Abstract
Background: α-synuclein(α-Syn) is the major component of Lewy body which appears in α-synucleinopathies like Parkinson's disease, Dementia with Lewy bodies and multiple system atrophy. The aggregates and amyloid fibril formation of α-Syn are thought to be responsible for initiating pathological process of α-synucleinopathies. Inhibiting the formation of aggregates and fibrils can be a potential disease-modifying therapy. It was reported previously that ferulic acid (FA), a type of natural organic compounds abundant in plant cell walls, could inhibit the formation of β-amyloid (Aβ) fibrils in vitro. However, whether FA and its derivatives inhibit the formation of α-Syn and fibrils have not been fully elucidated.
Objective: In this study, we investigated the inhibitory potency of FA and its derivatives to the formation of α-Syn fibrils and evaluated its pharmacokinetics such as brain uptake and metabolism.
Results: The fibril formation and aggregation of α-Syn fibrils were confirmed by thioflavin T assay, SDS-PAGE and electron microscope. FA did not suppress the formation of α-Syn fibrils, while several derivatives of FA whose chemical backbone includes 1,2-dihydroxybenzene groups could inhibit the formation of α-Syn fibrils in vitro. We suggested 1,2-dihydroxybenzene groups plays an important role in inhibitory potency. Specifically, among all derivatives of FA,we focused on caffeic acid phenethyl ester (CAPE), which is a lipid-soluble active component of propolis extracts. CAPE showed a positive effect on inhibiting the formation of α-Syn fibrils. We proved that only a small amount of CAPE penetrated the blood -brain barrier and most of the CAPE was metabolized to ferulic acid phenethyl ester (FAPE) by catechol-O-methyltransferase (COMT) in vivo, determined by LC-MS. The metabolite, FAPE,could inhibit the formation of α-Syn fibrils in vitro.
Conclusion: CAPE, a natural organic compound of the derivative of FA, can be a key molecular for the development of disease-modifying therapy for α-synucleinopathies.
