Toxic influence of chronic oral administration of paraquat on nigrostriatal dopaminergic neurons in C57BL/6 mice.
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.
Ren
Jin-peng
JP
Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Zhao
Yu-wu
YW
Sun
Xiao-jiang
XJ
D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000032:analysis / Q000235:genetics; D005979:Glutathione Peroxidase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010269:Paraquat / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology*; D012333:RNA, Messenger / Q000032:analysis; D013378:Substantia Nigra / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D010269:Paraquat; D004298:Dopamine