Institute of Neuroscience, Carleton University, Life Sciences Research Building, 1125 Colonel By Drive, Ottawa, ON K1S 5B6 Canada.
Neuroscience. 2009 Dec 29;164(4):1894-906. doi: 10.1016/j.neuroscience.2009.09.025. Epub 2009 Sep 24.
In addition to nigrostriatal pathology and corresponding motor disturbances, Parkinson's disease (PD) is often characterized by co-morbid neuropsychiatric symptoms, most notably anxiety and depression. Separate lines of evidence indicate that inflammatory processes associated with microglial activation and cytokine release may be fundamental to the progression of both PD and its co-morbid psychiatric pathology. Accordingly, we assessed the contribution of the pro-inflammatory cytokine, interferon-gamma (IFN-gamma), to a range of PD-like pathology provoked by the ecologically relevant herbicide and dopamine (DA) toxin, paraquat. To this end, paraquat provoked overt motor impairment (reduced home-cage activity and impaired vertical climbing) and signs of anxiety-like behavior (reduced open field exploration) in wild-type but not IFN-gamma-deficient mice. Correspondingly, paraquat promoted somewhat divergent variations in neurochemical activity among wild-type and IFN-gamma null mice at brain sites important for both motor (striatum) and co-morbid affective pathologies (dorsal hippocampus, medial prefrontal cortex, and locus coeruleus). Specifically, the herbicide provoked a dosing regimen-dependent reduction in striatal DA levels that was prevented by IFN-gamma deficiency. In addition, the herbicide influenced serotonergic and noradrenergic activity within the dorsal hippocampus and medial prefrontal cortex; and elevated noradrenergic activity within the locus coeruleus. Although genetic ablation of IFN-gamma had relatively few effects on monoamine variations within the locus coeruleus and prefrontal cortex, loss of the pro-inflammatory cytokine did normalize the paraquat-induced noradrenergic alterations within the hippocampus. These findings further elucidate the functional implications of paraquat intoxication and suggest an important role for IFN-gamma in the striatal and motor pathology, as well as the co-morbid behavioral and hippocampal changes induced by paraquat.
除了黑质纹状体病理学和相应的运动障碍外，帕金森病（PD）通常还伴有神经精神共病症状，尤其是焦虑和抑郁。有独立的证据表明，与小胶质细胞激活和细胞因子释放相关的炎症过程可能是 PD 及其共病精神病理学进展的基础。因此，我们评估了促炎细胞因子干扰素-γ（IFN-γ）对生态相关除草剂和多巴胺（DA）毒素百草枯引起的一系列 PD 样病理学的贡献。为此，百草枯引起野生型小鼠明显的运动障碍（减少笼内活动和垂直攀爬能力受损）和焦虑样行为迹象（减少旷场探索），但 IFN-γ缺陷型小鼠没有。相应地，百草枯在与运动（纹状体）和共病情感病理学（背海马、内侧前额叶皮质和蓝斑）都有关的大脑部位，促进了野生型和 IFN-γ 缺失小鼠之间神经化学活性的一些不同变化。具体而言，该除草剂引起了剂量依赖性的纹状体 DA 水平降低，IFN-γ 缺乏可预防这种降低。此外，该除草剂影响了背海马和内侧前额叶皮质中的 5-羟色胺能和去甲肾上腺素能活性；并增加了蓝斑中的去甲肾上腺素能活性。虽然 IFN-γ 的遗传缺失对蓝斑和前额叶皮质中的单胺变化几乎没有影响，但促炎细胞因子的缺失使百草枯引起的海马去甲肾上腺素变化正常化。这些发现进一步阐明了百草枯中毒的功能意义，并表明 IFN-γ 在纹状体和运动病理学以及百草枯引起的共病行为和海马变化中具有重要作用。
