Discovery of potent and selective dual cholinesterases and ?-secretase inhibitors in pomegranate as a treatment for Alzheimer?s disease

Pomegranate (Punica granatum L.) extract has been reported to inhibit cholinesterase and the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1); however, most of its constituents' potential inhibition of these enzymes remains unknown. Thus, we investigated the anti-Alzheimer's disease (anti-AD) potential of 16 ella-gitannin and gallotannin, and nine anthocyanin derivatives' inhibition of BACE1, AChE, and BChE, and gallagic acid inhibited both the best. Further, a kinetic study identified different modes of inhibition, and a molecular docking simulation revealed that active compounds inhibited these three enzymes with low binding energy through hydrophilic and hydrophobic interactions in the active site cavities. Gallagic acid and castalagin decreased A beta peptides secretion from neuroblastoma cells that overexpressed human beta-amyloid precursor protein significantly by 10 mu M. Further, treatment with gallagic acid and castalagin reduced BACE1 and APPs beta expression levels significantly without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Co-incubation of A beta 42 with gallagic acid reduced A beta 42-induced intracellular reactive oxygen species (ROS) production significantly. Our results suggest that pomegranate constituents, specifically gallagic acid, may be useful in developing therapeutic treatment modalities for AD.

Automated summary

Gallagic acid, a constituent of pomegranate extract, shows potential in treating Alzheimer's disease by inhibiting BACE1 and AChE, thereby reducing Aβ peptide accumulation and intracellular reactive oxygen species production.