Table 2.

Various pharmacological action of W. somnifera or its chemical constituents

W. somnifera	Dosage and mode of administration	Diseased condition/model	Mechanism of action	References
Methanolic leaf extract	2 mg/ml in vitro	Methicillin resistant Staphylococcus aureus and Enterococcus spp.	Anti-bacterial activity	[60]
Methanolic extract	0.125–2 mg/ml in vitro	Oral infections by Streptococcus mutans and Streptococcus sobrinus	Inhibited acid production, acid tolerance, and biofilm formation of oral bacteria	[66]
Withanolides (F5 and F6 fractions)	60 and 15 μg/ml in vitro	Leishmania donovani	Apoptosis, DNA nicks, cell cycle arrest and externalization of phosphatidylserine, increased ROS, and decreased mitochondrial potential	[67]
Glycoproteins	20 µg/ml in vitro	Aspergillus flavus, Fusarium oxysporum, F. verticilloides	Inhibiting spore germination and hyphal growth	[73]
Root extract	500 µg/ml and 1000 mg/kg b.wt. (rectal route)	TNBS-induced inflammatory bowel disease in rats	Mucorestorative and anti-inflammatory, resolved edema, neutrophil infiltration and necrosis	[74–76]
	500 and 1000 mg/kg b.wt. (orally)	Mouse model of lupus	Inhibited proteinuria, nephritis, TNF-α, NO and ROS
Withaferin-A	1.882 µg per mouse (I.V.)	Human umbilical vein endothelial cells	Inhibited TNF-α and IL-1β	[77, 79, 82]
	2 µM in vitro	Murine fibrosarcoma	Attenuated p38, ERK-1/2, C jun JNK
	3 µM/ml in vitro	Cellular models of Cystic Fibrosis inflammation (KKLEB cells)	Inhibited Iκβ phosphorylation and degradation by blocking NFκ-β  translocation, inhibited IL-8
Aqueous extract of root powder	10 mg/ml in vitro	Human osteoarthritis (cartilage damage explant models)	Chondroprotective actions by inhibiting gelatinase activity of collagenase type-2 enzyme and decreased NO	[83, 88]
	600 and 800 mg/kg (orally)	Collagen-induced arthritis in rats	Attenuated cartilage degradation, improved the functional recovery of motor activity and radiological score
Crude ethanolic extract	1 mg/ml in vitro	Rheumatoid arthritis (PBM cells)	Suppression of LPS-induced production of cytokines, interleukins, and TNF-α	[85]
Leaf extract	6, 15, 21, 25, and 32 µg/ml in vitro	Cancer cells (TIG1, U2OS, and HT1080)	Activated p53, apoptosis pathway, and arresting cell cycle	[95]
Withaferin-A	3 µM/ml in vitro	Human melanoma cells (M14, Lu1205, and Sk28)	Promoted ROS-induced apoptosis by lowering Bax/Bcl2 and Bcl2/Bim ratio	[96, 107, 108, 111]
	2 and 3 µM/ml in vitro	Breast cancer cells (MDA-MB-231 and MCF-7)	Translocation of Bax to mitochondrial membrane resulting in cytochrome c release and activation of caspase-9 and 3 and PARP
	5 and 10 µM/L in vitro and injections of 4 mg/kg b.wt. 5 days/week for 5 weeks. (i.p.)	Breast tumor progression in xenograft and transgenic mouse models	G2 and M-phase cell cycle arrest, up-regulated ERK/RSK axis, activation of DR-5, Elk1 and CHOP
	25 µg/ml in vitro	Human laryngeal carcinoma Hep2 cells	Cell cycle arrest with concomitant blockade of angiogenesis
	4 µM/ml in vitro	Renal cancers (Caki cells)	PARP cleavage through down-regulation of STAT-3 pathway	[101, 114]
	26 µM/ml in vitro		ER stress-specific XBP1 splicing, and up-regulation of GRP-78 and CHOP
Whole extract	30, 60 and 90 mg/kg/day for 60 days (orally)	Myocardial infarction in rats	Cardiotropic and cardioprotective	[116, 117, 120, 122, 125]
	50, 75 and 100 mg/ml in vitro	Coronary artery occlusion in rats	Activated Nrf2, stimulated phase II detoxification enzymes, abrogated apoptosis in a Nrf2-dependent manner
	50 mg/kg b.wt. for 30 days (orally)		Anti-apoptotic/pro-apoptotic effects, and reduced TUNEL positivity and lessened histopathologic deterioration of myocardium
Root extract	3 g/day human subjects (orally)	Diabetes	Stabilized blood glucose levels	[130, 131, 133, 134]
Aqueous extract	200 and 400 mg/kg b.wt./day for 5 weeks (orally)	Non-insulin-dependent diabetes mellitus in rats	Improved insulin sensitivity index and blocked the rise in homeostasis model assessment of insulin resistance
Root and leaf extract	200 mg/kg b.wt. for 8 weeks(orally)	Alloxan-induced diabetes mellitus in rats	Normalized the urine sugar, blood glucose, glucose-6-phosphatase and tissue glycogen levels
