N-Methyl-4-phenylpyridinium Scaffold-Containing Lipophilic Compounds Are Potent Complex I Inhibitors and Selective Dopaminergic Toxins.

Although the exact cause or causes of Parkinson's disease (PD) are not fully understood, it is believed that environmental factors play a major role. The discovery that a synthetic chemical, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-derived N-methyl-4-phenylpyridinium (MPP), recapitulates major pathophysiological characteristics of PD in humans has provided the strongest support for this possibility. While the mechanism of the selective dopaminergic toxicity of MPP has been extensively studied and is, in most respects, well accepted, several key aspects of the mechanism are still debatable. In the present study, we use a series of structurally related, novel, and lipophilic MPP derivatives [ N-(2-phenyl-1-propene)-4-phenylpyridinium] to probe the mechanism of action of MPP using dopaminergic MN9D and non-neuronal HepG2 cells in vitro. Here we show that effective mitochondrial complex I inhibition is necessary and that the specific uptake through plasma membrane dopamine transporter is not essential for dopaminergic toxicity of MPP and related toxins. We also provide strong evidence to support our previous proposal that the selective vulnerability of dopaminergic cells to MPP and similar toxins is likely due to the high inherent propensity of these cells to produce excessive reactive oxygen species as a downstream effect of complex I inhibition. Based on the current and previous findings, we propose that MPP is the simplest of a larger group of unidentified environmental dopaminergic toxins, a possibility that may have major public health implications.