Deep Eutectic Solvents Improve Protective Effects of Quercetin against Cytotoxic Amyloid Fibrillation of α-Synuclein

Natural polyphenols are among the most frequently investigated small molecules showing promising therapeutic effects against neurodegenerative diseases. However, drawbacks such as poor aqueous solubility and bioavailability have significantly restricted the biological applications of polyphenols, leading to research to overcome these limitations. Deep eutectic solvents (DESs) are a new class of green and biocompatible solvents with multiple applications, including their use to increase the aqueous solubility and bioavailability of natural polyphenols. This finding motivated us to investigate the effect of ethaline, a DES composed of choline chloride and ethylene glycol, on the capacity of quercetin in modulating the cytotoxic amyloid fibrillation of α-synuclein (α-syn). The results showed that dissolving quercetin in ethaline considerably increased the potential of quercetin to inhibit cytotoxic fibril formation of α-syn. We suggest that increasing the aqueous solubility of quercetin is likely the main mechanism contributing to the beneficial effects of ethaline. Thanks to its enhanced aqueous solubility, quercetin would interact more effectively with surrounding molecules, including α-syn monomers and reactive oxygen species. This increases not only the anti-amyloidogenic effects of quercetin, but can also improve its antioxidant activity, leading to more effective inhibition of α-syn fibrillation process as well as protecting cells against damage induced by α-syn aggregates. These findings may suggest that DESs could serve as new candidates to increase the therapeutic effects of polyphenols in relation to neurodegenerative diseases, including Parkinson's disease.