The primary motor symptoms of Parkinson's disease (PD) result from the degeneration of dopamine-producing neurons of the substantia nigra pars compacta (SNc), and often, the loss is asymmetrical, resulting in unilateral tremor presentation. Notably, age is the primary risk factor for PD, and it is likely that the disease ultimately stems from the impact of environmental factors, which interact with the aging process. Recent research has focused on the role of microglia and pro-oxidative responses in dopaminergic neuronal death. In this study, we sought to examine the neurodegenerative, inflammatory, and stress effects of exposure to the etiologically relevant pesticide, paraquat, over time (up to 6 months after injections). We also were interested in whether a high-resolution, 7-Tesla animal magnetic resonance imaging would be sensitive enough to detect the degenerative impact of paraquat. We found that paraquat induced a loss of dopaminergic SNc neurons and activation of microglia that surprisingly did not change over 6 months after the last injection. A long-lasting reduction was evident for body weight, and alterations in organ (lung and heart) weight were evident, which reflect the peripheral impact of the toxicant. The microglial proinflammatory actin-remodeling factor, WAVE2, along with the inflammatory transcription factor, nuclear factor kappa B were also elevated within the brain. Remarkably, the stress hormone, corticosterone, was still significantly elevated 1 month after paraquat, whereas the inflammasome factor, caspase-1, and antigen presentation factor, MFG-E8, both displayed delayed rises after the 6-month time. Using high-resolution magnetic resonance imaging, we detected no striatal changes but modest hemispheric differences in the SNc and time-dependent volumetric enlargement of the ventricles in paraquat-treated mice. These data suggest that paraquat induces long-term nigrostriatal pathology (possibly asymmetric) and inflammatory changes and stress and trophic/apoptotic effects that appear to either increase with the passage of time or are evident for at least 1 month. In brief, paraquat may be a useful nonspecific means to model widespread stress and inflammatory changes related to PD or age-related disease in general, but not the progressive nature of such diseases.

中文翻译：

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表征百草枯对帕金森病小鼠模型的长期神经生物学和神经解剖学影响。


帕金森病 (PD) 的主要运动症状是由黑质致密部 (SNc) 产生多巴胺的神经元变性引起的，而且这种损失通常是不对称的，导致单侧震颤表现。值得注意的是，年龄是帕金森病的主要危险因素，该疾病最终很可能源于与衰老过程相互作用的环境因素的影响。最近的研究重点是小胶质细胞和促氧化反应在多巴胺能神经元死亡中的作用。在这项研究中，我们试图研究随着时间的推移（注射后最多 6 个月）接触与病因相关的农药百草枯对神经退行性、炎症和应激的影响。我们还对高分辨率 7-特斯拉动物磁共振成像是否足够灵敏以检测百草枯的退化影响感兴趣。我们发现百草枯会导致多巴胺能 SNc 神经元的损失和小胶质细胞的激活，令人惊讶的是，在最后一次注射后的 6 个月内，这些情况没有发生变化。体重明显持久减少，器官（肺和心脏）重量发生明显变化，这反映了有毒物质的外周影响。大脑内小胶质细胞促炎肌动蛋白重塑因子 WAVE2 以及炎症转录因子核因子 kappa B 的含量也有所升高。值得注意的是，服用百草枯后 1 个月，应激激素皮质酮仍显着升高，而炎症体因子 caspase-1 和抗原呈递因子 MFG-E8 在 6 个月后均出现延迟升高。 使用高分辨率磁共振成像，我们检测到百草枯处理小鼠的纹状体没有变化，但 SNc 存在适度的半球差异，并且心室体积随时间增大而增大。这些数据表明，百草枯会引起长期的黑质纹状体病理（可能不对称）、炎症变化以及应激和营养/细胞凋亡效应，这些效应似乎随着时间的推移而增加，或者在至少 1 个月内明显。简而言之，百草枯可能是一种有用的非特异性方法，可以模拟与 PD 或一般年龄相关疾病相关的广泛压力和炎症变化，但不能模拟此类疾病的进展性质。