Effect of melatonin on temporal changes of reactive oxygen species and glutathione after MPP+ treatment in human astrocytoma U373MG cells

被引:30
作者
Chuang, JI [1 ]
Chen, TH [1 ]
机构
[1] Natl Cheng Kung Univ, Coll Med, Dept Physiol, Tainan, Taiwan
关键词
apoptosis; astrocyte; melatonin; MPP+; oxidative stress;
D O I
10.1046/j.1600-079X.2003.00107.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
1-Methyl-4-phenylpyridinium (MPP+) ion, a toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, is produced by monoamine oxidase B in astrocytes. MPP+ causes a selective dopaminergic neurodegeneration, the pathophysiologic hallmark of Parkinson disease. However, the toxic effect of MPP+ on astrocytes remains unclear. Here, we examined the effect of MPP+ on human astrocytoma U373MG cells, with particular attention to the temporal interaction of glutathione (GSH) and reactive oxygen species (ROS) (H2O2 and O-2(.-)). MPP+ induced astrocyte apoptosis in a dose-dependent manner 48 hr after treatment. Distinctive early ( < 6 hr) and late (24-48 hr) responses were observed. ROS production and the oxidized GSH (GSSG)/GSH ratio, indicators of oxidative stress, rose dramatically after 24 hr of MPP+ exposure, whereas the H2O2 level transiently decreased at 6 hr. ROS overproduction and GSH dysfunction were concomitantly associated with caspase-3 activation and finally led to cell apoptosis. Moreover, GSH depletion by diethyl maleate, but not buthionine sulfoximine, caused cells to die quickly and potentiated the cytotoxicity of MPP+. Co-treatment with melatonin, a known antioxidant secreted by the pineal gland, significantly prevented cell apoptosis by inhibiting oxidative stress and caspase-3 activation, but it did not affect that the early changes due to MPP+ treatment. Our results demonstrate that in astrocytes, GSH is involved in the early decrease and late increase in ROS levels induced by MPP+ treatment. Melatonin remedies the dysfunction of GSH system to block caspase-3 activation and cell apoptosis induced by oxidative stress during the long-term exposure of MPP+.
引用
收藏
页码:117 / 125
页数:9
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