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Effect of melatonin on temporal changes of reactive oxygen species and glutathione after MPP + treatment in human astrocytoma U373MG cells
Author(s) -
Chuang JihIng,
Chen TsungHung
Publication year - 2004
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1046/j.1600-079x.2003.00107.x
Subject(s) - glutathione , oxidative stress , melatonin , reactive oxygen species , buthionine sulfoximine , apoptosis , chemistry , programmed cell death , biology , endocrinology , pharmacology , biochemistry , medicine , enzyme
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) (H 2 O 2 and O). 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 H 2 O 2 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 + .