Anti-amnesic effects of withaferin A,a steroidal lactone isolated from Withania adpressa,on scopolamine-induced memory impairment in mice

Natural secondary metabolites have long served as sources of drugs against various health disorders, among them neurodegenerative diseases especially Alzheimer’s disease (AD). Withanolides, isolated from Withania species, have shown acetylcholinesterase inhibition activity and their neuroprotective effects may be beneficial in the treatment of cholinergic system associated diseases, such as AD. This study was undertaken to highlight the neuroprotective effects of withaferin A (WA), isolated from W. adpressa leaves, using a scopolamine-induced memory impairment model in mice. The in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition potentials of WA were assessed. The learning and memory enhancing activities of WA at different doses (1, 3 and 5 mg/kg) were investigated utilizing Novel Object Recognition (NOR) and Barnes maze (BM). WA substantially inhibited AChE and BuChE enzymes with IC₅₀ values of 45.5 ± 0.14 and 68.2 ± 0.27 µg/mL, respectively. Noteworthy, rotarod results revealed no significant differences between WA and control groups. Also, learning, and spatial memory performance in NOR and BM tests were improved compared to the control groups. Furthermore, the activity of acetylcholinesterase in the brain was significantly inhibited (p < 0.05) by WA at the three tested doses. WA possessed certain affinity in both enzymes with low binding energy compared to the reference drug donepezil in a molecular docking study. This study displays that WA could be used for enhancing learning and memory impairment and appears to be a promising candidate for Alzheimer’s disease treatment.