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Background: Owing to the increasing aged population globally, disorders and diseases of the CNS are anticipated to increase and profoundly impact the health care. As these neurodegenerative diseases (NDD) are complex, multifactorial and do not have identified etiological factors, unfortunately, drugs developed for the purpose have not met with the expected success. Hence, there has been a constant demand for the development of natural therapeutic adjuvants which are safe and possess the potential to attenuate multiple pathways., Methods: Numerous herbal/natural products have been used as therapeutics in Ayurvedic system of medicine to treat NDD and other memory-related disorders. Withania somnifera (Ashwagandha, WS), popularly called as "Indian Ginseng" is one such plant which possesses a variety of beneficial neuropharmacological properties. In this review, we have attempted to review critically the existing literature and patents related to the neuroprotective efficacy of WS roots and the underlying mechanism/s., Results: Standardized extracts of Withania somnifera (WS) have been demonstrated to possess multidimensional neuromodulatory effects both in vitro and animal models. The spectrum of effects evidenced comprises of attenuation of oxidative damage by enhancing the antioxidant defense system with concomitant enhancement of the expression of marker proteins responsible for growth, differentiation and communication of neural cells. Specific effects of WS are attributable to its potential to modulate neurotrophic factors, cytoskeletal elements, cell adhesion molecules and synaptic proteins., Conclusion: Generation of new data by employing systematic contemporary approaches such as bioinformatics, molecular docking studies, identification of specific gene targets and epigenetic regulation would provide the necessary impetus to validate fully the neurotherapeutic potential of the phytochemicals derived from WS. More importantly, well-designed clinical trials are required to exploit the neuromodulatory propensity of WS extract/bioactives in specific neurodegenerative diseases such as AD and PD.

Male reproductive dysfunctions and infertility are the common consequences of overt diabetes. Available evidence support oxidative stress to be the underlying mechanism for the manifestation of testicular complications during diabetes. In the present study, we assessed the attenuating effects of Withania somnifera root extract (WS) on diabetes-induced testicular oxidative disturbances in prepubertal rats. Four-week-old prepubertal rats were assigned into nondiabetic control, streptozotocin (STZ)-treated and STZ+WS supplemented (500 mg/kg b.w./d, oral, 15 days) groups. Experimental diabetes was induced by a single intraperitoneal injection of STZ (90 mg/kg b.w). Terminally, all animals were killed, and markers of oxidative stress were determined in the testis cytosol and mitochondrial fraction. Severe hyperglycemia and regression in testis size were apparent in diabetic rats. A decline in antioxidant defenses with subsequent elevation in the generation of reactive oxygen species and lipid peroxidation was discernible in testis cytosol and mitochondria of diabetic prepubertal rats, which was significantly reversed by WS. However, there was partial restoration of glucose-6-phosphate dehydrogenase, lactate dehydrogenase, and 3-beta hydroxysteroid dehydrogenase activities in testis of diabetic prepubertal rats administered with WS. Taken together, data accrued suggest the potential of WS to improve diabetes-induced testicular dysfunctions in prepubertal rats.

Withania somnifera (WS) an ayurvedic medicinal herb is widely known for its memory enhancing ability and improvement of brain function. In the present study, we tested the hypothesis that WS prophylaxis could offset neurotoxicant-induced oxidative dysfunctions in developing brain employing a rotenone (ROT) mouse model. Initially, we assessed the potential of WS oral supplements (100-400 mg/ kg b.w/ d, 4wks) to modulate the endogenous levels of oxidative markers in cerebellum (cb) and striatum (st) of prepubertal (PP) mice. Further, we assessed the induction of oxidative stress in cb and st of mice administered with ROT (i.p. 0.5 and 1mg/ kg b.w, 7d). ROT caused significant elevation in the levels of reactive oxygen species (ROS), malondialdehyde (MDA), hydroperoxides (HP) and nitric oxide (NO) levels in both brain regions. Further ROT caused significant perturbations in the levels of reduced glutathione (GSH), activity levels of antioxidant enzymes, acetylcholinesterase and mitochondrial dysfunctions suggesting a state of oxidative stress. In a satellite study, we examined the protective effects of WS root powder (400mg/ kg b.w/ d, 4wks) in PP mice challenged with ROT (0.5 mg/ kg b.w/ d, 7 d). WS prophylaxis significantly offset ROT-induced oxidative damage in st and cb as evident by the normalized levels of oxidative markers (MDA, ROS levels and HP) and restoration of depleted GSH levels. Further, WS effectively normalized the NO levels in both brain regions suggesting its antiinflammatory action. Furthermore, WS prophylaxis restored the activity levels of cytosolic antioxidant enzymes, neurotransmitter function and dopamine levels in st. Taken together, these findings suggest that WS prophylaxis has the propensity to modulate neurotoxicant-mediated oxidative impairments and mitochondrial dysfunctions in specific brain regions of mice. While the exact mechanism/s underlying the neuroprotective effects of WS merit further investigation, based on our findings, we hypothesize that it may be wholly or in part due to its ability to enhance GSH, thiols and antioxidant defences in the brain of mice.