2 and Aβ induced AD PC12 cells Increase in cell viability [172]
(Withaferin A)
Aqueous extract of root Sleep deprivation Rats Increase in alertness, recognition memory, and [204]
explorative nature
Standard extract (Shoden) Anxiety Human Decrease in HAM-A, DASS-21, cortisol, DHEA-S [190]
Withanolide free root extract Stress Mice Decrease in stress-triggered alternation [86]
Methanolic root extracts Behavioral changes Male Spradue-Dawley rats Decrease in morphine/ethanol mediated [40]
stimulation
Root powder PTSD induced memory impairment Rats Decrease in PTSD induced oxidative stress [18]
Ethanol root extract BPA induced cognitive dysfunction Swiss albino mice Increase in antioxidant property, NMDAR [57]
Standard root extract Schizophrenic depression and anxiety Human Decrease in single item depression, anxiety [109]
depression cluster subscores
Root extract amyotrophic lateral sclerosis (ALS)/ hTDP-43A315T mice Decrease in cytoplasmic mislocalization of hTDP-43 [96]
frontotemporal lobar degeneration (FTLD)
WS extracts ALS OD1G93A mice Increase in immunomodulatory effect, autophagy, [97,98]
decrease in glial activation NF-κB phosphorylation
Compound Herbal Preparation attention deficit hyperactivity disorder Human (73 child patients) Increase in attention, cognition, impulse control [154]
(CHP) that includes WS (ADHD)
Standard WS extract (WSE) schizophrenia Human (66 patients) Decrease in symptoms, stress [71]
Standard WS extract (WSE) bipolar disorder Human (53 patients) Increase in auditory-verbal working memory, social [70]
cognition
WS extract bipolar disorder Human (60 patients) Increase in thyroid function [108]
Mamsyadi Kwatha that includes depression Swiss albino mice Decrease in behavioral despair, ↑anti-reserpine [332]
WS activity
WS root extract obsessive-compulsive disorder (OCD) Human (30 patients) Decrease in disease symptoms [140]
placebo-controlled trial [68]. With a dose of 2 g every 8 h, the root showed increased testosterone and Dehydroepiandrosterone sulfate
extract of WS caused lower fatigue scores (Schwartz Cancer Fatigue (DHEA-S) (18%) resulting IN sexual and psychological well-being with
Scale) and improvement in quality of life in breast cancer patients more vigour and less fatigue in a randomized, double-blind, placebo-
receiving chemotherapy [59]. WS treatment caused a better harmonic controlled, crossover study among overweight males [189].
balance between reproductive hormones and metabolites of seminal
plasma in infertile males [120]. Standard water extract of WS improved 4. Toxicity studies
cognitive and psychomotor performance in a double-blind, multi-dose,
placebo-controlled, crossover study among 20 healthy males. Significant WS is being considered a reasonably safe drug. Several general
improvements in reaction time, choice, discrimination, card sorting, toxicity studies of the extracts of whole plant parts and pure compounds
digit vigilance, and digit symbol substitution were noted [269]. A isolated from WS have been reported. In a central nervous system study,
standardized WS extract (Shoden beads) (240 mg) once daily for 60 days the acute toxicity (LD50) of total alkaloids isolated from the roots was
in a double-blind, placebo-controlled, randomized study significantly 465 mg/kg and 432 mg/kg in rats and mice, respectively. For testing,
deceased morning cortisol and depression according to Hamilton Anxi 2% suspension of alkaloids was used along with 10% propylene glycol
ety Rating Scale (HAM-A) [190]. Intake of Shoden beads for 8 weeks and 2% gum acacia as the suspending agent [200]. The toxicity (LD50) of
31
the alcoholic extract of seeds (dissolved in normal saline) was commonly available drugs to treat neurodegenerative diseases include
1750 ± 41 mg (p.o) in albino mice [338]. Aqueous extract of WS galantamine, donepezil, rivastigmine, and selegiline, but they are only
(100 mg/kg/day) in drinking water for long-term treatment (8 months) able to delay the progression of the disease and provide symptomatic
was found to be nontoxic in rats [320]. LD50 of alcoholic root extract was relief [390]. Besides, some of them come with side effects. Hence, it
found to be 1260 mg/kg b.w. in mice [318]. LD50 of aqueous methanol becomes obligatory to focus on herbal and natural drugs like Withania
extract of WS by intraperitoneal (i.p.) administration in mice was that can provide overall protection to mental and neuronal health [100].
1076 ± 78 mg/kg and that of an equimolar combination of sitoindosides Ashwagandha houses a varied range of bioactive compounds ranging
VII and VIII and withaferin-A was 1564 ± 92 mg/kg [117]. LD50 of from alkaloids to steroids, flavonoids to phenols. Research has been
withaferin A (i.p. administrated) was around 80 mg/kg in mice [319]. carried out for a long time now to explore the potential of WS extract
Withanolide-free aqueous fraction of roots showed no toxicity up to against several pathological conditions. The antioxidant nature of WS
3000 mg/kg b.w. in Foster rats and Swiss albino mice [406]. No toxic extract makes it very suitable for treating neurological disorders asso
signs or mortality were observed with 2000 mg/kg of WS root hydro ciated with oxidative burst. Moreover, it can promote neuronal health
alcoholic extract (WSR) in Wistar rats [270]. Oral LD dose of standard that can help to restore neurodegradation. Besides, few reports also
WS extract (WSE) was found to be more than 2000 mg/kg in Wistar Rats claim that psychological symptoms like depression, memory loss, and
[260]. sleep deprivation can also be cured with WS. This review will further
provide the researchers with a comprehensive summary that highlights
5. Recent developments the immense pharmacological potential of WS extracts and compounds
