Metallothioneins 1 and 2 attenuate peroxynitrite-induced oxidative stress in Parkinson disease
Metallothioneins 1 and 2 attenuate peroxynitrite-induced oxidative stress in Parkinson disease
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DOI：
10.1177/153537020623100919
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发表时间：
2006-10-01
影响因子：
3.2
通讯作者：
Sharma, Sushil
中科院分区：
文献类型：
--
作者：
Ebadi, Manuchair;Sharma, Sushil
我们已经研究了有效的过氧亚硝酸根离子（ONOO-）发生器3-吗啉代壬亚胺（SIN-1）诱导的神经毒性在对照野生型（对照（wt））小鼠，金属硫蛋白双敲除（MTdko）小鼠，金属硫蛋白转基因（MTtranss）小鼠，并在培养的人多巴胺能（SK-N-SH）神经元，以确定对ONOO诱导的帕金森病（PD）神经变性的金属硫蛋白的神经保护潜力。SIN-1诱导的脂质过氧化，活性氧的合成，caspase-3的激活，和细胞凋亡的金属硫蛋白基因过表达和金属硫蛋白基因下调增强衰减。一个渐进的黑质纹状体多巴胺能神经退行性病变的韦弗突变（wv/wv）小鼠与增强亚硝酸根离子的合成，金属硫蛋白下调，并显着减少多巴胺的合成和F-18-多巴摄取高分辨率微正电子发射断层扫描神经成像。MTtranss小鼠的纹状体F-18-DOPA摄取显著高于MTdko和α-突触核蛋白敲除（α-Syn（ko））小鼠。这些观察结果提供了进一步的证据，一氧化氮合酶的激活和ONOO-合成可能参与PD的发病机制，金属硫蛋白基因诱导可能提供神经保护。
We have examined potent peroxynitrite ion (ONOO-) generator 3-morpholinosydnonimine (SIN-1)-induced neurotoxicity in control wild-type (control(wt)) mice, metallothionein double knockout (MTdko) mice, metal lothionein-transgenic (MTtrans) mice, and in cultured human dopaminergic (SK-N-SH) neurons to determine the neuroprotective potential of metallothionein against ONOO- induced neurodegeneration in Parkinson disease (PD). SIN-1-induced lipid peroxidation, reactive oxygen species synthesis, caspase-3 activation, and apoptosis were attenuated by metallothionein gene overexpression and augmented by metallothionein gene down-regulation. A progressive nigrostriatal dopaminergic neurodegeneration in weaver mutant (wv/wv) mice was associated with enhanced nitrite ion synthesis, metallothionein down-regulation, and significantly reduced dopamine synthesis and F-18-DOPA uptake as determined by high-resolution micropositron emission tomography neuroimaging. The striatal F-18-DOPA uptake was significantly higher in MTtrans mice than in MTdko and alpha-synuclein knockout (alpha-Syn(ko)) mice. These observations provide further evidence that nitric oxide synthase activation and ONOO- synthesis may be involved in the etiopathogenesis of PD, and that metallothionein gene induction may provide neuroprotection.