Anti-fibrillogenic and fibril-destabilizing activities of anti-Parkinsonian agents for α-synuclein fibrils in vitro

The aggregation of alpha-synuclein (alpha S) in the brain has been implicated as a critical step in the development of Lewy body diseases (LBD) and multiple system atrophy (MSA). Among the antioxidant strategies proposed, increasing evidence points to the possibility of achieving neuroprotection by dopamine agonists, as well as monoamine oxidase B inhibitors. We showed previously that the anti-Parkinsonian agents dose-dependently inhibited beta-amyloid fibrils (fA beta)(1-40) and fA beta(1-42) formation as well as destabilized preformed fA beta s. Using fluorescence spectroscopy with thioflavin S, electron microscopy, and atomic force microscopy, we examined the effects of anti-Parkinsonian agents, selegiline, dopamine, pergolide, bromocriptine, and trihexyphenidyl on the formation of alpha S fibrils (f alpha S) and on preformed f alpha S. All molecules except for trihexyphenidyl, dose-dependently inhibited the formation of f alpha S. Moreover, these molecules dose-dependently destabilized preformed f alpha S. The overall activity of the molecules examined was in the order of: selegiline = dopamine > pergolide > bromocriptine. These agents and other compounds related structurally could be key molecules for the development of therapeutics. for LBD and MSA. (c) 2007 Wiley-Liss, Inc.