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Toxicology. 2017 Apr 1;380:1-10. doi: 10.1016/j.tox.2017.02.009. Epub 2017 Feb 13.

Paraquat and maneb co-exposure induces noradrenergic locus coeruleus neurodegeneration through NADPH oxidase-mediated microglial activation.

Author information

1
Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
2
Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
3
Department of Nutrition, Second Hospital, Dalian Medical University, Dalian 116023, China.
4
Institute of Toxicology, School of Public Health, Shandong University, 44 West Wenhua Road, Jinan, Shandong, China.
5
Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China. Electronic address: wangq4@126.com.

Abstract

Co-exposure to paraquat (PQ) and maneb (Mb) has been shown to increase the risk of Parkinson's disease (PD) and dopaminergic (DA) neurodegeneration in the substantia nigra pars compacta (SNpc) is observed in PQ and Mb-treated experimental animals. The loss of noradrenergic locus coeruleus (LC/NE) neurons in brainstem is a common feature shared by multiple neurodegenerative diseases, including PD. However, whether PQ and Mb is able to damage LC/NE neurons remains undefined. In this study, mice treated with combined PQ and Mb displayed progressive LC/NE neurodegeneration. Time course studies revealed that the activation of microglia preceded LC/NE neurodegeneration. Mechanistically, the activation of NADPH oxidase contributed to microglial activation and subsequent LC/NE neurodegeneration. We found that PQ and Mb co-exposure induced activation of NADPH oxidase as shown by increased superoxide production and membrane translocation of p47phox, a cytosolic subunit of NADPH oxidase. Inhibition of NADPH oxidase by apocynin, a widely used NADPH oxidase inhibitor, suppressed microglial activation and gene expressions of proinflammatory factors. Furthermore, reduced activation of nuclear factor-κB (NF-κB) pathway was observed in apocynin-treated mice. More importantly, inhibition of NADPH oxidase by apocynin afforded LC/NE neuroprotection against PQ and Mb-induced neurotoxicity. Thus, our findings revealed the critical role NADPH oxidase-mediated microglial activation in driving LC/NE neurodegeneration induced by PQ and Mb, providing new insights into the pathogenesis of environmental toxins-induced PD.

KEYWORDS:

Locus coeruleus; Microglia; NADPH oxidase; Neuroinflammation; Pesticide

PMID:
28202386
DOI:
10.1016/j.tox.2017.02.009
[Indexed for MEDLINE]

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