Mechanisms of neurotoxicity of metal ethylene-bis-dithiocarbamates: A structure-function approach.

摘要

Epidemiological studies consistently link age, genetics and agricultural environments, including pesticide exposure, to an increased risk for idiopathic Parkinson's Disease (PD). Some researchers have also reported symptoms of parkinsonism in agricultural workers exposed to Maneb, a dithiocarbamate fungicide whose active ingredient is manganese ethylene-bis-dithiocarbamate (MnEBDC). Further experiments in rodents treated with MnEBDC indicate a perturbation in their dopaminergic system. It is unclear, however, what role Maneb may play in this neurotoxic process.; Using a structure-function approach involving metal-EBDCs and metal-diethyldithiocarbamates, we examined the potential ability of these organometallics to catalyze catechol-mediated reactive oxygen species (ROS) production, inhibit mitochondrial respiration, promote lipid peroxidation, or reduce energy charge in vitro. In addition, we developed a straightforward synthetic scheme to synthesize both classes of compounds, and systematically characterized them using elemental analysis, powder x-ray diffraction and UV-vis spectroscopy.; When complexed with either EBDC or DEDC, both manganese and zinc were able to significantly catalyze N-acetylated dopamine-mediated ROS production. These results indicated that modulation of the organic moiety did not affect the reactivity of these compounds, but that changing the metal significantly altered their potential toxicity. Other experiments, conducted only with metal-EBDC complexes, indicated that Mn- and CuEBDC, not ZnEBDC, inhibited whole-brain rat mitochondrial respiration at low micromolar concentrations. We also determined that, while CuEBDC catalyzed lipid peroxidation in whole-brain rat synaptosomes, neither Mn- nor ZnEBDC were effective. Finally, none of the compounds were able to significantly suppress synaptosomal energy charge when compared to vehicle, DMSO.; These results suggest a multi-hit model to explain the apparently selective dopaminergic neurotoxicity of Maneb. In this model, exposure to MnEBDC may result in general or global mitochondrial inhibition. However, this inhibition would be at levels insufficient to cause cell death. In contrast, catacholaminergic neurons would not only be energy compromised due to mitochondrial inhibition, but they would also be exposed to increased ROS production via catechol oxidation. Taken together, these consequences lead to an environment whereby catacholaminergic neurons are rendered more vulnerable than other cell types.