Lipophilic ferulic acid derivatives protect PC12 cells against oxidative damage via modulating beta-amyloid aggregation and activating Nrf2 enzymes

Ferulic acid (FA) has been shown to have a neuroprotective effect on Alzheimer's disease induced by amyloid-beta (A beta) neurotoxicity. This work aims to ascertain the structure-activity relationship of FA and its alkyl esters (FAEs) for evaluating the antioxidant activities in PC12 cells and A beta(1-42) aggregation inhibitory activities in vitro, as well as the signaling mechanisms against oxidative stress elicited by A beta(1-42) in PC12 cells. Our data showed that alterations in the subcellular localization and cytotoxicity of FAEs caused by the lipophilicity of FA were crucial when evaluating their antioxidant capacities. Pre-treating cells with butyl ferulate (FAC4) significantly attenuated A beta(1-42)-evoked intracellular ROS formation. Besides, FAC4 exhibited the highest A beta(1-42) aggregation inhibitory effectiveness. The molecular docking results showed that FAC4 binds to amide NH in Gln15 and Lys16 via a hydrogen bond. Notably, FAC4 could upregulate antioxidant defense systems by modulating the Keap1-Nrf2-ARE signaling pathway. Identification of the functions of FAEs could be useful in developing food supplements or drugs for treating AD.