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dc.contributor.authorLickteig, Bryan
dc.contributor.authorWimalasena, Virangika K.
dc.contributor.authorWimalasena, Kandatege
dc.identifier.citationLickteig, Bryan; Wimalasena, Virangika K.; Wimalasena, Kandatege. 2019. N-methyl-4-phenylpyridinium scaffolds containing lipophilic compounds are potent complex i inhibitors and selective dopaminergic toxins. ACS Chemical Neuroscience 2019en_US
dc.descriptionClick on the DOI link to access the article (may not be free).en_US
dc.description.abstractAlthough 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.en_US
dc.relation.ispartofseriesACS Chemical Neuroscience;2019
dc.subjectDopaminergic toxinsen_US
dc.subjectEnvironmental toxinsen_US
dc.subjectMPP + derivativesen_US
dc.subjectParkinson's diseaseen_US
dc.subjectReactive oxygen speciesen_US
dc.subjectComplex Inhibitorsen_US
dc.titleN-methyl-4-phenylpyridinium scaffolds containing lipophilic compounds are potent complex i inhibitors and selective dopaminergic toxinsen_US
dc.rights.holder© 2019, American Chemical Societyen_US

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