Synthesis of formononetin derivatives and their neuroprotective activities

Abstract

To develop a series of derivatives (C1–14) of Formononetin (FMN) and evaluate their neuroprotective effects and potential mechanisms in N2a/APP695 cells. The levels of Aβ1–42 were quantified using ELISA, while mitochondrial membrane potential and ROS content were assessed via JC-1 and DCFH-DA methods, respectively. Additionally, mitochondrial function was evaluated by measuring ATP levels. Protein expressions of PINK1, Parkin, p62, LC3, and p-Tau S396 were analyzed using Western blotting. The results showed that compared to the control group, C1–14 significantly reduced the level of Aβ1–42, with C7 exhibiting the most pronounced effect. Further investigation revealed that C7 improved mitochondrial function, upregulated the expression of PINK1, Parkin, and LC3, and downregulated the levels of p62 and p-Tau S396. The results indicate that C7 demonstrates a neuroprotective effect by activating mitochondrial autophagy, optimizing mitochondrial function, and inhibiting the accumulation of Aβ1–42 and p-Tau S396 in nerve cells. This is achieved through the promotion of mitochondrial autophagy-related proteins PINK1 and Parkin. Thus, C7 represents a promising candidate for the prevention and treatment of AD, offering a novel therapeutic strategy