Paraquat and maneb co-exposure induces noradrenergic locus coeruleus neurodegeneration through NADPH oxidase-mediated microglial activation
Paraquat and maneb co-exposure induces noradrenergic locus coeruleus neurodegeneration through NADPH oxidase-mediated microglial activation
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DOI：
10.1016/j.tox.2017.02.009
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发表时间：
2017-04-01
期刊：
影响因子：
4.5
通讯作者：
Wang, Qingshan
中科院分区：
文献类型：
--
作者：
Hou, Liyan;Zhang, Cong;Wang, Qingshan
同时接触百草枯（PQ）和代森锰（Mb）已被证明会增加帕金森病（PD）的风险，并在PQ和Mb处理的实验动物中观察到黑质丘脑部（SNpc）的多巴胺能（DA）神经变性。脑干去甲肾上腺素能蓝斑（LC/NE）神经元的缺失是包括PD在内的多种神经退行性疾病的共同特征。然而，PQ和Mb是否能够损伤LC/NE神经元仍不清楚。在这项研究中，PQ和Mb联合治疗的小鼠显示出进行性LC/NE神经变性。时程研究表明，小胶质细胞的激活之前LC/NE神经变性。从机制上讲，NADPH氧化酶的激活有助于小胶质细胞的激活和随后的LC/NE神经变性。我们发现PQ和Mb共同暴露可诱导NADPH氧化酶的激活，表现为超氧化物产生增加和p47（Phox）（NADPH氧化酶的胞浆亚基）的膜移位。夹竹桃黄素是一种广泛使用的NADPH氧化酶抑制剂，通过抑制NADPH氧化酶，抑制小胶质细胞活化和促炎因子的基因表达。此外，在夹竹桃素处理的小鼠中观察到核因子-κ B（NF-κ B）途径的活化减少。更重要的是，抑制NADPH氧化酶夹竹桃麻素提供LC/NE神经保护PQ和Mb诱导的神经毒性。因此，我们的研究结果揭示了NADPH氧化酶介导的小胶质细胞活化在驱动PQ和Mb诱导的LC/NE神经变性中的关键作用，为环境毒素诱导的PD的发病机制提供了新的见解。(C)2017爱思唯尔B. V.保留所有权利。
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 p47(Phox), 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-kappa B (NF-kappa B) 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 PQand Mb, providing new insights into the pathogenesis of environmental toxins-induced PD. (C) 2017 Elsevier B.V. All rights reserved.