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Adaptogenic and anti-stress activity of Withania somnifera in stress induced mice

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Abstract

The aim of the study was to evaluate the effect of ethanolic extract of roots of Withania somnifera 23 mg/kg (p.o), on acute stress induced biochemical and immunological perturbations in mice. The standard group was administered water soluble root powder of Panax ginseng 100 mg/kg (p.o), while the stress control group was administered distilled water orally. After 7 days of pretreatment with the extract, the animals were concomitantly exposed to swim endurance test and cold restraint stress (4°C for 2 hours). Cold restraint stress resulted in significant increase in adrenal gland weight with concomitant decrease in spleen weight in stress control group which was significantly reverted by pretreatment with the extract of Withania somnifera. The activation of HPA system results in secretion of corticotropin-releasing hormone, adrenocorticotropic hormone (ACTH), β-endorphin and glucocorticoids into the circulation. Pretreatment of animals with Withania somnifera extract 23 mg/kg (p.o), improved the swim duration in mice and significantly restored back the stress induced alterations in plasma cortisol, blood glucose and triglyceride levels.

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... As stress is implicated in all three of the other common disorders, we first review the evidence for the anti-stress effect of WS, and then discuss the evidence for the use of WS in anxiety, depression, and insomnia. [45], exposing animals to cold [40], hypoxia [46], and/or prolonged restraint [17,38,40,47,48], either alone or in combination [41,42,49,50], or applying electrical shocks to the feet of animals [51][52][53][54]. In these studies, WS attenuated a variety of stress-induced changes, including behavioral changes (e.g., memory impairment [45,46,52,53,55]), biochemical changes (e.g., increased glucocorticoids [38, 39, 41, 42, 46-48, 50, 54, 56]) and physical changes (e.g., gastric ulcers [17,38,40,52]). ...
... Anti-stress effects were also seen for a leaf extract [45], a leaf and root extract [36] and an extract made from defatted seeds [40]. Extraction methods and test preparations varied, and included alcoholic extracts [40][41][42]51], aqueous extracts [45,49,50], hydroalcoholic extracts [36-38, 46, 52, 53, 55], a traditional extract made with water, ghee, and honey [53], a withanolide-free fraction [37,38], a glycowithanolide-rich [52] fraction, and several isolated compounds, including sitoindosides VII and VIII [17], 1-oxo-5β, 6β-epoxy-witha-2-ene-27-ethoxy-olide [64], and a substance named Compound X [49]. ...
... Similar effects were seen in a rat model of restraint stress, where a root preparation of WS attenuated stressinduced declines in peripheral T-lymphocytes counts (CD3+, CD4+, and CD8+ populations), IL-2, INF-γ, and polymorphonuclear leukocyte counts [48]. However, in rodent models of cold restraint stress and forced swimming-induced stress, stress increased white blood cell counts, neutrophils, lymphocytes, and eosinophils [41,42]. These effects were reversed by WS, suggesting immune-modulating activity [41,42]. ...
Article
Background Withania somnifera (WS), also known as Ashwagandha, is commonly used in Ayurveda and other traditional medicine systems. WS has seen an increase in public use worldwide due to its reputation as an adaptogen. This popularity has elicited increased scientific study of its biological effects, including a potential application for neuropsychiatric and neurodegenerative disorders. Objective This review aims to provide a comprehensive summary of preclinical and clinical studies examining the neuropsychiatric effects of WS, specifically its application in stress, anxiety, depression, and insomnia. Methods Reports of human trials and animal studies of WS were collected primarily from the PubMed, Scopus, and Google Scholar databases. Results WS root and leaf extracts exhibited noteworthy anti-stress and anti-anxiety activity in animal and human studies. WS also improved symptoms of depression and insomnia, though fewer studies investigated these applications. WS may alleviate these conditions predominantly through modulation of the hypothalamic-pituitary-adrenal and sympathetic-adrenal medullary axes, as well as through GABAergic and serotonergic pathways. While some studies link specific withanolide components to its neuropsychiatric benefits, there is evidence for the presence of additional yet unidentified active compounds in WS. Conclusion While benefits were seen in the reviewed studies, significant variability in the WS extracts examined prevents a consensus on the optimum WS preparation or dosage from treating neuropsychiatric conditions. WS generally appears safe for human use; however, it will be important to investigate potential herb-drug interactions involving WS if used alongside pharmaceutical interventions. Further elucidation of active compounds of WS is also needed.
