Synergistic depletion of astrocytic glutathione by glucose deprivation and peroxynitrite: Correlation with mitochondrial dysfunction and subsequent cell death

Chung Ju, Keum Na Yoon, Yu Kyoung Oh, Hyoung Chun Kim, Chan Young Shin, Jae Ryun Ryu, Kwang Ho Ko, Won Ki Kim

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Abstract

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 μM) 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.

Original languageEnglish
Pages (from-to)1989-1998
Number of pages10
JournalJournal of Neurochemistry
Volume74
Issue number5
DOIs
Publication statusPublished - 2000 May 3
Externally publishedYes

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Keywords

  • Astrocyte
  • Glucose deprivation
  • Glutathione
  • Mitochondrial transmembrane potential
  • Nitric oxide
  • Peroxynitrite

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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