Anti-fibrillogenic and fibril-destabilizing activity of nicotine in vitro: implications for the prevention and therapeutics of Lewy body diseases.
The aggregation of alpha-synuclein (alphaS) has been implicated as a critical step in the development of Lewy body diseases (LBD) and multiple system atrophy (MSA). Both retrospective and prospective epidemiological studies have consistently demonstrated an inverse association between cigarette smoking and Parkinson's disease (PD). We used fluorescence spectroscopy with thioflavin S, electron microscopy and atomic force microscopy to examine the effects of nicotine, pyridine, and N-methylpyrrolidine on the formation of alphaS fibrils (f alphaS) from wild-type alphaS (alphaS (WT)) and A53T mutant alphaS (A53T) and on preformed f alpha Ss. Nicotine dose-dependently inhibited the f alphaS formation from both alphaS (WT) and A53T. Moreover, nicotine dose-dependently destabilized preformed f alpha Ss. These effects of nicotine were similar to those of N-methylpyrrolidine. The anti-fibrillogenic activity of nicotine may be exerted not only by the inhibition of f alphaS formation but also by the destabilization of preformed f alphaS. Additionally, this effect may be attributed to N-methylpyrrolidine moieties of nicotine.
Ono
Kenjiro
K
Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Hirohata
Mie
M
Yamada
Masahito
M
D052160:Benzothiazoles; D006801:Humans; D007700:Kinetics; D020961:Lewy Body Disease / Q000473:pathology / Q000517:prevention & control*; D020894:Microfibrils / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D018625:Microscopy, Atomic Force; D008854:Microscopy, Electron; D009154:Mutation; D009538:Nicotine / Q000494:pharmacology* / Q000627:therapeutic use*; D018722:Nicotinic Agonists / Q000494:pharmacology* / Q000627:therapeutic use*; D011725:Pyridines / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013050:Spectrometry, Fluorescence; D013844:Thiazoles; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D052160:Benzothiazoles; D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; D013844:Thiazoles; D051844:alpha-Synuclein; C054965:N-methylpyrrolidine; C009462:thioflavin T; D009538:Nicotine; C023666:pyridine