Over-expression of antioxidant enzymes protects cultured hippocampal and cortical neurons from necrotic insults.
There is now considerable knowledge concerning neuron death following necrotic insults, and it is believed that the generation of reactive oxygen species (ROS) and oxidative damage play a pivotal role in the neuron death. Prompted by this, we have generated herpes simplex virus-1 amplicon vectors over-expressing the genes for the antioxidant enzymes catalase (CAT) or glutathione peroxidase (GPX), both of which catalyze the degradation of hydrogen peroxide. Over-expression of each of these genes in primary hippocampal or cortical cultures resulted in increased enzymatic activity of the cognate protein. Moreover, each enzyme potently decreased the neurotoxicity induced by kainic acid, glutamate, sodium cyanide and oxygen/glucose deprivation. Finally, these protective effects were accompanied by parallel decreases in hydrogen peroxide accumulation and the extent of lipid peroxidation. These studies not only underline the key role played by ROS in the neurotoxicity of necrotic insults, but also suggest potential gene therapy approaches.
Wang
Hui
H
Department of Biological Sciences, and Neurology and Neurological Sciences, Stanford University, Gilbert Laboratory, Stanford, California 94305, USA.
Cheng
Elise
E
Brooke
Sheila
S
Chang
Pearl
P
Sapolsky
Robert
R
D000818:Animals; D002374:Catalase / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000821:virology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors; D018698:Glutamic Acid / Q000633:toxicity; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology* / Q000821:virology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007239:Infections; D007608:Kainic Acid / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000821:virology; D051381:Rats; D018139:Simplexvirus / Q000235:genetics; D012966:Sodium Cyanide / Q000633:toxicity
D008869:Microtubule-Associated Proteins; D018698:Glutamic Acid; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase; D012966:Sodium Cyanide; D007608:Kainic Acid