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.