... 4 Recent studies in animals have demonstrated a significant increase in swim endurance and reduction in cold restraint stress using either aqueous suspension or ethanolic extracts of ashwagandha root. 5 Researchers used chronic footshock to determine stress induced changes in rat brain frontal cortex and striatum, and found that animals treated with Withania somnifera an hour before the foot shock experienced a significantly reduced level of stress. 6 This research confirms the theory that ashwagandha has a significant anti-stress adaptogenic effect . ...
... The chopped roots were dried and powdered under aseptic conditions. The baseline withanolide concentration of the root powder without milk treatment was 0.37 (% w/w), as measured by HPLC (High performance liquid chromatography) as per USP Preparation of cold water extract 5 Kg of withania roots was powdered coarsely and two parts of water was added. The mixture was left undisturbed for a period of 24 h. ...
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Background: The duration one can apply energy to an activity is limited by stamina (endurance). Recent studies using extracts of ashwagandha (Withania) root powder, either aqueous or ethanolic suspension, have demonstrated a significant increase in physical endurance. Milk treatment enhances the potency of herbal preparations. Objectives: To evaluate the efficacy of milk treated root powder of ashwagandha as compared to standard preparation, in enhancing the physical endurance in mice, using swim endurance model. Methods: Male, Swiss albino mice (31-35 g, 6-8 weeks old) were randomized into 3 groups of 6 animals each : Control-Carboxy Methyl Cellulose 0.5%, Standard-commercial preparation of ashwagandha (100mg / Kg), test-milk treated ashwagandha root powder (100 mg/ Kg). Study drugs were administered per oral, once daily, for 7 days. On day 8, animals were allowed to swim in a propylene tank of dimension 40 cm x 25 cm x 15 cm, with water level at 25 cm. The animals were allowed to swim till exhaustion. The end point of swim endurance was when the mice near drowned. Results: There was a significant increase in
... The alcoholic whole plant extract when orally administered (100 mg/ kg of body weight) twice a day reduced stress-induced elevation in blood urea level, blood lactic acid, and adrenal hypertrophy in rats (231). The extract improved the swimming duration of mice with restoration of plasma cortisol, blood glucose, and triglyceride levels (232). The role of the plant for synergistic activation of the differential gamma-aminobutyric acid receptor as a potential pathway for the adaptogenic and neurological disorders (anxiety, nervous exhaustion, insomnia, etc.) in mice was investigated and found to be prominent (233). ...
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Withania somnifera L. is a multipurpose medicinal plant of family Solanaceae occurring abundantly in sub-tropical regions of the world. The folk healers used the plant to treat several diseases such as fever, cancer, asthma, diabetes, ulcer, hepatitis, eyesores, arthritis, heart problems, and hemorrhoids. The plant is famous for the anti-cancerous activity, low back pain treatment, and muscle strengthening, which may be attributed to the withanolide alkaloids. W. somnifera is also rich in numerous valued secondary metabolites such as steroids, alkaloids, flavonoids, phenolics, saponins, and glycosides. A wide range of preclinical trials such as cardioprotective, anticancer, antioxidant, antibacterial, antifungal, anti-inflammatory, hepatoprotective, anti-depressant, and hypoglycemic have been attributed to various parts of the plant. Different parts of the plant have also been evaluated for the clinical trials such as male infertility, obsessive-compulsive disorder, antianxiety, bone and muscle strengthening potential, hypolipidemic, and antidiabetic. This review focuses on folk medicinal uses, phytochemistry, pharmacological, and nutrapharmaceutical potential of the versatile plant.
... Another study evaluated the effect of ethanolic extract of Withania somnifera roots against acute stress induced in mice showing that pre-treatment of animals with Withania somnifera extract improved the swimming duration in mice. Further, the treatment with Ashwagandha significantly restored the stress-induced alterations in plasma cortisol, blood glucose, and triglyceride levels [26]. Similar effects of Ashwagandha root extract were also seen in stressed and overweight adults [17]. ...