with a special note on their ethno-medical uses, different pharmaco
Coronavirus disease 2019 (COVID-19) is a viral infection that has logical activities especially neuroprotective and psychoactive roles.
spread around the world since December 2019 [21] and hence, there is
an urgent need to develop a potential therapy to combat COVID-19 Funding
disease [22]. A preprint from Balkrishna et al. [37] predicts with
anone from WS could bind with receptor-binding domain (RBD) com The corresponding author (AD) received the Faculty Research and
plex of COVID-19 spike protein and human angiotensin-converting Professional Development Fund (FRPDF) for financial assistance from
enzyme 2 (ACE-2) and concomitantly reduce viral entry. Withanone Presidency University, Kolkata, West Bengal, India.
from WS was predicted to inhibit COVID-19 replication by interacting
with N343 to reduce spike glycosylation [264]. Another preprint de CRediT authorship contribution statement
tailing in silico analysis from Parida et al. [256] reveals inhibition of
COVID-19 spike and NSP3 by 2,3-Dihydrowithaferin A and 27- All authors listed have contributed to the concept, literature mining,
Deoxy-14-hydroxywithaferin A. Four compounds from WS have been writing and methodology of the review, provided critical feedback and
found to inhibit COVID-19 envelope (E) protein by binding with the pore revising the manuscript critically. All authors contributed to the writing
region and reduce viral replication [3]. Alongside COVID-19, an or revision of the final manuscript. SP: Came up with the study idea,
aqueous root extract of WS also reduced the Tilapia lake virus (TiLV) wrote the first draft of the manuscript, prepared the tables. SC: Came up
mediated stress level and mortality [388]. with the study idea, wrote the first draft of the manuscript, prepared the
Quercetin-3-rutinoside-7-glucoside, rutin, and isochlorogenic acid B tables. UA: Planned and designed the review structure, writing-review &
from WS worked better than withanolide and withanone against chief editing, arranged the references, revised the tables and figures, revision,
protease of SARS-CoV2 [184]. Molecular docking studies thus empha final draft. SD: Wrote the first draft of the manuscript, designed the
size the promiscuous activity of WS phytochemicals compared with tables and figures, arranged the references. SN: Wrote the first draft of
standard viral inhibitors (lopinavir, nelfinavir). Withanoside II the manuscript, designed the tables and figures. MG: Participated in
(− 11.30 Kcal/mol), Withanoside IV (− 11.02 Kcal/mol), Withanoside V review structure, arranged the references, revised the manuscript,
(− 8.96 Kcal/mol) and Sitoindoside IX (− 8.37 Kcal/mol) are found to be responded to reviewer comments. SCS: Planned and designed the review
bind strongly with the main protease of SARS-CoV2 [373]. These find structure, completed the critical revision of the entire manuscript, data
ings suggest potent antiviral especially anti-SARS-CoV2 activity but validation, addressed reviewer comments. MTP: Completed the critical
these in silico findings are needed to be validated in “in vitro” and “in revision of the entire manuscript, data validation, response, suggestions,
vivo systems”. addressed reviewer comments. RK: Completed the critical revision of
the entire manuscript, addressed and supervised the revision process of
6. Conclusions the review. JP: Completed the critical revision of the entire manuscript,
supervised the drafting process of the review, response, final draft, re
There has been a strong conflict between Ayurvedic treatment and sources, project administration and funding acquisition. AD: Came up
modern medicine for a long time. While biomedicine or modern drugs with the study idea, revised the review structure, suggestions, completed
mainly deal with the reduction of pathology, Ayurveda has been known the critical revision of the entire manuscript, formal interpretation, su
to put up a holistic approach to diseases as well as overall health [20, pervised the drafting process of the review, resources, final draft. The
126]. Rasayana, a branch of Ayurvedic science, aims to promote the authors SP, SC and UA contributed equally to this review article and
body’s resistance to diseases, increase strength and intellect, and delay have the right to list their name first in their CV/any other scientific
ageing. Withania somnifera happens to be one of the prime examples of documents or scientific profile. All authors have read and approved the
the Rasyana medicinal plant which possesses immunomodulation, final version of the manuscript for submission to this journal.
anti-cancer, anti-depressant, neuroprotective, and other biological
properties [73]. Modern conventional medicines suffer from limitations Conflict of interest statement
like increased resistance, unavoidable side effects, loss of efficacy due to
prolonged use, and high cost [23,159]. This has compelled researchers The authors declare no conflict of interest.
to derive bioactive therapeutic compounds and drugs from natural
sources such as herbal plants [20,38,126,219,362]. Neuroprotective and Acknowledgement
psychoactive drugs for clinical use are rare and most of them, despite
being effective when tested in animal models, failed to come up with All the authors are highly grateful to the authority of the respective
similar results when exposed to clinical trials. There are still no clinical departments and institutions for their support in carrying out this
drugs available for treating patients with ischemic stroke [105]. The research.
32
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40

