o 22: reactive oxygen species and epilepsy

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. live cell imaging techniques in glio-neuronal cultures and in ex vivo epileptic brain tissue. 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. inhibition of nadph or xo markedly reduced seizure-like activity-induced neuronal apoptosis. in addition, ros were upregulated in chronic epilepsy in ex vivo brain slices. inhibition of ros production in vivo by aebsf, a nadph oxidase inhibitor, markedly reduced seizure-induced cell death. these findings demonstrate a critical role for ros, generated by nadph oxidase, contributing to seizure-induced cell death. these findings point to nadph oxidase inhibition as a novel treatment strategy to prevent brain injury in seizures, status epilepticus and chronic epilepsy.