Improving the inhibition of β-amyloid aggregation by withanolide and withanoside derivatives

Abstract

Here, we have studied the ameliorative effects of Withania somnifera derivatives (Withanolide A, Withanolide B, Withanoside IV, and Withanoside V) on the fibril formation of amyloid-β ₄₂ for Alzheimer's disease. We analyzed reduction in the aggregation of β amyloid protein with these Ashwagandha derivatives by Thioflavin T assay in the oligomeric and fibrillar state. We have tested the cytotoxic activity of these compounds against human SK-N-SH cell line for 48 h, and the IC ₅₀ value found to be 28.61 ± 2.91, 14.84 ± 1.45, 18.76 ± 0.76 and 30.14 ± 2.59 μM, respectively. After the treatment of the cells with half the concentration of IC ₅₀ value, there was a remarkable decrease in the number of apoptotic cells stained by TUNEL assay indicating the DNA damage and also observed significant decrease of reactive oxygen species. Also, the binding and molecular stability of these derivatives with amyloid β was also studied using bioinformatics tools where these molecules were interacted at LVFFA region which is inhibition site of amyloid-β1 ₄₂. These studies revealed that the Withanolides and Withanosides interact with the hydrophobic core of amyloid-β _1-42 in the oligomeric stage, preventing further interaction with the monomers and diminishing aggregation.