Citrus Flavonoid Hesperetin Inhibits α-Synuclein Fibrillogenesis, Disrupts Mature Fibrils, and Reduces Their Cytotoxicity: In Vitro and In Vivo Studies

Misfolding and subsequent fibrillogenesis of alpha-synuclein (alpha SN) significantly influence the development of Parkinson's disease (PD). This study reports the inhibitory effect of citrus flavonoid hesperetin (Hst) on alpha SN fibrillation. Based on thioflavin T fluorometry and atomic force microscopy studies, Hst inhibited alpha SN fibrillation by interfering with initial nucleation and slowing the elongation rate. Furthermore, the inhibitory effect was concentration-dependent with a half-maximal inhibitory concentration of 24.4 mu M. Cytotoxicity experiments showed that 100 mu M Hst significantly reduced the cytotoxicity of alpha SN aggregates and maintained 98.4% cell activity. In addition, Hst disassembled the preprepared alpha SN fibrils into smaller and less-toxic aggregates. Excitingly, supplementation with 100 mu M Hst inhibited the accumulation of 36.3% alpha SN in NL5901 and restored the amyloid-induced reduction in NL5901 lipid abundance, extending the mean lifespan of NL5901 to 23 d. These findings could support the use of Hst as a dietary supplement to regulate alpha SN fibrillation and prevent the development of PD.

Automated summary

This study shows that the citrus flavonoid hesperetin (Hst) can inhibit the fibrillation of alpha-synuclein (alpha SN) and reduce its cytotoxicity, potentially serving as a dietary supplement to prevent the development of Parkinson's disease (PD).