Institute of Neuroscience, Carleton University, Ottawa, Ontario, Canada.
Neurobiol Aging. 2012 Jul;33(7):1411-26. doi: 10.1016/j.neurobiolaging.2011.02.016. Epub 2011 Apr 11.
Exposure to environmental contaminants, particularly pesticides, may be an important etiological factor in Parkinson's disease (PD); and evidence suggests a role for microglia-dependent inflammatory and oxidative processes in nigrostriatal pathology induced by such toxins. Yet, the events mediating microglial activation and their effects are not fully known. To this end, we hypothesized that the proinflammatory cytokine, interferon-gamma (IFN-γ), may be a prime factor in the pathogenesis of PD, given its critical role in regulating microglial responses to pathogens. Indeed, the present investigation demonstrated that genetic deletion of IFN-γ protected substantia nigra pars compacta (SNc) dopamine (DA) neurons from the toxic effects of the pesticide, paraquat, and normalized changes in inflammatory and oxidative factors within this brain region. Specifically, IFN-γ knockout prevented the paraquat-induced morphological signs of microglial activation and expression of key nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, while also preventing time-dependent changes in proinflammatory enzymes (inducible nitric oxide synthase [iNOS], cyclooxygenase-2 [COX-2]), cytokines (interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α]), and signaling factors (c-Jun N-terminal kinase [JNK], p38 MAP kinase [p38], Signal transducer and activator of transcription-1 [STAT1], nuclear factor kappa B [NF-κB]). Moreover, paraquat transiently suppressed substantia nigra pars compacta expression of trophic and proneuroplastic factors (cyclic-AMP response element binding protein [CREB], brain-derived neurotrophic factor [BDNF]), and IFN-γ deficiency again reversed these effects. These data suggest that IFN-γ is important for paraquat-induced neurodegeneration and the accompanying oxidative, inflammatory, and trophic changes that characterize the response to the toxin. Targeting IFN-γ could thus have therapeutic implications for PD and other neurodegenerative conditions that involve multiple inflammatory pathways.
暴露于环境污染物，特别是杀虫剂，可能是帕金森病 (PD) 的一个重要病因；有证据表明，此类毒素引起的黑质纹状体病理学中，小胶质细胞依赖性炎症和氧化过程发挥了作用。然而，介导小胶质细胞激活的事件及其影响尚不完全清楚。为此，我们假设，由于干扰素-γ (IFN-γ) 在调节小胶质细胞对病原体的反应方面起着关键作用，因此它可能是 PD 发病机制中的一个主要因素。事实上，本研究表明，IFN-γ 基因缺失可保护黑质致密部 (SNc) 多巴胺 (DA) 神经元免受杀虫剂百草枯的毒性作用，并使该脑区的炎症和氧化因子的变化正常化。具体而言，IFN-γ 敲除可防止百草枯诱导的小胶质细胞激活的形态学标志和关键烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶亚基的表达，同时还可防止促炎酶 (诱导型一氧化氮合酶 [iNOS]、环氧化酶-2 [COX-2])、细胞因子 (白细胞介素-1β [IL-1β]、肿瘤坏死因子-α [TNF-α]) 和信号转导因子 (c-Jun N 末端激酶 [JNK]、p38 丝裂原活化蛋白激酶 [p38]、信号转导和转录激活因子 1 [STAT1]、核因子 kappa B [NF-κB]) 的时间依赖性变化。此外，百草枯可短暂抑制黑质致密部中营养和神经形成前因子 (环磷腺苷反应元件结合蛋白 [CREB]、脑源性神经营养因子 [BDNF]) 的表达，而 IFN-γ 缺乏再次逆转了这些作用。这些数据表明，IFN-γ 对于百草枯诱导的神经退行性变以及伴随的氧化、炎症和营养变化是重要的，这些变化是对毒素的反应的特征。因此，针对 IFN-γ 可能对 PD 和其他涉及多种炎症途径的神经退行性疾病具有治疗意义。
