Studies on curcumin-glucoside in the prevention of alpha-synuclein aggregation.

BACKGROUND: α-synuclein (α-syn) deposition in the mid-brain region is one of the hallmark pathologies of Parkinson's disease (PD). The key steps involve the transformation of α-synuclein into a toxic oligomer and insoluble fibrillar aggregates. OBJECTIVE: To understand the role of curcumin-glucoside in the prevention of α-syn aggregation, a mechanistic approach. METHODS: In the present study, we synthesized a novel molecule, curcumin-glucoside (Curc-gluc), to improve the water solubility and partition coefficient, making the molecule with high bioavailability. The present study is focused on understanding the α-syn aggregation kinetics in the presence and absence of Curc-gluc, curcumin (Cur), copper (Cu), and iron (Fe) through Thioflavin T analysis, circular dichroism (CD), mathematical approach by self-association kinetics, and molecular docking models. RESULTS: The results indicated that Curc-gluc potentially prevented synuclein aggregation compared to Curc alone and inhibited Cu and Fe-induced synuclein aggregation. CD studies indicated that Curc-gluc favored α-helix formation. The docking studies indicated that Curc-gluc derivatives interacted with various chains of α-syn fibrils, namely G-chain, A-chain, I-Chain, and E-chain and the Pi-Pi interaction indicate that, Curc-gluc shows the most favorable binding affinity with the α-syn fibrils with 60.7222 kcal/mol of -CDOCKER_ ENERGY and 89.6516 kcal/mol of -CDOCKER INTERACTION_ ENERGY. The Absorption, Distribution, Metabolism, Excretion (ADME) analysis indicated that Curc-mono and di-gluc have the highest solubility, bioavailability, and tissue distribution compared to Curc alone. CONCLUSIONS: The studies indicated that Curc-gluc prevented α-syn aggregation by favoring α-helix, binding to α-syn, and preventing aggregation, and had high bioavailability.