百草枯慢性经口染毒对 C57BL/6 小鼠黑质纹状体多巴胺能神经元的毒性作用。
Toxic influence of chronic oral administration of paraquat on nigrostriatal dopaminergic neurons in C57BL/6 mice.
机构信息
Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
出版信息
Chin Med J (Engl). 2009 Oct 5;122(19):2366-71.
BACKGROUND
Paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium), a widely used herbicide, has been repeatedly suggested as a potential etiologic factor for the development of Parkinson's disease (PD), owing to its structural similarity to the known dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This study aimed to observe the influence of paraquat on nigrostriatal dopaminergic neurons in C57BL/6 mice.
METHODS
A total of 24 male C57BL/6 mice were assigned randomly to 3 groups: control group (treated by saline), PQ treated group, and MPTP treated group. Mice in PQ treated group were taken orally with PQ (10 mg/kg) daily for four months. Locomotor activity was measured. Level of dopamine (DA) and its metabolites levels in the striatum were measured by high-performance liquid chromatography with an electrochemical detector (HPLC-ECD), and tyrosine hydroxylase (TH) positive neurons were detected by using immunohistochemistry. At the same time, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and the content of malondialdehyde (MDA) in substantia nigra were measured by spectrophotometry. mRNA expression of dopamine transporter (DAT) in dopaminergic neurons of substantia nigra was also determined by reverse transcription (RT)-PCR technique.
RESULTS
Locomotor activities were significantly impaired in the PQ treated group. Level of DA and its metabolites levels in the striatum were declined. The activities of SOD and GSH-PX were decreased, and the content of MDA was increased in PQ treated mice compared with that in control group. Numbers of TH positive neurons and the mRNA expression of DAT in substantia nigra of mice were also decreased after PQ taken orally for four months.
CONCLUSIONS
The present study suggests that chronic oral administration of PQ could trigger dopaminergic neuron degeneration. Oxidative stress could be involved in the pathogenic mechanism of PD induced by PQ.
背景
百草枯（PQ；1,1'-二甲基-4,4'-联吡啶）是一种广泛使用的除草剂，由于其与已知的多巴胺能神经毒性 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）结构相似，因此被反复提出作为帕金森病（PD）发展的潜在病因。本研究旨在观察百草枯对 C57BL/6 小鼠黑质纹状体多巴胺能神经元的影响。
方法
将 24 只雄性 C57BL/6 小鼠随机分为 3 组：对照组（生理盐水处理）、PQ 处理组和 MPTP 处理组。PQ 处理组小鼠每日口服 PQ（10mg/kg），连续 4 个月。通过高效液相色谱电化学检测法（HPLC-ECD）测量纹状体中多巴胺（DA）及其代谢物水平，并用免疫组织化学法检测酪氨酸羟化酶（TH）阳性神经元。同时，通过分光光度法测量黑质中超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-PX）的活性以及丙二醛（MDA）的含量。还通过逆转录（RT）-PCR 技术测定黑质多巴胺转运体（DAT）在多巴胺能神经元中的 mRNA 表达。
结果
PQ 处理组的运动活动明显受损。纹状体中 DA 及其代谢物水平下降。与对照组相比，PQ 处理组小鼠的 SOD 和 GSH-PX 活性降低，MDA 含量增加。口服 PQ 4 个月后，黑质中 TH 阳性神经元数量和 DAT 的 mRNA 表达也减少。
结论
本研究表明，慢性口服 PQ 可引发多巴胺能神经元变性。氧化应激可能参与了 PQ 诱导的 PD 发病机制。
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