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Activation of Endogenous Antioxidant Defenses in Neuronal Cells Prevents Free Radical‐Mediated Damage
Author(s) -
Duffy Steven,
So Austin,
Murphy Timothy H.
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.71010069.x
Subject(s) - antioxidant , glutathione , glutathione reductase , dimethyl fumarate , ionomycin , biochemistry , chemistry , catalase , toxicity , pharmacology , pentose phosphate pathway , neuroprotection , enzyme , programmed cell death , intracellular , glutathione peroxidase , biology , apoptosis , immunology , glycolysis , organic chemistry , multiple sclerosis
Dopamine (DA) is oxidized to the neurotoxic prooxidant species H 2 O 2 , 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 H 2 O 2 ‐metabolizing enzyme catalase. Pretreatment with DMF (30 µ M , 24 h) significantly attenuated DA and H 2 O 2 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.