TY - JOUR
T1 - Effect of melatonin on temporal changes of reactive oxygen species and glutathione after MPP+ treatment in human astrocytoma U373MG cells
AU - Chuang, Jih Ing
AU - Chen, Tsung Hung
PY - 2004/2
Y1 - 2004/2
N2 - 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 O2 •-). 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+.
AB - 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 O2 •-). 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+.
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U2 - 10.1046/j.1600-079X.2003.00107.x
DO - 10.1046/j.1600-079X.2003.00107.x
M3 - Article
C2 - 14962063
AN - SCOPUS:1342280378
SN - 0742-3098
VL - 36
SP - 117
EP - 125
JO - Journal of Pineal Research
JF - Journal of Pineal Research
IS - 2
ER -