Activation of Endogenous Antioxidant Defenses in Neuronal Cells Prevents Free Radical-Mediated Damage |
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Authors: | Steven Duffy Austin So Timothy H Murphy |
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Institution: | Departments of Psychiatry and Physiology, University of British Columbia, Vancouver, British Columbia, Canada |
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Abstract: | Abstract: Dopamine (DA) is oxidized to the neurotoxic prooxidant species H2O2, OH?, and DA quinones. We tested whether dimethyl fumarate (DMF), an electrophile shown to induce a pleiotropic antioxidant response in nonneuronal cells, could reduce the toxicity of DA metabolites in neural cells. Treatment of the N18-RE-105 neuroblastoma-retina hybridoma cell line with 30–150 µ M dopamine led to cell death within 24 h, which increased steeply with dose, decreased with higher plating density, and was blocked by the H2O2-metabolizing enzyme catalase. Pretreatment with DMF (30 µ M , 24 h) significantly attenuated DA and H2O2 toxicity (40–60%) but not that caused by the calcium ionophore ionomycin. DMF treatment also elevated total intracellular GSH and increased activities of the antioxidant enzymes quinone reductase (QR), glutathione S -transferase (GST), glutathione reductase, and the pentose phosphate enzyme glucose-6-phosphate dehydrogenase. To assess the protective efficacy of QR and GST, a stable cell line was constructed in which these enzymes were overexpressed. Cell death in the overexpressing line was not significantly different from that in a cell line expressing normal QR and GST activities, indicating that these two enzymes alone are insufficient for protection against DA toxicity. Although the relative importance of a single antioxidant enzyme such as QR or GST may be small, antioxidant inducers such as DMF may prove valuable as agents that elicit a broad-spectrum neuroprotective response. |
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Keywords: | Dopamine toxicity Hydrogen peroxide toxicity Glutathione pathway Antioxidant inducer Oxidative stress |
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