Dihydromyricetin inhibits α-synuclein aggregation, disrupts preformed fibrils and protects neuronal cells in culture against amyloid-induced cytotoxicity.

Fibrillogenesis of alpha-synuclein (aSN) 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 aSN fibrillogenesis and attenuate the corresponding cytotoxicity. Herein, we found that DHM could inhibit aSN fibrillogenesis and destabilize mature aSN fibrils in a dose-dependent manner. Moreover, DHM protected against aSN-induced cytotoxicity by improving the cell viability by 34.73 3.68% at a 1:1 molar ratio of aSN to DHM. Molecular dynamics simulations showed that DHM interacts with the aSN trimer mainly via nonpolar mechanisms. The key residues by which aSN 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 aSN.