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Background Stress, anxiety and impeded sleep are a frequent feature of life in modern societies. Across socio-economic strata, stress, anxiety and ineffective sleep detract from healthful living and serve as precursors of various ailments. The use of herbs to offset these antecedents and outcomes has greatly increased in recent years. Ashwagandha, an adaptogenic Ayurvedic herb, has been often used to combat and reduce stress and thereby enhance general wellbeing. While there have been other studies documenting the use of Ashwagandha for stress resistance, this is the first study to use a high-concentration root extract while also varying the dosage substantially. Therefore, this is the first study to offer insight into dose-response of a high concentration root extract. Material and methods In this eight-week, prospective, randomized, double-blind, placebo-controlled study, the stress-relieving effect of Ashwagandha root extract was investigated in stressed healthy adults. Sixty male and female participants with a baseline perceived stress scale (PSS) score >20 were randomized to receive capsules of Ashwagandha extract 125 mg, Ashwagandha extract 300 mg or identical placebo twice daily for eight weeks in a 1:1:1 ratio. Stress was assessed using PSS at baseline, four weeks and eight weeks. Anxiety was assessed using the Hamilton-Anxiety (HAM-A) scale and serum cortisol was measured at baseline and at eight weeks. Sleep quality was assessed using a seven-point sleep scale. A repeat measures ANOVA (general linear model) was used for assessment of treatment effect at different time periods. Post-hoc Dunnett's test was used for comparison of two treatments with placebo. Results Two participants (one each in 250 mg/day Ashwagandha and placebo) were lost to follow-up and 58 participants completed the study. A significant reduction in PSS scores was observed with Ashwagandha 250 mg/day (P < 0.05) and 600 mg/day (P < 0.001). Serum cortisol levels reduced with both Ashwagandha 250 mg/day (P < 0.05) and Ashwagandha 600 mg/day (P < 0.0001). Compared to the placebo group participants, the participants receiving Ashwagandha had significant improvement in sleep quality. Conclusion Ashwagandha root aqueous extract was beneficial in reducing stress and anxiety.
... Results indicate that W. somnifera, like Prostaglandin, has significant antistress adaptogenic activity confirming the clinical use of the plant in Ayurveda. Similar result was further confirmed by another investigation in which ethanolic extract of roots of W. somnifera 23 mg/kg (p.o), on acute stress induced biochemical and immunological perturbations in mice improved the swim duration in mice and significantly restored back the stress induced alterations in plasma cortisol, blood glucose and triglyceride levels (Anju 2011). Very recently, Candelario and his group proved that differential activation of GABA receptor subtypes explains a potential mechanism for its reported adaptogenic properties (Candelario et al. 2015). ...
Article
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Withania somnifera Dunal, is a commonly used herb in Indian Ayurvedic medicine system. Due to its pharmacological value and an inexhaustible source of novel biologically active compounds, it has been a great interest for researchers. The plant is known to possess anti-inflammatory, antitumor, antistress, antioxidant, immunomodulatory and hemopoetic properties. Various withanolides, steroidal lactones, have been isolated from W. somnifera and were known to have high therapeutic value. Based on the differences in the substitution patterns of withanolides the species has been classified into various chemotypes. So far, three different chemotypes have been identified, which have been further classified into ecotypes based on the contents of withanolides. Present review summarizes the phytochemical variability and pharmacological advances reported in literature.
Article
The objective of the present study was to observe the effect of cold water and fresh water swimming stress on physiological and biochemical parameters. 42 adult male 'albino rats of wistar strain with body weight ranging between (50-125g) were subjected to fresh water and cold water swimming stress. The body weight was measured before and after the stress period in all the rats. The animals were sacrificed by decapitation and blood samples were collected. The wet weight of the organs (heart, right and left kidneys, liver, spleen) was expressed per 100g of body weight. Total leucocyte count, red blood cell count, Platelet count, and Hemoglobin were estimated by standard physiological methods. Blood sugar level and serum total cholesterol level were measured by colorimetric method. We conclude that body weight, liver weight, spleen weight increased significantly followed by cold water swimming stress. Significant hypoglycemia was observed followed by both Fresh water and cold water swimming stress. Platelet count decreased significantly followed by both Fresh water and cold water swimming stress. Total leucocyte count increased significantly followed by Fresh water swimming stress.
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The effect of subacute cold swimming stress on the immune system of albino rats was investigated. Subacute cold stressed animals showed an increase in total WBC count, eosinophils and basophils. Phagocytic index and avidity index were also increased indicating hyperactive phagocytic process. On the other hand NBT reduction and soluble immune complex levels decreased significantly in stressed animals. There were no significant changes in the weight of the lymphoid organs.