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Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

Withania somnifera (L.) Dunal (Ashwagandha): A comprehensive review on

1. Introduction extensively implemented as herbal medicine. An evergreen woody shrub

Maharashtra - India - Powder, homogenized in

Table 2 Table 2 (continued )

Table 2 (continued ) Table 2 (continued )

jatamansi), Arjun Carom

Table 2 (continued ) Table 2 (continued )

Table 2 (continued ) Table 2 (continued )

(Anacyclus serrata), Rose Hip

Table 2 (continued ) Table 2 (continued )

Table 2 (continued ) Table 2 (continued )

cordifolia), Marica (Piper

Fig. 2. Different classes of phytochemicals present in Withania somnifera.

Fig. 3. Chemical structures of phytochemicals from Withania somnifera (from www.ChemSpider.com).

very promising anti-cancer activities in both in vitro and in vivo con­

1. Withanolide C28H38O6 53477765 470.6 1.6. Anti-inflammatory activity

Table 4 immunostimulatory preparations or Rasayanas that are popularly used

WS is known to possess cardioprotective and cardiotropic properties

Proteasome inhibition and

Deoxynucleotidyl Inhibition of Notch-1,

suppress the tumor growth

Measurement of ROS Elevated dopamine

maintain their native

Glycowithanolides Neuroprotective activity Mice Decrease in lipid peroxidation [176]

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very promising anti-cancer activities in both in vitro and in vivo con