Gao Hui-Ming, Jiang Janwei, Wilson Belinda, Zhang Wanqin, Hong Jau-Shyong, Liu Bin
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, North Carolina, USA.
J Neurochem. 2002 Jun;81(6):1285-97. doi: 10.1046/j.1471-4159.2002.00928.x.
The etiology of sporadic Parkinson's disease (PD) remains unknown. Increasing evidence has suggested a role for inflammation in the brain in the pathogenesis of PD. However, it has not been clearly demonstrated whether microglial activation, the most integral part of the brain inflammatory process, will result in a delayed and progressive degeneration of dopaminergic neurons in substantia nigra, a hallmark of PD. We report here that chronic infusion of an inflammagen lipopolysaccharide at 5 ng/h for 2 weeks into rat brain triggered a rapid activation of microglia that reached a plateau in 2 weeks, followed by a delayed and gradual loss of nigral dopaminergic neurons that began at between 4 and 6 weeks and reached 70% by 10 weeks. Further investigation of the underlying mechanism of action of microglia-mediated neurotoxicity using rat mesencephalic neuron-glia cultures demonstrated that low concentrations of lipopolysaccharide (0.1-10 ng/mL)-induced microglial activation and production of neurotoxic factors preceded the progressive and selective degeneration of dopaminergic neurons. Among the factors produced by activated microglia, the NADPH oxidase-mediated release of superoxide appeared to be a predominant effector of neurodegeneration, consistent with the notion that dopaminergic neurons are particularly vulnerable to oxidative insults. This is the first report that microglial activation induced by chronic exposure to inflammagen was capable of inducing a delayed and selective degeneration of nigral dopaminergic neurons and that microglia-originated free radicals play a pivotal role in dopaminergic neurotoxicity in this inflammation-mediated model of PD.
散发性帕金森病（PD）的病因仍不清楚。越来越多的证据表明，大脑中的炎症在PD发病机制中起作用。然而，作为大脑炎症过程中最主要部分的小胶质细胞激活是否会导致黑质中多巴胺能神经元的延迟性和进行性退化（PD的一个标志），尚未得到明确证实。我们在此报告，以5 ng/h的速度向大鼠脑内慢性输注炎性介质脂多糖2周，会引发小胶质细胞的快速激活，这种激活在2周时达到平台期，随后黑质多巴胺能神经元出现延迟性且逐渐的丢失，这一过程在4至6周开始，到10周时达到70%。使用大鼠中脑神经元-胶质细胞培养物对小胶质细胞介导的神经毒性作用的潜在机制进行进一步研究表明，低浓度脂多糖（0.1 - 10 ng/mL）诱导的小胶质细胞激活和神经毒性因子的产生先于多巴胺能神经元的进行性和选择性退化。在激活的小胶质细胞产生的因子中，NADPH氧化酶介导的超氧化物释放似乎是神经退行性变的主要效应因子，这与多巴胺能神经元特别易受氧化损伤的观点一致。这是第一份报告，表明长期暴露于炎性介质诱导的小胶质细胞激活能够诱导黑质多巴胺能神经元的延迟性和选择性退化，并且在这种炎症介导的PD模型中，小胶质细胞产生的自由基在多巴胺能神经毒性中起关键作用。
