Therapeutic potential of flavonoids against α-synuclein aggregation in Parkinson's Disease: Integrative in silico and in vitro analysis

Abstract

Amyloidogenic protein aggregation is the key factor in neurodegenerative diseases. Due to the cost-effectiveness and low side effects, attention to herbal medicines has been recently increased. Flavonoids are a group of plant compounds with high potential for reducing the accumulation of amyloidogenic proteins. This research aims to identify the most effective flavonoids for inhibiting the fibrillation of α-synuclein (α-syn). For this purpose, 98 flavonoids from different databases were selected for analysis. The pharmacokinetic properties of these flavonoids were evaluated using OSIRIS and Swiss-ADME web tools. The interaction of α-syn and flavonoids was investigated in the positions predicted via DoGSiteScorer and CASTp web servers. Subsequently, luteolin and baicalein, the flavonoids with the most negative binding energy and interaction with the amino acids of α-syn amyloidogenic regions, were selected for further in vitro studies. In this phase, α-syn was incubated under fibrillation conditions in the presence and absence of flavonoid treatment. Results from the thioflavin T (ThT) fluorescence assay, atomic force microscopy (AFM), and proteinase K (PK) enzymatic digestion assay showed that baicalein and luteolin significantly inhibited α-syn fibril formation. Fourier transform infrared spectroscopy (FTIR) demonstrated a decrease in β-sheet content and confirmed the inhibitory effect of baicalein and luteolin. In addition, cell culture analysis also showed that luteolin could increase the viability of SH-SY5Y cells exposed to α-syn fibrils by destabilizing toxic fibrils and converting them into non-toxic amorphous aggregates. These findings can be useful to develop flavonoid-based therapeutic strategies for synucleinopathies, such as Parkinson's disease (PD).