Attenuation of zinc-induced intracellular dysfunction and neurotoxicity by a synthetic superoxide dismutase/catalase mimetic, in cultured cortical neurons.
Excessive extracellular zinc may contribute to neuronal cell death following ischemia and seizures, although the mechanisms mediating zinc-induced cell death remain largely unknown. In this study, we examined potential cellular and molecular mechanisms associated with zinc neurotoxicity and determined the neuroprotective effects of the superoxide dismutase (SOD)/catalase mimetic, EUK-134. Cortical neuron cultures exposed to zinc for 24 h exhibited concentration-dependent increases in lactate dehydrogenase (LDH) release and number of apoptotic cell bodies. Both effects were prevented by treatment with EUK-134. Zinc exposure resulted in increased release of cytochrome c from the mitochondria into the cytosol. Treatment with EUK-134 blocked this parameter of mitochondrial dysfunction. Exposure of cultures to zinc for 4 h produced an elevation of reactive oxygen species (ROS) as determined by increased 2,7-dichlorofluorescein (DCF) fluorescence, which was followed by an increase in lipid peroxidation. EUK-134 completely attenuated ROS production and subsequent oxidative damage. Finally, zinc exposure activated NF-kappaB, an effect also prevented by EUK-134. These data indicate that multiple cellular and molecular mechanisms are involved in zinc neurotoxicity. As all these mechanisms appear to be sensitive to treatment with EUK-134, our data suggest that oxidative stress occurs early in the cascade of events triggered by zinc.
Pong
Kevin
K
Neuroscience Program, University of Southern California, Los Angeles, CA 90089, USA. pongk@wyeth.com
Rong
Yongqi
Y
Doctrow
Susan R
SR
Baudry
Michel
M
D000818:Animals; D002374:Catalase / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D007424:Intracellular Fluid / Q000187:drug effects*; D009942:Organometallic Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000737:chemistry / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology* / Q000633:toxicity
C433928:EUK-134; D009942:Organometallic Compounds; D012459:Salicylates; D002374:Catalase; D013482:Superoxide Dismutase; D015032:Zinc