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Involvement of NF Kappa B in Potentiated Effect of Mn-containing Dithiocarbamates on MPP+ Induced Cell Death

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Abstract

Humans are exposed to various chemical mixtures daily. The toxic response to a mixture of chemicals could be potentiated or suppressed. This study demonstrates that non-toxic doses of pesticides can induce cellular changes that increase cell sensitivity to other toxins or stress. Pesticide exposure is an environmental risk factor for Parkinson’s disease. Manganese (Mn) is essential but high dose exposure may results in neurological dysfunction. Mn-containing dithiocarbamates, maneb (MB) and mancozeb (MZ), are primarily used as pesticides. Studies have shown that MB can augment dopaminergic damage triggered by sub-toxic doses of Parkinsonian mimetic MPTP. However, the mechanism underlying this effect is not clear. Activation of nuclear factor kappa B (NF-κB) has been implicated in MPTP toxicity. Mn stimulates the activation of NF-κB and subsequently induces neuronal injury via an NF-κB dependent mechanism. We speculate that MB and MZ enhance MPTP active metabolite (methyl-4-phenylpyridine ion, MPP+) toxicity by activating NF-κB. The activation of NF-κB was observed using Western blot analysis and NF-κB response element driven Luciferase reporter assay. Western blot data demonstrated the nuclear translocation of NF-κB p65 and the degradation of IkBα after MB and MZ 4-h treatments. Results of NF-κB response element luciferase reporter assay confirmed that MB and MZ activated NF-κB. The NF-κB inhibitor (SN50) was also shown to alleviate cytotoxicity induced by co-treatment of MB or MZ and MPP+. This study demonstrates that activation of NF-κB is responsible for the potentiated toxic effect of MB and MZ on MPP+ induced cytotoxicity.

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Acknowledgments

We thank John Jay Start up fund and PSC CUNY for supporting this project. We also thank Program for Research Initiatives for Science Majors (PRISM) at John Jay College. PRISM is funded by the Title V, HSI-STEM and MSEIP programs within the US Department of Education; the PAESMEM program through the National Science Foundation; and New York State’s Graduate Research and Technology Initiative.

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The authors declare that there are no conflicts of interest.

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  1. Department of Sciences, John Jay College of Criminal Justice, City University of New York, 524 West 59th Street, 5.61.09NB, New York, NY, 10019, USA

    Cindi-Ann Williams, Ying Lin, Arlene Maynard & Shu-Yuan Cheng

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  1. Cindi-Ann Williams
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Correspondence to Shu-Yuan Cheng.

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Williams, CA., Lin, Y., Maynard, A. et al. Involvement of NF Kappa B in Potentiated Effect of Mn-containing Dithiocarbamates on MPP+ Induced Cell Death. Cell Mol Neurobiol 33, 815–823 (2013). https://doi.org/10.1007/s10571-013-9948-1

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