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 γ-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 gila conditioned medium. Neurons maintained in gila conditioned medium up-regulated the level of TRE- binding activity, γ-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.