Low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine causes inflammatory activation of astrocytes in nuclear factor-κB reporter mice prior to loss of dopaminergic neurons.
Low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine causes inflammatory activation of astrocytes in nuclear factor-κB reporter mice prior to loss of dopaminergic neurons.
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低剂量1-甲基-4-苯基-1,2,3,6-四氢吡啶会在核因子-κB报告小鼠中引起星形胶质细胞的炎症激活，然后再失去多巴胺能神经元。
DOI：
10.1002/jnr.22549
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发表时间：
2011-03
影响因子：
4.2
通讯作者：
Tjalkens RB
中科院分区：
文献类型：
--
作者：
Miller JA;Trout BR;Sullivan KA;Bialecki RA;Roberts RA;Tjalkens RB
神经炎症与许多中枢神经系统疾病状态的进展有关，但神经胶质细胞中的早期炎症信号事件可能使神经元易受损伤，但在体内不容易表征。为了解决这个问题，我们将表达核因子-κB （NF-κB）驱动的增强型绿色荧光蛋白（EGFP）报告结构的转基因小鼠暴露于低剂量的1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）中，并检测星形胶质细胞的炎症激活与神经行为和神经病理结果的关系。MPTP最高剂量（60mg /kg总剂量）导致运动活动减少和步幅缩短。在任何剂量下，黑质多巴胺能神经元都没有明显的损失。相反，60 mg/kg MPTP降低纹状体纤维中酪氨酸羟化酶的表达，多巴胺和DOPAC水平也降低。当MPTP浓度为30和60 mg/kg时，星形胶质细胞中出现EGFP和诱导型一氧化氮合酶（NOS2）的共定位表达，并与神经多巴胺能神经元中蛋白质硝化的增加有关。表达突变体i -κB α抑制原代星形胶质细胞中NF-κB抑制NOS2的表达，保护共培养神经元免受星形胶质细胞介导的凋亡。这些数据表明，在多巴胺能神经元丧失之前，低剂量MPTP会导致星形胶质细胞的炎症激活和亚硝化应激的增强。NF-κ b介导的NOS2表达似乎是神经炎症的敏感指标，该指标与mptp诱导的神经化学和神经行为缺陷相关，随后黑质中多巴胺能神经元丢失。
Neuroinflammation is implicated in the progression of numerous disease states of the CNS, but early inflammatory signaling events in glial cells that may predispose neurons to injury are not easily characterized in vivo. To address this question, we exposed transgenic mice expressing a nuclear factor-κB (NF-κB)-driven enhanced green fluorescent protein (EGFP) reporter construct to low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and examined inflammatory activation of astrocytes in relation to neurobehavioral and neuropathological outcomes. The highest dose of MPTP (60 mg/kg total dose) caused a decrease in locomotor activity and a reduction in stride length. No significant loss of dopaminergic neurons in the substantia nigra was apparent at any dose. In contrast, expression of tyrosine hydroxylase in striatal fibers was reduced at 60 mg/kg MPTP, as were levels of dopamine and DOPAC. Colocalized expression of EGFP and inducible nitric oxide synthase (NOS2) occurred in astrocytes at 30 and 60 mg/kg MPTP and was associated with increased protein nitration in nigral dopaminergic neurons. Inhibition of NF-κB in primary astrocytes by expression of mutant IκBα suppressed expression of NOS2 and protected cocultured neurons from astrocyte-mediated apoptosis. These data indicate that inflammatory activation of astrocytes and enhanced nitrosative stress occurs at low doses of MPTP prior to loss of dopaminergic neurons. NF-κB-mediated expression of NOS2 appears to be a sensitive indicator of neuroinflammation that correlates with MPTP-induced neurochemical and neurobehavioral deficits prior to loss of dopaminergic neurons in the subtantia nigra.
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影响因子：
14.8
作者：
Jackson-Lewis, Vernice;Przedborski, Serge
通讯作者：
Przedborski, Serge
影响因子：
14.5
作者：
Cho, Ik-Hyun;Hong, Jinpyo;Lee, Sung Joong
通讯作者：
Lee, Sung Joong
DOI：
10.4049/jimmunol.0802954
发表时间：
2009-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Brambilla R;Persaud T;Hu X;Karmally S;Shestopalov VI;Dvoriantchikova G;Ivanov D;Nathanson L;Barnum SR;Bethea JR
通讯作者：
Bethea JR
DOI：
10.1016/1055-8330(95)90015-2
发表时间：
1995-09-01
期刊：
NEURODEGENERATION
影响因子：
--
作者：
JACKSONLEWIS, V;JAKOWEC, M;PRZEDBORSKI, S
通讯作者：
PRZEDBORSKI, S
影响因子：
3.9
作者：
Block, M. L.;Hong, J. -S.
通讯作者：
Hong, J. -S.