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 se izures and subsequent neurodegeneration similar to that observed in certain types of human epilepsy, and it is a commonly used animal model for this d isease. Oxidative stress has been suggested to play a role in the neuronal injury associated with KA administration. Based on this observation, chroni c treatment with antioxidants has been proposed as a possible protective th erapy against neuronal damage associated with epileptic seizures. Here we d emonstrate by histochemical, electrophysiological, and biochemical means th at knockout mice with decreased activity of the protective antioxidant enzy me glutathione peroxidase, which display elevated basal brain oxidative str ess levels, are resistant to KA-induced seizure activity and neurodegenerat ion. 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 antiox idants as antiepileptic agents to modulate NMDA-dependent seizure-induced n eurodegeneration may be detrimental rather than protective and calls into q uestion their use as a therapeutic agent in the treatment Of epilepsy. (C) 2000 Academic Press.