Increased susceptibility of glutathione peroxidase-1 transgenic mice to kainic acid-related seizure activity and hippocampal neuronal cell death.
Glutathione peroxidase (GSHPx) has been demonstrated in several in vivo studies to reduce both the risk and severity of oxidatively-induced tissue damage. The seizure-inducing neurotoxin kainic acid (KA) has been suggested to elicit its toxic effects in part via generation of oxidative stress. In this study, we report that expression of elevated levels of murine GSHPx-1 in transgenic mice surprisingly results in increased rather than decreased KA susceptibility including increased seizure activity and neuronal hippocampal damage. Isolated transgenic primary hippocampal culture neurons also display increased susceptibility to KA treatment compared with those from wildtype animals. This could be due to alterations in the redox state of the glutathione system resulting in elevated glutathione disulfide (GSSG) levels which, in turn, may directly activate NMDA receptors or enhanced response of the NMDA receptor.
Boonplueang
R
R
Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA.
Akopian
G
G
Stevenson
F F
FF
Kuhlenkamp
J F
JF
Lu
S C
SC
Walsh
J P
JP
Andersen
J K
JK
D000818:Animals; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004827:Epilepsy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D019803:Glutathione Disulfide / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D005979:Glutathione Peroxidase; D007608:Kainic Acid; D019803:Glutathione Disulfide