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Synergistic Depletion of Astrocytic Glutathione by Glucose Deprivation and Peroxynitrite
Author(s) -
Ju Chung,
Yoon KeumNa,
Oh YuKyoung,
Kim HyoungChun,
Shin Chan Young,
Ryu Jae Ryun,
Ko Kwang Ho,
Kim WonKi
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0741989.x
Subject(s) - peroxynitrite , glutathione , chemistry , buthionine sulfoximine , lactate dehydrogenase , mitochondrial permeability transition pore , biochemistry , nitric oxide , programmed cell death , astrocyte , superoxide , endocrinology , apoptosis , biology , enzyme , organic chemistry , central nervous system
Previously we reported that immunostimulated astrocytes were highly vulnerable to glucose deprivation. The augmented death was mimicked by the peroxynitrite (ONOO ‐ ‐producing reagent 3‐morpholinosydnonimine (SIN‐1). Here we show that glucose deprivation and ONOO ‐ synergistically deplete intracellular reduced glutathione (GSH) and augment the death of astrocytes via formation of cyclosporin A‐sensitive mitochondrial permeability transition (MPT) pore. Astrocytic GSH levels were only slightly decreased by glucose deprivation or SIN‐1 (200 μ M ) alone. In contrast, a rapid and large depletion of GSH was observed in glucose‐deprived/SIN‐1‐treated astrocytes. The depletion of GSH occurred before a significant release of lactate dehydrogenase (a marker of cell death). Superoxide dismutase and ONOO ‐ scavengers completely blocked the augmented death, indicating that the reaction of nitric oxide with superoxide to form ONOO ‐ was implicated. Furthermore, nitrotyrosine immunoreactivity (a marker of ONOO ‐ ) was markedly enhanced in glucose‐deprived/SIN‐1‐treated astrocytes. Mitochondrial transmembrane potential (MTP) was synergistically decreased in glucose‐deprived/SIN‐1‐treated astrocytes. The glutathione synthase inhibitor L‐buthionine‐( S,R )‐sulfoximine markedly decreased the MTP and increased lactate dehydrogenase (LDH) releases in SIN‐1‐treated astrocytes. Cyclosporin A, an MPT pore blocker, completely prevented the MTP depolarization as well as the enhanced LDH releases in glucose‐deprived/SIN‐1‐treated astrocytes.