Chronic brain oxidation in a glutathione peroxidase knockout mouse model results in increased resistance to induced epileptic seizures.
Systemic administration of kainic acid (KA) to rodents results in limbic seizures and subsequent neurodegeneration similar to that observed in certain types of human epilepsy, and it is a commonly used animal model for this disease. Oxidative stress has been suggested to play a role in the neuronal injury associated with KA administration. Based on this observation, chronic treatment with antioxidants has been proposed as a possible protective therapy against neuronal damage associated with epileptic seizures. Here we demonstrate by histochemical, electrophysiological, and biochemical means that knockout mice with decreased activity of the protective antioxidant enzyme glutathione peroxidase, which display elevated basal brain oxidative stress levels, are resistant to KA-induced seizure activity and neurodegeneration. This appears to be a result of decreased NMDA receptor function due to oxidation of its NR1 subunit. This suggests that the chronic use of antioxidants as antiepileptic agents to modulate NMDA-dependent seizure-induced neurodegeneration may be detrimental rather than protective and calls into question their use as a therapeutic agent in the treatment of epilepsy.
Division of Neurogerontology, University of Southern California, Los Angeles, California 90089, USA.
D
D
Jiang
G
G
Akopian
Y S
YS
Ho
J P
JP
Walsh
J K
JK
Andersen
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004827:Epilepsy / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D007608:Kainic Acid; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D013438:Sulfhydryl Compounds; D016291:Dizocilpine Maleate; D005979:Glutathione Peroxidase; D007608:Kainic Acid