Cuminaldehyde as the Major Component of Cuminum cyminum, a Natural Aldehyde with Inhibitory Effect on Alpha-Synuclein Fibrillation and Cytotoxicity

Fibrillation of alpha-synuclein (alpha-SN) is a critical process in the pathophysiology of several neurodegenerative diseases, especially Parkinson's disease. Application of bioactive inhibitory compounds from herbal extracts is a potential therapeutic approach for this cytotoxic process. Here, we investigated the inhibitory effects of the Iranian Cuminum cyminum essential oil on the fibrillation of alpha-SN. Analysis of different fractions from the total extract identified cuminaldehyde as the active compound involved in the antifibrillation activity. In comparison with baicalein, a well-known inhibitor of alpha-SN fibrillation, cuminaldehyde showed the same activity in some aspects and a different activity on other parameters influencing alpha-SN fibrillation. The presence of spermidine, an alpha-SN fibrillation inducer, dominantly enforced the inhibitory effects of cuminaldehyde even more intensively than baicalein. Furthermore, the results from experiments using preformed fibrils and monobromobimane-labeled monomeric protein also suggest that cuminaldehyde prevents alpha-SN fibrillation even in the presence of seeds, having no disaggregating impact on the preformed fibrils. Structural studies showed that cuminaldehyde stalls protein assembly into beta-structural fibrils, which might be achieved by the interaction with amine groups through its aldehyde group as a Schiff base reaction. This assumption was supported by FITC labeling efficiency assay. In addition, cytotoxicity assays on PC12 cells showed that cuminaldehyde is a nontoxic compound, treatment with cuminaldehyde throughout alpha-SN fibrillation showed no toxic effects on the cells. Taken together, these results show for the first time that the small abundant natural compound, cuminaldehyde, can modulate alpha-SN fibrillation. Hence, suggesting that such natural active aldehyde could have potential therapeutic applications.