Neuropharmacology Section, Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Mail Drop F1-01Research Triangle Park, North Carolina, 27709, USA.
Institute of Toxicology, School of Public Health, Shandong University, Jinan, Shandong, China.
Mol Neurobiol. 2019 Apr;56(4):2653-2669. doi: 10.1007/s12035-018-1235-1. Epub 2018 Jul 27.
Environmental toxicant exposure has been strongly implicated in the pathogenesis of Parkinson's disease (PD). Clinical manifestations of non-motor and motor symptoms in PD stem from decades of progressive neurodegeneration selectively afflicting discrete neuronal populations along a caudo-rostral axis. However, recapitulating this spatiotemporal neurodegenerative pattern in rodents has been unsuccessful. The purpose of this study was to generate such animal PD models and delineate mechanism underlying the ascending neurodegeneration. Neuroinflammation, oxidative stress, and neuronal death in mice brains were measured at different times following a single systemic injection of lipopolysaccharide (LPS). We demonstrate that LPS produced an ascending neurodegeneration that temporally afflicted neurons initially in the locus coeruleus (LC), followed by substantia nigra, and lastly the primary motor cortex and hippocampus. To test the hypothesis that LPS-elicited early loss of noradrenergic LC neurons may underlie this ascending pattern, we used a neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to deplete brain norepinephrine. DSP-4 injection resulted in a time-dependent ascending degenerative pattern similar to that generated by the LPS model. Mechanistic studies revealed that increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX2)-dependent superoxide/reactive oxygen species (ROS) production plays a key role in both LPS- and DSP-4-elicited neurotoxicity. We found that toxin-elicited chronic neuroinflammation, oxidative neuronal injuries, and neurodegeneration were greatly suppressed in mice deficient in NOX2 gene or treated with NOX2-specific inhibitor. Our studies document the first rodent PD model recapturing the ascending neurodegenerative pattern of PD patients and provide convincing evidence that the loss of brain norepinephrine is critical in initiating and maintaining chronic neuroinflammation and the discrete neurodegeneration in PD.
环境毒物暴露与帕金森病 (PD) 的发病机制密切相关。PD 患者的非运动和运动症状的临床表现源于数十年的进行性神经退行性变，选择性地影响沿着尾到头轴的离散神经元群体。然而，在啮齿动物中重现这种时空神经退行性模式一直未能成功。本研究的目的是生成这种动物 PD 模型，并阐明上行神经退行性变的机制。在单次全身注射脂多糖 (LPS) 后不同时间测量小鼠大脑中的神经炎症、氧化应激和神经元死亡。我们证明 LPS 产生了一种上行神经退行性变，最初影响蓝斑 (LC) 中的神经元，然后影响黑质，最后影响初级运动皮层和海马体。为了测试 LPS 诱导的去甲肾上腺素能 LC 神经元早期丢失可能是这种上行模式的基础的假设，我们使用神经毒素 N-(2-氯乙基)-N-乙基-2-溴苯甲胺 (DSP-4) 耗尽大脑去甲肾上腺素。DSP-4 注射导致类似于 LPS 模型产生的时间依赖性退行性变模式。机制研究表明，烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶-2 (NOX2) 依赖性超氧阴离子/活性氧 (ROS) 产生的增加在 LPS 和 DSP-4 诱导的神经毒性中起关键作用。我们发现，NOX2 基因缺失或用 NOX2 特异性抑制剂治疗可大大抑制毒素诱导的慢性神经炎症、氧化神经元损伤和神经退行性变。我们的研究记录了第一个重现 PD 患者上行神经退行性变模式的啮齿动物 PD 模型，并提供了令人信服的证据，即大脑去甲肾上腺素的丧失在启动和维持 PD 中的慢性神经炎症和离散神经退行性变中至关重要。
