Table 2.
Anti-stress effects of Ashwagandha (Withania somnifera, WS) in animal studies.
| Nature of Extract, Standardization | Dosage | Model | Outcomes | Refs. | |||||
|---|---|---|---|---|---|---|---|---|---|
| Root powder (KSM-66), standardized to ≥5% withanolides | 2.5, 5, or 10 g/day p.o. for 21 days | Horse (exercise-, separation-, and noise-induced stress) | ▲stress-induced decrease in peripheral total erythrocyte count, total leukocyte count, hemoglobin, lymphocyte percentage, serotonin, GSH and SOD activity, HDL and LDL cholesterol ▼stress-induced increase in peripheral cortisol, epinephrine, TBARs, blood glucose, ALT, AST, creatinine, triglycerides, IL-6 |
[56] | |||||
| Water-ethanol (7:3) root extract, containing 0.23% (w/w) isowithanone | 500 mg/kg p.o., 6 days per week for 6 weeks | Rat (SPS) | ▲short- and long-term memory (RAWM) ▲hippocampal oxidative stress biomarkers (▼GSSG, ▲GSH/GSSG, ▲GPx activity, catalase, and SOD) |
[55] | |||||
| Withanolide-free root extract | 3.3, 10, 33.3, and 100 mg/kg p.o. for 12 days | Rat (FSS) | ▼stress-induced weight loss ▼stress-induced increase in rectal temperature ▼transient hyperthermic response (FSS) ▼anxiety-like or depression-like behavior (MBT) ▼stress-induced increase in adrenal weight ▼stress-induced increase in plasma cortisol and blood glucose |
[54] | |||||
| Methanolic root extract, standardized to 2.7% (w/w) total withanolides | 10, 20, and 40 mg/kg/day p.o. for 11 days, or as a single dose | Rat (FSS, HPT, TST) | ▼stress-induced weight loss ▼transient hyperthermic response (FSS) ▲reaction time (HPT) ▼depression-like behavior (TST) |
[51] | |||||
| Aqueous methanolic (75:25) root extract, NR | 200 mg/kg p.o. for 21 days before hypoxia and 7 days during hypoxia | Rat (hypobaric hypoxia) | ▼stress-induced increase in corticosterone*^, NO^, AChE activity^, ROS^, lipid peroxidation^, synaptophysin^, nNOS^, L-type calcium channels^, pyknotic cells in CA3 region of hippocampus^, Bax^ ▲stress-induced decrease in ACh^, GSH^, SOD activity^, BDNF^, NCAM^, Bcl-2^ ▼stress-induced memory impairment (MWM) |
[46] | |||||
| Aqueous leaf extract (ASH-WEX), NR | 140 mg/kg/bwt, p.o. for 15 days prior to acute sleep deprivation | Rat (acute sleep deprivation) | ▼stress-induced learning and memory impairments ▼stress-induced motor dysfunction ▼anxiety-like behavior (▼grooming activity) Modulated markers of synaptic plasticity (▼hippocampal PSA-NCAM and NCAM, ▲PSA-NCAM in the pyriform cortex)^ ▼mortalin^, ▲Akt-1 phosphorylation^ |
[45] | |||||
| Ethanolic root extract, NR | 23 mg/kg p.o. for 7 days prior to assessment | Mouse (FST, CRS) | ▲swim duration (FST) ▼stress-induced increase in WBC count, blood glucose, plasma cortisol, and serum triglyceride levels (CRS) |
[41] | |||||
| Alcoholic root extract, NR | FST: 100 mg/kg p.o. for 7 days CRS: 100 mg/kg p.o. for 10 days |
Rat (FST, CRS) | ▲swim duration (FST) ▼stress-induced increase in blood glucose, total cholesterol, triglycerides, serum corticosterone, RBC count, WBC count, neutrophils, lymphocytes, and eosinophils (FST, CRS) ▼stress-induced increase in monocytes, liver weight, and adrenal weight (CRS) ▲stress-induced decrease in spleen weight (CRS) |
[42] | |||||
