Differing effects of copper,zinc superoxide dismutase overexpression on neurotoxicity elicited by nitric oxide, reactive oxygen species, and excitotoxins.
Overexpression of Cu,Zn superoxide dismutase (SOD1) reduces ischemic injury in some stroke models but exacerbates injury in a neonatal stroke model and in other settings. The current study used a SOD1 transgenic (SOD1-Tg) murine cortical culture system, derived from the same mouse strain previously used for the stroke models, to identify conditions that determine whether SOD1 overexpression in neurons is protective or detrimental. The nitric oxide (NO) donors S-nitroso-N-acetylpenicillamine, spermine-NONOate, and diethylamine-NONOate produced less death in SOD1-Tg neurons than in wild-type neurons (p < 0.01). Also, NO produced markedly less 3-nitrotyosine in SOD1-Tg cells. In contrast, the superoxide generator menadione produced significantly greater death and nearly twice as much 2'7'-dichlorofluorescein fluorescence in SOD1-Tg neurons than in wild-type neurons, suggesting increased peroxide formation in the SOD1-Tg cells. No significant difference was observed in the vulnerability of the two cell types to H2O2, the product of the SOD reaction. Overexpression of SOD1 also had no effect on neuronal vulnerability to glutamate, N-methyl-D-aspartate, or kainate. These observations suggest that SOD1 overexpression can reduce neuronal death under conditions where peroxynitrite formation is a significant factor, but may exacerbate neuronal death under conditions of rapid intracellular superoxide formation or impaired H2O2 disposal.
Ying
W
W
Department of Neurology, University of California and Veterans Affairs Medical Center, San Francisco, USA.
Anderson
C M
CM
Chen
Y
Y
Stein
B A
BA
Fahlman
C S
CS
Copin
J C
JC
Chan
P H
PH
Swanson
R A
RA
D000818:Animals; D001253:Astrocytes / Q000166:cytology; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D009498:Neurotoxins / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009589:Nitrogen Oxides; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D014812:Vitamin K / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D006834:Hydrazines; D009498:Neurotoxins; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; C110881:S-nitro-N-acetylpenicillamine; D014812:Vitamin K; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D018698:Glutamic Acid; D014443:Tyrosine; D016202:N-Methylaspartate; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D013482:Superoxide Dismutase; D010396:Penicillamine; D007608:Kainic Acid