Withania somnifera

Withania somnifera (L.) Dunal (Solanaceae) root, known as ‘ashwagandha’ in Sanskrit, is classed among ‘Rasayanas’, the rejuvenative tonics, and its use dates back almost 4000 years. It is considered to be one of the most highly regarded herbs in Ayurvedic medicine. The Ayurvedic scholar Charaka (10 BC) described the reputed effects associated with Withania somnifera: ‘One obtains longevity, regains youth, gets a sharp memory and intellect and freedom from diseases, gets a lustrous complexion and strength of a horse’. It has also traditionally been used to treat some inflammatory conditions such as arthritis.

Numerous studies provide experimental evidence to support the traditional uses of Withania somnifera, and many of these have associated the biological activities with various steroidal derivatives found in the root. The sitoindosides IX and X isolated from the root augmented learning acquisition and memory in both young and old rats. This observation could be explained by a modulatory effect on cholinergic function, since another study with an extract of Withania somnifera containing the sitoindosides VII-X and withaferin A resulted in enhanced acetylcholinesterase activity in the lateral septum and globus pallidus and decreased acetylcholinesterase activity in the vertical diagonal band, enhanced muscarinic M1 receptor binding in the lateral and medial septum and the frontal cortices, and increased muscarinic M2 receptor binding sites in cortical regions, when administered to rodents. However, it was not shown to affect GABAa, benzodiazepine receptor binding, or NMDA or amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor subtypes in this study. Another study showed a similar extract containing the same sitoindosides and withaferin A to reverse the ibotenic acid-induced cognitive deficit and the reduction in cholinergic markers (e.g. acetylcholine, choline acetyltransferase) in rodents. Tests in vitro have shown a methanol extract of Withania somnifera to inhibit acetylcholinesterase and some withanolides inhibit acetylcholinesterase and butyrylcholinesterase, with withaferin A,2,3-dihydrowithaferin A and 5β,6β-epoxy-4β-hydroxy-l-oxowitha-2,14,24-trienolide being more active against acetylcholinesterase activity. These studies indicate that Withania somnifera and some of its components, particularly some withanolides and sitoindosides, may improve cognition by influencing cholinergic neuro-transmission, although other mechanisms of action have also been suggested.

A reversal of scopolamine-induced disruption of acquisition and attention and attenuation of amnesia was observed when a root extract of Withania somnifera was administered to mice, and these effects were suggested to be due to a nootropic effect. Other studies have shown that Withania somnifera root (methanol extract), and some of the withanolide derivatives in particular, could dose-dependently promote dendrite formation in human neuroblastoma cells in vitro. Withanolide A and withanosides IV and VI are also reported to extend axons and dendrites, respectively, in vitro, and withanolide A is considered to reconstruct neuronal networks in vivo. The clinical relevance of these effects is unknown, but cholinergic function could be modulated if neurite outgrowth were to occur in the CNS at therapeutic doses and with consideration of pharmacokinetic profiles of the relevant compounds in vivo. The main metabolite of withanoside IV following oral administration was identified as the aglycone sominone, which induced axonal and dendritic regeneration and synaptic reconstruction in cultured rat cortical neurons. The use of Withania somnifera to improve some memory disorders shows promise, if compounds demonstrate a suitable pharmacokinetic profile for efficacy. A neuroprotective action has also been considered as an explanation for the reputed effects of the root of this medicinal plant, since a root extract significantly reduced the number of hippocampal degenerating cells in the brains of stressed rodents and was neuroprotective in an animal model of Parkinson’s disease.

In addition to the steroidal derivatives, other compounds may contribute to the reputed and pharmacological effects of Withania somnifera root preparations. The cognitive benefits associated with nicotine could also explain the effects on memory observed with Withania somnifera, since this alkaloid is reported to occur in Withania somnifera root. However, other studies have not reported it to be present. Chemical variation in Withania somnifera plants has been reported to occur, which emphasises the need for standardisation of plant-derived products for therapeutic use.

Other activities that may be advantageous in the alleviation of some cognitive disorders are anti-inflammatory and antioxidant effects, both of which have been associated with Withania somnifera. Inhibition of lipid peroxidation both in vitro and in vivo has been observed with extracts of the root, with the root extract and the glycowithanolides (containing equimolar concentrations of sitoindosides VII-X and withaferin A) protecting against lipid peroxidation due to an antioxidant action. In addition to the withanolides being antioxidant and decreasing lipid peroxidation in rodent brains, withanolides and sitoindosides (VII-X) also enhanced catalase and glutathione peroxidase activities in rat frontal cortex and striatum. Phenolic compounds from Withania somnifera root might also contribute to the overall antioxidant properties of this plant.

Evidence for the anti-inflammatory effects of Withania somnifera is apparent in several studies. Root extracts were effective against arthritis and associated biochemical markers in rodents; they reduced serum protein levels β2-macroglobulin, an indicator of inflammatory conditions) and also reduced interleukin-1 (IL-1) and tumour necrosis factor (TNF)-α levels in vivo, which may be of some clinical relevance as some inflammatory mediators have been linked with senile plaque formation in some cognitive disorders. The compounds responsible for these observations require further study, although a dimeric withanolide, ashwagandhanolide, is an inhibitor of COX-2 activity. The leaves of Withania somnifera leaves are also reported to have anti-inflammatory activity.

Withania somnifera root has been extensively studied and shown to possess a variety of activities that could be relevant to improve cognitive impairment. It appears to have therapeutic potential for treating memory-related disorders, but further evidence of clinical safety and efficacy is still needed before this promising herbal drug could be considered for wider use in cognitive disorders.