Small molecules interacting with α-synuclein: antiaggregating and cytoprotective properties

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Curcumin, a polyphenol, exhibits antioxidant and anti-inflammatory properties beneficial for neurodegenerative disorders like Alzheimer's and Parkinson's.
• Curcumin's rapid degradation at physiological pH limits its therapeutic potential.
• Investigating curcumin by-products and analogues is crucial for developing effective treatments.

Purpose of the Study:

• To evaluate curcumin by-products and their biphenyl analogues for interaction with alpha-synuclein (AS).
• To assess the antioxidant and cytoprotective effects of these compounds.
• To determine the compounds' ability to inhibit AS aggregation.

Main Methods:

• Circular dichroism (CD) and fluorescence spectroscopy were used to study AS interactions.
• Antioxidant properties were assessed, alongside cytoprotective effects in PC12 cells.
• The Congo red assay was employed to evaluate AS aggregation inhibition.

Main Results:

• The biphenyl zingerone analogue (6) demonstrated high-affinity interaction with AS and superior antioxidant activity.
• Biphenyl analogues of dehydrozingerone (4) and O-methyl-dehydrozingerone (5) partially inhibited AS aggregation.
• A hydroxylated biphenyl scaffold shows potential for designing AS aggregation inhibitors.

Conclusions:

• Curcumin by-products and their biphenyl analogues can interact with AS and inhibit its aggregation.
• The biphenyl zingerone analogue exhibits significant potential as a therapeutic agent.
• These findings suggest a promising direction for developing novel therapeutic strategies for neurodegenerative diseases.