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Withanolide D, the major component of the leaves of Withania somnifera chemotype II, is a steroidal lactone of the withanolide type, isomeric with withaferin A. It has been identified as 5, 6β-epoxy-4β, 20α-dihydroxy-1-oxo-(5β)witha-2, 24-dienolide. The structure has been elucidated by NMR measurements and by chemical degradation to 4β-acetoxy-5,6β-epoxy (5β) pregnan-1, 20-dione.
Article
In a preliminary publication (1) attention has been called to a syndrome which appears when a severe injury is inflicted upon the organism. This syndrome is independent of the nature of the damaging agent and represents rather a response to damage as such. Exposure to cold, traumatic injuries, excessive muscular exercise, spinal shock, acute infections, and intoxications with various drugs will evoke this syndrome if they damage the organism sufficiently. The course of this reaction, which we have interpreted as an expression of general defence, may be divided into three stages. During the first, or acute stage, observed in the rat ordinarily 6 to 48 hours after the initial injury, one notes a rapid decrease in the size of the thymus, spleen, lymph glands and liver; disappearance of fat tissue; edema formation, especially in the thymus and loose retroperitoneal connective tissue; accumulation of pleural and peritoneal transudate; loss of muscular tone; fall of body temperature; formation of acute erosions in the digestive tract, particularly in the stomach, small intestine and appendix; loss of cortical lipoids and chromaffin substance from the adrenals; and sometimes hyperemia of the skin, exophthalmos, increased lachrymation and salivation.
Article
ANIMALS continuously exposed to a uniform damaging stimulus (a drug, exposure to cold, excessive muscular exercise, etc.) at first display the symptoms of the `alarm reaction'1 and later pass into a resistant phase; sooner or later, however, the power of resistance is exhausted and the symptoms reappear. It has now been found that this third stage of the general adaptation syndrome may be reached more regularly and more promptly by withholding food.
Article
Two new acylsterylglucosides, sitoindoside VII and sitoindoside VIII, were isolated from the roots of Withania somnifera Dun., and were screened for putative anti-stress activity because the plant is widely regarded as the ‘Indian Ginseng’ by practitioners of the traditional Indian system of medicine. Since an acceptable paradigm of pharmacological tests for anti-stress screening has yet to be evolved, a battery of tests were employed to delineate the activity of the test compounds. The total MeOH-H2O (1:1) extractives of the roots of W. somnifera (SG-1) and equimolecular combination of sitoindosides VII, VIII and withaferin-A, a common withanolide, (SG-2), exhibited significant anti-stress activity in all the test parameters used. The two sitoindosides also produced per se anti-stress activity, which was potentiated by withaferin-A. A preliminary acute toxicity study indicated that the compounds have a low order of acute toxicity. The anti-stress activity of SG-1 and SG-2 is consonant with the therapeutic use of W. somnifera in the Ayurveda, the Indian system of medicine.
Article
Two new glycowithanolides, sitoindoside IX (1) and sitoindoside X (2), isolated from Withania somnifera Dun., were evaluated for their immunomodulatory and CNS effects (anti-stress, memory and learning) in laboratory animals, because the plant extract is used by practitioners of the Indian systems of medicine for similar purposes. The two compounds, in doses of 100–400 μg/mouse, produced statistically significant mobilization and activation of peritoneal macrophages, phagocytosis and increased activity of the lysosomal enzymes secreted by the activated macrophages. Both these compounds (50–200 mg/kg p.o.) also produced significant anti-stress activity in albino mice and rats and augmented learning acquisition and memory retention in both young and old rats. These findings are consistent with the use of W. somnifera, in Ayurveda, to attenuate cerebral function deficits in the geriatric population and to provide non-specific host defence.
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The biological response to stress involves the activation of two main neuroendocrine components, the hypothalamic-pituitary-adrenal axis and the sympathoadrenal medullary systems. Looking at the responses to stressors in a laboratory setting, e.g., cortisol production after exercising on a treadmill, is a valid and controlled way to study how people react to psychological and physical stressors. A common finding in such studies is that individuals respond bimodally to stress. More recently, researchers have been interested in the possible reasons why healthy individuals exhibit differential reactivity to stressors. The literature on the neuroendocrine responses to stress, with a particular focus on investigations of individual reactivity to psychological and physical stressors, is reviewed.
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