Pyridoxamine inhibits dopamine-induced α-synuclein oligomerization through scavenging neurotoxic dopamine quinone

Parkinson’s disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons causing reduced levels of dopamine (DA), and the presence of Lewy bodies, whose main component is fibrillar α-synuclein (α-Syn). DA is easily oxidized to DA o-quinone (DAQ), which is a key mechanism for neuronal cell death and α-Syn accumulation. Therefore, a DAQ-quenching molecule should prevent DA-induced pathogenicity in PD. Pyridoxamine (PM) is a promising drug candidate for various chronic diseases, including diabetes, because it scavenges reactive carbonyl species. In this study, we found that PM traps DAQ through stable adduct formation. The initial reaction of PM occurred at the DAQ carbonyl carbon to yield pyridoxal (PL) after hydrolysis. DA then reacted with the PL aldehyde, followed by intramolecular cyclization to produce a PL–DA adduct. The adduct structure was shown by LC-MS and NMR analyses to be 1-(2-methyl-3-hydroxy-5-hydroxymethyl-4-pyridyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline. The PL–DA adduct was also detected under intracellular-like conditions. DA caused α-Syn oligomerization via oxidation of methionine residues, which was inhibited by PM in a dose-dependent manner. Therefore, PM could prevent DA-induced adverse effects in the brains of PD patients by forming the PL–DA adduct, suggesting a possible therapeutic use of PM for scavenging DAQ.