LAUSR

Graphical abstract Figure. No Caption available. HighlightsWith the increase in life expectancy there is sharp increase in the older patient base raising concerns about the increase in the age related degenerative diseases specifically AD.Since AD is a multiple pathogenetic disease, finding multi‐potent agent that aims at multiple targets is attracting more and more attention.We evaluated different constituent compounds present in the root extract of W. somnifera for its anti‐Alzheimer’s effect and zeroed in on Withanone, (WS‐2) that shows significant activity.WS‐2 at graded oral doses administered once daily to wistar rats for duration of 21 days significantly improved the cognitive impairment by inhibiting amyloid &bgr;‐42.It attenuated the elevated levels of pro‐inflammatory cytokines like TNF alpha, IL‐1 beta, IL‐6, MCP‐1, Nitric oxide, lipid peroxidation and both &bgr;‐ and &ggr;‐ secretase enzymatic activity.Administration of WS‐2 also significantly enhanced the acetyl choline and Glutathione (GSH) activity.WS‐2 inhibited Th1 and Th17 cytokine expression in peripheral blood and non‐significantly increased the levels of Th2 cytokines.With the increase of information on natural moieties obtained from medicinal plants and the effort of evaluating compound WS‐2 from a revered plant Withania somnifera, paves way for its future exploration as a multi‐factorial therapeutic agent for AD. Abstract Alzheimer's disease (AD) is a chronic disorder that slowly worsens and impairs the person's memory, learning, reasoning, judgment, communication and familiar tasks with loss of orientation. AD is characterized clinically by cognitive deficit and pathologically by the deposition of &bgr; amyloid plaques, neurofibrillary tangles, associated with degeneration of the cholinergic forebrain. Withanone (WS‐2), a compound isolated from root extract of Withania somnifera at doses administered orally/day to wistar rats for duration of 21 days showed significant improvement in the cognitive skill by inhibiting amyloid &bgr;‐42 and attenuated the elevated levels of pro‐inflammatory cytokines like TNF alpha, IL‐1 beta, IL‐6, MCP‐1, Nitric oxide, lipid peroxidation and both &bgr;‐ and &ggr;‐ secretase enzymatic activity. Administration of WS‐2 also significantly reversed the decline in acetyl choline and Glutathione (GSH) activity. None of the treatments that are available today alter the underlying causes of this terminal disease. Few preliminary clinical treatments have demonstrated that some plant medicines do ameliorate and improve memory and learning in patients with mild‐to‐moderate AD. WS‐2 showed promise in AD treatment because of cognitive benefits and more importantly, mechanisms of action with respect to the fundamental pathophysiology of the disease, not limited to the inhibition of AChE, but also include the modification of A&bgr; processing, protection against oxidative stress and anti‐inflammatory effects.