title: Paraquat and maneb co-exposure induces noradrenergic locus coeruleus neurodegeneration through NADPH oxidase-mediated microglial activation.
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.
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Hou
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Nutrition, Second Hospital, Dalian Medical University, Dalian 116023, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Yuning
authors.initials: Y
authors.lastname: Che
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Institute of Toxicology, School of Public Health, Shandong University, 44 West Wenhua Road, Jinan, Shandong, China.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D059331:Adrenergic Neurons / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008125:Locus Coeruleus / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008344:Maneb / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000517:prevention & control; D010269:Paraquat / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology; D012307:Risk Factors
chemical_list: D000098:Acetophenones; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D008344:Maneb; C056165:acetovanillone; D019255:NADPH Oxidases; D010269:Paraquat
keywords: Locus coeruleus; Microglia; NADPH oxidase; Neuroinflammation; Pesticide