| Root extract, NR | 40 mg/kg/bwt p.o. for 30 days | Mouse (RST) | ▼stress-induced increase in corticosterone* and hippocampal nNOS-positive neurons ▲stress-induced decrease in ChAT reactivity^ and serotonin^ |
[47] | |||||
| Nature of Extract, Standardization | Dosage | Model | Outcomes | Refs. | |||||
| Water:methanol 40:60 leaf and root extract (“Sensoril®”), standardized to 10% total withanolides | 50 and 100 mg/kg p.o. for 7 or 30 days | Mouse (FST) | ▲stress-induced decrease in ATP, AEC, TAN, and ATP/ADP ratio (7- and 30-day FST) | [36] | |||||
| Root (preparation unclear), NR | 25, 50, 100, and 200 mg/kg p.o. for 14 days | Mouse (RST) | ▲stress-induced decrease in T lymphocyte count (CD3+, CD4+, and CD8+ populations)*, IL-2*, IFN-γ*, polymorphonuclear leucocyte count*, and organ weights (thymus, spleen, axillary lymph nodes) ▼stress-induced increase in serum cortisol |
[48] | |||||
| Glycowithanolide-rich fraction (containing sitoindosides VII-X and withaferin) isolated from aqueous ethanolic (1:1) root extract, standardized to 28-30% withanolide glycosides | 25 and 50 mg/kg p.o. for 21 days, administered 1 hr before assessment | Rat (FSS) | ▼stress-induced hyperglycemia, perturbed glucose tolerance test, and gastric ulcers (FSS) ▼depression-like behavior (FST, LHT) ▼stress-induced memory impairment (EPM, PAT), sexual behavior inhibition (FSS), and immunosuppression (FSS) |
[52] | |||||
| Isolated fraction and pure compound (1-oxo-5β, 6β-epoxy-witha-2-ene-27-ethoxy-olide), extracted from aqueous root extract | Fraction: 20 mg/kg/bwt p.o., administered 30 mins prior to assessment Compound: 2.5 mg/kg/bwt p.o., administered 30 mins prior to assessment |
Rat (CHR) | ▼stress-induced increase in serum corticosterone, CPK, LDH (fraction, compound) ▼stress-induced increase in LPO (compound) ▲time taken to achieve 23˚C rectal temperature (fraction, compound) ▼recovery time taken to achieve 37˚C rectal temperature (fraction, compound) |
[50] | |||||
| Traditional root extract consisting of water:ghee:honey (60:7.5:32.5) and 50% methanolic root extract, NR | Traditional extract: 250 mg/kg Methanolic extract: 250 mg/kg |
Rat (FSS) | ▼depression-like behavior (FST, methanolic extract) ▼stress-induced memory impairment (PAT, both extracts) |
[53] | |||||
| Withanolide-free aqueous fraction (BF), isolated from hydroalcoholic (30:70) root extract and a root extract, NR | Withanolide-free fraction: 12.5, 25, 50, and 100 mg/kg p.o., administered 2 hrs before assessment Root extract: 125 mg/kg p.o., administered 2 hrs before assessment |
Rat (FST) | ▼stress-induced increase in serum GPT, GOT, ALP, triglycerides, and hepatic LPO (fraction, extract) ▲stress-induced decrease in hepatic glycogen (fraction, extract) |
[37] | |||||
| Aqueous root extract and isolated compound (Compound X) from aqueous root extract, NR | Root extract: 360 mg/kg/bwt, administered 30 mins before assessment Compound: 20 mg/kg/bwt, administered 30 mins before assessment |
Rat (CHR) | ▲time taken to achieve 23˚C rectal temperature (extract, compound) ▼recovery time taken to achieve 37˚C rectal temperature (extract, compound) |
[49] | |||||
| Withanolide-free aqueous fraction (BF), isolated from hydroalcoholic (30:70) root extract and a commercial root extract, NR | Fraction: 12.5, 25, 50, 100 mg/kg p.o. for 15 days Root extract: 125 mg/kg p.o. for 15 days |