Aqueous fraction of roots	25, 50, 100 and 200 mg/kg for 14 days (orally)	Mouse model of chronic stress	Reduced in T-cell population and up-regulated Th1 cytokines	[140]
EuMil, poly herbal formulation	100 mg/kg for 14 days(orally)	Chronic electroshock stress in rats	Ameliorated cerebral monoamine levels	[142, 143]
	100 mg/kg for 14 days (orally)		Attenuated cognitive dysfunction, immunosuppression, gastric ulceration, and plasma corticosterone levels
Glycowithanolides	20 and 50 mg/kg for 5 days (orally)	Pentylenetetrazole induced anxiety in rats	Anxiolytic effects and reduced rat brain levels of tribulin	[145]
Leaf extract and Withanone	100, 200 and 300 mg/kg b.wt. for 7 days (orally)	Scopolamine induced toxicity in mice	Produced neuronal and glial protection cells by activating neuronal proteins, oxidative stress and DNA damage	[151]
Root extract	20 mg/kg b.wt. for 30 days (orally)	Immobilization stress in albino rats	Markedly rescued the number of degenerating cells in CA2 and CA3 subareas of rat hippocampus	[155]
Withanolide-A, withanolides-IV, Withanoside-VI	10 µM/kg/day (orally)	Amyloid- β toxicity (rat cortical neurons)	Promoted neurite outgrowth, axonal and dendritic and synaptic rejuvenation	[157, 158]
Water extract	0.05 and 0.1 % in vitro	Glutamate induced excitotoxicity in IMR-32 and C6 cells	Reversed glutamate-evoked stress response by up-regulation of HSP70, restored neuronal plasticity, reduced kainic acid-induced excitotoxic damage by mitigating oxidative stress	[159, 160]
Whole extract	100, 200 and 300 mg/kg b.wt. for 3 weeks (orally)	6-OHDA induced toxicity in rats	Attenuated lipid peroxidation, reduced glutathione content, and activities of glutathione-S- transferase, glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase, increased number of dopaminergic neurons	[161]
Root extract	100 mg/kg b.wt. (orally)	MPTP induced toxicity in mice	Normalized catecholamine content, reduced oxidant stress, and functional activity	[162, 164]
Root powder	100 and 400 mg/kg b.wt./day for 4 weeks (orally)	Rotenone-induced impairment in mice	Antioxidant and anti-inflammatory actions and corrected mitochondrial dysfunctions, normalized neurotransmitter function, and dopamine levels in striatum	[166]
Ethanolic extract	100 mg/kg b.wt. for 3, 6, and 9 weeks (orally)	MBPQ-induced toxicity in mice	Rescued dopaminergic neurons, replenished dopamine levels in substantia nigra and attenuated locomotor activity and reduced oxidative stress and inflammation	[167, 168]
	100 mg/kg b.wt. for 9 weeks(i.p)		Activated anti-apoptotic Bcl-2 protein expression and down-regulated pro-apoptotic Bax and astrocytes and expression of GFAP
Standardized aqueous extract	250 mg twice daily for 14 days to human subjects (orally)	Psychomotor functional disorders in healthy humans	Improved cognitive and psychomotor performance	[169]
Root extract	1 g/kg b.wt. for 7–30 days (orally)	Alzheimer’s disease models	Reversed the behavioral deficits and pathological clues as well as Aβ clearance by up-regulating lipoprotein receptor-related protein in liver	[170]
Withanolides	6.25, 12.5, 25, 50, 100 μg/ml in vitro	Alzheimer’s disease transgenic mice	Prevented the fibril formation and thus protect cells from amyloid- β toxicity	[171]
Withanoside-IV and Sominone	10 µM/kg/day (orally)	Alzheimer’s disease mice	Attenuated Aβ(25,35) induced neurodegeneration and improved memory deficits in mice and prevented loss of axons, dendrites, and synapses	[158]
Whole extract	0.15 and 0.3 µg/ml in vitro	Aβ toxicity in SK-N-MC cells	Enhanced cell viability and PPARγ levels, inhibited of acetyl- cholinesterase activity	[175, 176]
Whole extract	1 g/kg for 15 and 30 days (orally)	Middle cerebral artery occlusion in rats	Attenuated oxidative stress marker malondialdehyde, reduced lesion area, and restoration of neurological deficits	[178]
Root extract	50, 100, 150, 200 and 250 mg/kg b.wt. for 21 days (orally)	Hypoxia pathway in hippocampal cells	Enhanced memory and attenuated hippocampal neurodegeneration by repleting glutathione levels through activation of glutathione biosynthesis	[181, 182]