Overexpression of Glutathione Peroxidase Protects Immature Murine Neurons from Oxidative Stress

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Abstract
Neuronal enzyme systems involved in free radical detoxification are developmentally regulated such that intracellular glutathione peroxidase (GPx-1) activity is low in the newborn mouse brain. We hypothesized that neurons expressing a higher level of GPx-1 will be more resistant to hydrogen peroxide (H(2)O(2)) exposure. We show a dose-dependent protection against H(2)O(2) in primary neuronal cultures from fetuses overexpressing human GPx-1 compared to wild types of the same genetic background. Exogenous antioxidants completely protected neurons, even at extremely high H(2)O(2 )concentrations and regardless of the genotype. Specific depletion of glutathione with buthionine sulfoximine increased cell death in transgenic cultures exposed to 200 microM H(2)O(2), reducing protection afforded by increased GPx-1 activity. Increased GPx-1 expression in immature cortical neurons confers protection from oxidative stress, but availability of reducing equivalents determines susceptibility to oxidative cell death.