Dihydromyricetin Inhibits Α-Synuclein Aggregation, Disrupts Preformed Fibrils, and Protects Neuronal Cells in Culture Against Amyloid-Induced Cytotoxicity

Fibrillogenesis of α-synuclein (αSN) is associated with the onset and progression of Parkinson's disease (PD). Dihydromyricetin (DHM), a natural flavonoid compound extracted from Ampelopsis grossedentata, has proven antioxidative, antineuroinflammatory, and neuroprotective effects in dementia. However, it remains unclear if DHM can impede αSN fibrillogenesis and attenuate the corresponding cytotoxicity. Herein, we found that DHM could inhibit αSN fibrillogenesis and destabilize mature αSN fibrils in a dose-dependent manner. Moreover, DHM protected against αSN-induced cytotoxicity by improving the cell viability by 34.73 ± 3.68% at a 1:1 molar ratio of αSN to DHM. Molecular dynamics simulations showed that DHM interacts with the αSN trimer mainly via nonpolar mechanisms. The key residues by which αSN interacts with DHM were hydrophobic, and their side chains and main chains showed a synergistic effect via hydrophobic and hydrogen-bonding interactions. These findings suggest that DHM possesses great potential to be developed into a new aggregation inhibitor for αSN.