MPP+ is only the simplest of a large group of unidentified potent dopaminergic toxins as shown by C. Elegans Parkinson's model studies

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Murphy, David
Wimalasena, Kandatege

Although the 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, has provided the strongest support for this possibility. While the mechanism of the selective dopaminergic toxicity of MPTP/MPP+ has been extensively studied and generally well accepted, several key aspects of the mechanism are still subject to debate. In contrast to the widely accepted view that MPP+ is a structurally unique, optimal and selective in vivo dopaminergic toxin here we show that MPP+ is most likely the simplest of a larger group of similar toxins using C. elegans PD model studies. We also provide strong evidence to support our previous proposal that the inherent predisposition of dopaminergic neurons to produce high oxidative stress in response to complex I inhibition, perturbation of oxidative energy metabolism, and other downstream effects is primarily responsible for their selective vulnerability to these toxins. More significantly, these findings suggest that structurally diverse and more powerful MPP+ scaffold derived dopaminergic toxins could be present in numerous industrial, agricultural, household, and academic settings causing far-reaching public health consequences and thus, these findings should be further investigated.

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Thesis (M.S.)-- Wichita State University, College of Liberal Arts and Sciences, Dept. of Chemistry