Glial cells protect neurons against oxidative stress via transcriptional up-regulation of the glutathione synthesis.
We examined the effects of oxidative stress on rat cultured mesencephalic neurons and glial cells. Glial cells were more resistant to 6-hydroxydopamine (6-OHDA) and H2O2 toxicity than neurons. In glial cells, incubation with 6-OHDA and H2O2 induced a significant increase in the expression of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione synthesis) mRNA, which correlated well with increased TPA-response element (TRE)-binding activity. Furthermore, a subsequent elevation in cellular total glutathione content was also observed. In neurons, both agents decreased TRE-binding activity, and these cells failed to up-regulate the glutathione synthesis. We also examined the mechanisms of the neuroprotective effects of glial cells using a glia conditioned medium. Neurons maintained in glia conditioned medium up-regulated the level of TRE-binding activity, gamma-glutamylcysteine synthetase mRNA expression, and total glutathione content in response to 6-OHDA or H2O2, and became more resistant to both agents than cells maintained in a normal medium. Neurons maintained in normal medium failed to up-regulate the glutathione synthesis. Our results suggest that transcriptional up-regulation of glutathione synthesis in glial cell appears to mediate brain glial cell resistance against oxidative stress, and that glial cells protect neurons via transcriptional up-regulation of the antioxidant system.
Iwata-Ichikawa
E
E
Department of Neuroscience, Institute of Molecular and Cellular Medicine, Okayama University Medical School, Japan.
Kondo
Y
Y
Miyazaki
I
I
Asanuma
M
M
Ogawa
N
N
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D005978:Glutathione / Q000096:biosynthesis*; D006861:Hydrogen Peroxide / Q000633:toxicity; D008636:Mesencephalon / Q000166:cytology / Q000502:physiology*; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D016627:Oxidopamine / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
D017077:Culture Media, Conditioned; D012333:RNA, Messenger; D016627:Oxidopamine; D006861:Hydrogen Peroxide; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate