Activation of endogenous antioxidant defenses in neuronal cells prevents free radical-mediated damage

J Neurochem. 1998 Jul;71(1):69-77. doi: 10.1046/j.1471-4159.1998.71010069.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism*
  • Dimethyl Fumarate
  • Dopamine / toxicity
  • Free Radicals / metabolism
  • Fumarates / pharmacology
  • Gene Expression Regulation, Enzymologic / physiology
  • Glutathione / metabolism
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Hybridomas
  • Hydrogen Peroxide / toxicity
  • Mice
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • Neuroblastoma
  • Neurons / drug effects*
  • Neurons / enzymology*
  • Neuroprotective Agents / pharmacology
  • Oxidants / toxicity
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Radiation-Sensitizing Agents / pharmacology
  • Rats

Substances

  • Antioxidants
  • Free Radicals
  • Fumarates
  • Neuroprotective Agents
  • Oxidants
  • Radiation-Sensitizing Agents
  • Hydrogen Peroxide
  • NAD(P)H Dehydrogenase (Quinone)
  • Glutathione Transferase
  • Dimethyl Fumarate
  • Glutathione
  • Dopamine