1-Methyl-4-phenyl-2,3-dihydropyridinium is transformed by ubiquinone to the selective nigrostriatal toxin 1-methyl-4-phenylpyridinium

AbstractWe have studied the interaction of coenzyme Q with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolites, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+) and 1-methyl-4-phenylpyridinium (MPP+), the real neurotoxin to cause Parkinson’s disease. Incubation of MPTP or MPDP+ with rat brain synaptosomes induced complete reduction of endogenous ubiquinone-9 and ubiquinone-10 to corresponding ubiquinols. The reduction occurred in a time- and MPTP/MPDP+ concentration-dependent manner. The reduction of ubiquinone induced by MPDP+ went much faster than that by MPTP. MPTP did not reduce liposome-trapped ubiquinone-10, but MPDP+ did. The real toxin MPP+ did not reduce ubiquinone in either of the systems. The reduction by MPTP but not MPDP+ was completely prevented by pargyline, a type B monoamine oxidase (MAO-B) inhibitor, in the synaptosomes. The results indicate that involvement of MAO-B is critical for the reduction of ubiquinone by MPTP but that MPDP+ is a reductant of ubiquinone per se. It is suggested that ubiquinone could be an electron acceptor from MPDP+ and promote the conversion from MPDP+ to MPP+ in vivo, thus accelerating the neurotoxicity of MPTP