Rat (HST, FST, RST, RTT) | ▲hypoxia-induced time to convulsion (HST, fraction, extract) ▲swimming duration (FST, fraction, extract) ▼stress-induced gastric ulcers (FST, RST, fraction, extract) ▲antifatigue activity (RTT, fraction, extract) ▼stress-induced hypothermia (FST, fraction, extract) ▼stress-induced autoanalgesia, increase in adrenal weight (RST, fraction, extract) ▲stress-induced decrease in adrenal content of ascorbic acid, cortisol, and cholesterol (RST, fraction, extract) |
[38] | |||||
| Nature of Extract, Standardization | Dosage | Model | Outcomes | Refs. | |||||
| Powdered root, NR | 100 mg/kg p.o. for 7 days | Rat (FST) | ▲swim duration ▼stress-induced increase in plasma corticosterone level, phagocytic index, and avidity index |
[39] | |||||
| Sitoindosides VII and VIII | PTZ: 20 mg/kg i.p., 30 mins prior to assessment FST: 20 and 50 mg/kg i.p., 30 mins prior to assessment OST, TCT: 50 mg/kg p.o. for 4 days RST: 50 and 100 mg/kg p.o. for 4 days; 100 mg/kg i.p., 30 mins before morphine administration Morphine toxicity: 50 mg/kg p.o. for 4 days |
Mouse (FST, OST, TCT) Rat (PTZ, RST) |
▼depression-like behavior (FST) ▼stress-induced autoanalgesia, gastric ulcers (RST) ▼morphine-induced hypothermia (RST) ▼morphine toxicity (OST, TCT) ▼anxiety-like behavior (PTZ-induced) ▼tribulin activity in urine (RST) ▲stress-induced decrease in adrenal content of ascorbic acid, corticosterone |
[17] | |||||
| Alcoholic extract from defatted seeds, NR | 100 mg/kg i.p., administered 30 mins or 1 hr before assessment | Mouse (FST, MIL) Rat (CST, RST, ASA) |
▲swim duration (FST) ▲stress-induced decrease in ascorbic acid and cortisol content in adrenals (FST) ▼stress-induced gastric ulcers (CST, RST, ASA) ▼milk-induced leukocytosis (MIL) |
[40] | |||||
*Peripheral; ^CNS; ▲ – Increased; ▼ – Decreased; ACh = Acetylcholine; AChE = Acetylcholinesterase; ADP = Adenosine diphosphate; AEC = Adenylate energy charge; ALP = Alkaline phosphatase; ALT/GPT = Alanine aminotransaminase; ASA = Aspirin administration; AST/GOT = Aspartate aminotransferase; ATP = Adenosine triphosphate; Bax = Bcl-2-associated X protein; BDNF = Brain-derived neurotrophic factor; ChAT = Choline acetyl transferase; CHR = Cold-Hypoxia-Restraint test; CRS = Cold restraint stress test; CST = Cold stress test; EPM = Elevated plus maze test; FSS = Foot shock stress test; FST = Forced swim test; GPx = Glutathione peroxidase; GSH = Reduced glutathione; GSSG = Oxidized glutathione; HDL = High density lipoprotein; HPT = Hot plate test; HST = Hypoxia stress test; IFN-γ = Interferon gamma; IL-2 = Interleukin 2; IL-6 = Interleukin 6; LDL = Low density lipoprotein; LHT = Learned helplessness test; LPO = Lipid peroxidation; MIL = Milk-induced leukocytosis; MWM = Morris Water Maze test; NCAM = Neural cell adhesion molecule; nNOS = Nitric oxide synthase; NO = Nitric oxide; NR = Not reported; OST = Overcrowding stress test; PAT = Passive avoidance test; PTZ = Pentylenetetrazol administration; RAWM = Radial arm water maze; RBC = Red blood cell; ROS = Reactive oxygen species; RST = Restraint stress test; RTT = Rotarod test; ROS = Reactive oxygen species; SOD = superoxide dismutase; SPS = Single prolonged stress; TAN = Total adenine nucleotide; TBARs = Thiobarbituric acid reactive substances; TCT = Tactile stress test; TST = Tail suspension test; WBC = White blood cell.