Granulocyte macrophage-colony stimulating factor protects against substantia nigra dopaminergic cell loss in an environmental toxin model of Parkinson's disease
Granulocyte macrophage-colony stimulating factor protects against substantia nigra dopaminergic cell loss in an environmental toxin model of Parkinson's disease
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DOI：
10.1016/j.nbd.2011.02.011
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发表时间：
2011-07-01
影响因子：
6.1
通讯作者：
Hayley, S.
中科院分区：
文献类型：
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作者：
Mangano, E. N.;Peters, S.;Hayley, S.
帕金森病（PD）与暴露于多种化学物质（如杀虫剂）和炎症剂有关，这些物质可能随着时间的推移而累积。寻找新的方法来限制与毒素接触相关的病理将具有巨大的临床重要性。为此，我们评估了造血营养细胞因子粒细胞巨噬细胞集落刺激因子（GM-CSF）是否会抑制农药百草枯的神经退行性作用，无论是单独给药还是与细菌内毒素脂多糖（LPS）一起给药。如前所述，百草枯引起了适度但显著的神经退行性作用，LPS启动显著增强了这种作用。向黑质致密部（SNc）中灌注GM-CSF可防止SNc多巴胺神经元的丢失，其程度与胶质源性神经营养因子相当。重要的是，全身给药GM-CSF也具有神经保护作用，这表明营养细胞因子可以穿过血脑屏障促进神经元存活。确实。GM-CSF抑制LPS和百草枯诱导的小胶质细胞反应，同时增强SNc内星形胶质细胞的免疫反应性。此外，GM-CSF减弱了百草枯诱导的海马和培养的中脑神经元中脑源性神经营养因子的减少。虽然百草枯降低了中脑抗凋亡蛋白Bcl-2和GM-CSF的水平，但在这方面没有影响。因此，GM-CSF似乎影响SNc内的炎症和/或神经可塑性因子，这些因子可能与神经退行性变以及其他脑区域（海马）有关，这可能对PD共病的非运动症状很重要。这些数据表明，外周GM-CSF给药可能有望治疗帕金森病。(C) 2011爱思唯尔公司版权所有。
Parkinson's disease (PD) has been linked to exposure to a variety of chemical (e.g., pesticides) and inflammatory agents, which may act cumulatively over time. Finding novel means of limiting pathology associated with toxin exposure would have tremendous clinical importance. To this end, we assessed whether the hematopoietic trophic cytokine, granulocyte macrophage colony stimulating factor (GM-CSF), would inhibit the neurodegenerative effects of the pesticide, paraquat, administered either alone or following priming with the bacterial endotoxin, lipopolysaccharide (LPS). As previously observed, paraquat provoked a modest but significant neurodegenerative effect that was markedly augmented with LPS priming. Central infusion of GM-CSF into the substantia nigra pars compacta (SNc) prevented the loss of SNc dopamine neurons to a degree comparable to that of glial derived neurotrophic factor. Importantly, systemic administration of GM-CSF also had neuroprotective consequences, suggesting that the trophic cytokine can cross the blood brain barrier to promote neuronal survival. Indeed. GM-CSF acted to inhibit the LPS and paraquat induced microglial response, while augmenting astrocyte immunoreactivity within the SNc. Moreover, GM-CSF blunted the paraquat induced reduction of brain derived neurotrophic factor within the hippocampus, as well as in cultured mesencephalic neurons. Although paraquat reduced mesencephalic levels of the anti-apoptotic protein, Bcl-2, GM-CSF had no effect in this regard. Hence, GM-CSF appears to affect inflammatory and/or neuroplastic factors within the SNc that may be linked to neurodegeneration, as well as in other brain regions (hippocampus), which could be important for co-morbid non-motor symptoms in PD. These data suggest that peripheral GM-CSF administration might hold promise as a treatment of PD. (C) 2011 Elsevier Inc. All rights reserved.