Neuroprotective effect of the antiparkinsonian drug pramipexole against nigrostriatal dopaminergic degeneration in rotenone-treated mice
Neuroprotective effect of the antiparkinsonian drug pramipexole against nigrostriatal dopaminergic degeneration in rotenone-treated mice
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DOI：
10.1016/j.neuint.2009.07.009
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发表时间：
2009-12-01
影响因子：
4.2
通讯作者：
Taniguchi, Takashi
中科院分区：
文献类型：
--
作者：
Inden, Masatoshi;Kitamura, Yoshihisa;Taniguchi, Takashi
普拉克索是一种多巴胺（DA）D2/D3受体激动剂，已用于治疗早期和晚期帕金森病（PD）。在这项研究中，我们检查了普拉克索对C57 BL/6小鼠的PD模型中DA神经元的影响，所述小鼠用鱼藤酮（30 mg/kg，p.o.）每天28天。普拉克索（1 mg/kg，i. p.）在每次口服施用鱼藤酮之前30分钟每天注射。长期口服鱼藤酮导致黑质多巴胺能神经元的损失，运动障碍和一些存活的DA能神经元中α-突触核蛋白免疫反应性的上调。普拉克索抑制鱼藤酮诱导的DA神经元死亡和运动缺陷，并降低α-突触核蛋白的免疫反应性。此外，普拉克索抑制H2 O2加细胞色素c引起的人野生型α-突触核蛋白的体外寡聚化。为了检查普拉克索对氧化应激的神经保护作用，我们使用DJ-1敲低的SH-SY 5 Y细胞系和电子自旋共振（ESR）光谱法。H2 O2和普拉克索同时处理导致DJ-1敲低细胞以浓度依赖性方式显著保护其免于细胞死亡。高浓度的普拉克索直接清除H2 O2和Fe 2+产生的羟基自由基（（OH）-O-中心点）。此外，普拉克索增加了SNpc中DA神经元的Bcl-2免疫反应性。这些结果表明，普拉克索可以保护DA神经元免受长期口服鱼藤酮暴露，这种作用是通过多种功能介导的，包括清除（OH）-O-中心点和诱导Bcl-2蛋白。(C)2009爱思唯尔有限公司版权所有。
Pramipexole, an agonist for dopamine (DA) D2/D3-receptors, has been used to treat both early and advanced Parkinson's disease (PD). In this study, we examined the effect of pramipexole on DA neurons in a PD model of C57BL/6 mice, which were treated with rotenone (30 mg/kg, p.o.) daily for 28 days. Pramipexole (1 mg/kg, i.p.) was injected daily 30 min before each oral administration of rotenone. Chronic oral administration of rotenone caused a loss of DA neurons in the substantia nigra pars compacta (SNpc), motor deficits and the up-regulation of alpha-synuclein immunoreactivity in some surviving DA neurons. Pramipexole inhibited rotenone-induced DA neuronal death and motor deficits, and reduced immunoreactivity for alpha-synuclein. In addition, pramipexole inhibited the in vitro oligomerization of human wild-type alpha-synuclein by H2O2 Plus cytochrome c. To examine the neuroprotective effect of pramipexole against oxidative stress, we used a DJ-1-knockdown SH-SY5Y cell line and electron spin resonance (ESR) spectrometry. Simultaneous treatment with H2O2 and pramipexole resulted in the significant protection of DJ-1-knockdown cells against cell death in a concentration-dependent manner. A high concentration of pramipexole directly scavenged hydroxyl radical ((OH)-O-center dot) generated from H2O2 and Fe2+. Furthermore, pramipexole increased Bcl-2 immunoreactivity in DA neurons in the SNpc. These results suggest that pramipexole may protect DA neurons against exposure to rotenone by chronic oral administration, and this effect is mediated by multiple functions including scavenging of (OH)-O-center dot and induction of Bcl-2 protein. (C) 2009 Elsevier Ltd. All rights reserved.