Immunology Lab, Department of Zoology, University of Calcutta, Kolkata, India.
J Neuroinflammation. 2011 Nov 24;8:163. doi: 10.1186/1742-2094-8-163.
Paraquat (1, 1-dimethyl-4, 4-bipyridium dichloride; PQ) causes neurotoxicity, especially dopaminergic neurotoxicity, and is a supposed risk factor for Parkinson's disease (PD). However, the cellular and molecular mechanisms of PQ-induced neurodegeneration are far from clear. Previous studies have shown that PQ induces neuroinflammation and dopaminergic cell loss, but the prime cause of those events is still in debate.
We examined the neuropathological effects of PQ not only in substantia nigra (SN) but also in frontal cortex (FC) and hippocampus of the progressive mouse (adult Swiss albino) model of PD-like neurodegeneration, using immunohistochemistry, western blots, and histological and biochemical analyses.
PQ caused differential patterns of changes in cellular morphology and expression of proteins related to PD and neuroinflammation in the three regions examined (SN, FC and hippocampus). Coincident with behavioral impairment and brain-specific ROS generation, there was differential immunolocalization and decreased expression levels of tyrosine hydroxylase (TH) in the three regions, whereas α-synuclein immunopositivity increased in hippocampus, increased in FC and decreased in SN. PQ-induced neuroinflammation was characterized by area-specific changes in localization and appearances of microglial cells with or without activation and increment in expression patterns of tumor necrosis factor-α in the three regions of mouse brain. Expression of interleukin-1β was increased in FC and hippocampus but not significantly changed in SN.
The present study demonstrates that PQ induces ROS production and differential α-synuclein expression that promotes neuroinflammation in microglia-dependent or -independent manners, and produces different patterns of dopaminergic neurotoxicity in three different regions of mouse brain.
百草枯（1,1-二甲基-4,4-联吡啶二氯化物；PQ）可导致神经毒性，尤其是多巴胺能神经毒性，被认为是帕金森病（PD）的一个危险因素。然而，PQ 诱导神经退行性变的细胞和分子机制尚不清楚。先前的研究表明，PQ 可诱导神经炎症和多巴胺能神经元丧失，但这些事件的主要原因仍存在争议。
我们不仅在帕金森病样神经退行性变的进展型小鼠（成年瑞士白化病）模型的黑质（SN）中，而且在额皮质（FC）和海马中，通过免疫组织化学、Western blot 以及组织学和生化分析，研究了 PQ 的神经病理学效应。
PQ 导致细胞形态和与 PD 及神经炎症相关的蛋白质表达在三个研究区域（SN、FC 和海马）中出现不同的变化模式。与行为障碍和脑内特异性 ROS 生成相一致，三个区域中酪氨酸羟化酶（TH）的免疫定位和表达水平降低，而海马中α-突触核蛋白的免疫阳性增加，FC 中增加，SN 中减少。PQ 诱导的神经炎症的特征是小胶质细胞的定位和外观出现区域特异性变化，而小胶质细胞的激活和肿瘤坏死因子-α表达模式的增加在小鼠脑的三个区域中均有发生。FC 和海马中白细胞介素-1β的表达增加，但在 SN 中无明显变化。
本研究表明，PQ 诱导 ROS 产生和不同的α-突触核蛋白表达，以小胶质细胞依赖或不依赖的方式促进神经炎症，并在小鼠脑的三个不同区域产生不同模式的多巴胺能神经毒性。
