title: Activation of endogenous antioxidant defenses in neuronal cells prevents free radical-mediated damage.
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 microM 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 microM, 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.
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Duffy
authors.forename: A
authors.initials: A
authors.lastname: So
authors.forename: T H
authors.initials: TH
authors.lastname: Murphy
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D000069462:Dimethyl Fumarate; D004298:Dopamine / Q000633:toxicity; D005609:Free Radicals / Q000378:metabolism; D005650:Fumarates / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006825:Hybridomas; D006861:Hydrogen Peroxide / Q000633:toxicity; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D051381:Rats
chemical_list: D000975:Antioxidants; D005609:Free Radicals; D005650:Fumarates; D018696:Neuroprotective Agents; D016877:Oxidants; D011838:Radiation-Sensitizing Agents; D006861:Hydrogen Peroxide; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase; D000069462:Dimethyl Fumarate; D005978:Glutathione; D004298:Dopamine