Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for α-synuclein fibrils in vitro

The aggregation of α-synuclein (αS) in the brain has been implicated as a critical step in the development of Lewy body diseases (LBD) [Parkinson's disease (PD)/dementia with Lewy bodies (DLB)] and multiple system atrophy (MSA). The involvement of neuroinflammation and microglial activation has been emphasized in the pathogenesis of PD. Recent epidemiological studies have revealed that therapeutic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing PD. Here, we examined the effects of NSAIDs, such as ibuprofen, aspirin, acetaminophen, meclofenamic acid sodium salt, sulindac sulfide, ketoprofen, flurbiprofen, diclofenac sodium salt, naproxen, and indomethacin, on the formation and destabilization of αS fibrils (fαS) at pH 7.5 and 37 °C in vitro, using fluorescence spectroscopy with thioflavin S and electron microscopy. All examined NSAIDs, except for naproxen and indomethacin, inhibited the formation of fαS in a dose-dependent manner. Moreover, these molecules dose-dependently destabilized preformed fαS. The overall activity was in the order: ibuprofen ≈ aspirin ≈ acetaminophen ≈ meclofenamic acid sodium salt ≈ sulindac sulfide > ketoprofen ≈ flurbiprofen ≈ diclofenac sodium salt > naproxen ≈ indomethacin. These findings indicate that NSAIDs could be key molecules for the development of therapeutic or preventive agents for LBD and MSA.