Increased susceptibility of glutathione peroxidase-1 transgenic mice to kainic acid-related seizure activity and hippocampal neuronal cell death

• Published in: Experimental neurology 2005-03, Vol.192 (1), p.203-214
• Main Authors: Boonplueang, R., Akopian, G., Stevenson, F.F., Kuhlenkamp, J.F., Lu, S.C., Walsh, J.P., Andersen, J.K.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Death - genetics; Cells, Cultured; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Epilepsy; Epilepsy - enzymology; Epilepsy - genetics; Epilepsy - physiopathology; Excitotoxicity; Genetic Predisposition to Disease - genetics; Glutathione; Glutathione disulfide; Glutathione Disulfide - metabolism; Glutathione peroxidase; Glutathione Peroxidase - genetics; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hippocampus - drug effects; Hippocampus - enzymology; Hippocampus - physiopathology; Kainic acid; Kainic Acid - pharmacology; Medical sciences; Mice; Mice, Transgenic; N-Methylaspartate - pharmacology; Nerve Degeneration - enzymology; Nerve Degeneration - genetics; Nerve Degeneration - physiopathology; Nervous system (semeiology, syndromes); Neurology; Neuronal cell death; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neurotoxins - pharmacology; NMDA receptors; Organ Culture Techniques; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - metabolism; Seizure; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2004.12.017

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.