title: Seizure activity results in calcium- and mitochondria-independent ROS production via NADPH and xanthine oxidase activation.
abstract: Seizure activity has been proposed to result in the generation of reactive oxygen species (ROS), which then contribute to seizure-induced neuronal damage and eventually cell death. Although the mechanisms of seizure-induced ROS generation are unclear, mitochondria and cellular calcium overload have been proposed to have a crucial role. We aim to determine the sources of seizure-induced ROS and their contribution to seizure-induced cell death. Using live cell imaging techniques in glioneuronal cultures, we show that prolonged seizure-like activity increases ROS production in an NMDA receptor-dependent manner. Unexpectedly, however, mitochondria did not contribute to ROS production during seizure-like activity. ROS were generated primarily by NADPH oxidase and later by xanthine oxidase (XO) activity in a calcium-independent manner. This calcium-independent neuronal ROS production was accompanied by an increase in intracellular [Na(+)] through NMDA receptor activation. Inhibition of NADPH or XO markedly reduced seizure-like activity-induced neuronal apoptosis. These findings demonstrate a critical role for ROS in seizure-induced neuronal cell death and identify novel therapeutic targets.
authors.affiliation: 1] UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK [2] Department of Neurology, University of Muenster, Muenster 48149, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kovac
authors.affiliation: Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb 10000, Croatia.
authors.forename: A-M
authors.initials: AM
authors.lastname: Domijan
authors.affiliation: UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors.forename: M C
authors.initials: MC
authors.lastname: Walker
authors.affiliation: UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors.forename: A Y
authors.initials: AY
authors.lastname: Abramov
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012964:Sodium / Q000378:metabolism; D014969:Xanthine Oxidase / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D009249:NADP; D012964:Sodium; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D002118:Calcium