Characterizing the protracted neurobiological and neuroanatomical effects of paraquat in a murine model of Parkinson's disease

黑质 多巴胺能 致密部 小胶质细胞 百草枯 神经科学 促炎细胞因子 神经退行性变 帕金森病 神经炎症 医学 氧化应激 内分泌学 内科学 心理学 病理 多巴胺 化学 炎症 疾病 生物化学
作者
Zach Dwyer,Chris Rudyk,Kyle Farmer,Sheryl Beauchamp,Pragya Shail,Alexa Derksen,T. Fortin,Katelyn Ventura,Carlos Torres,Kiara Ayoub,Shawn Hayley
出处
期刊:Neurobiology of Aging [Elsevier BV]
卷期号:100: 11-21 被引量:19
标识
DOI:10.1016/j.neurobiolaging.2020.11.013
摘要

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.
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