MPP+ scaffold containing lipophilic compounds are potent complex I inhibitors and selective dopaminergic toxins

Abstract

Although the exact cause(s) of Parkinson's disease (PD) is not fully understood, it is believed that environmental factors play a major role. The discovery that the synthetic chemical, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-derived N-methyl-4-phenylpyridinium (MPP+), recapitulates major pathophysiological characteristics of PD in humans, provides 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 used a series of structurally related, novel, and lipophilic MPP+ derivatives [N-(2-phenyl-1-propene)-4-phenyl-pyridinium (PP-PP+)] 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 dopamine transporter (DAT) 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 ROS 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.