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.
Highlights
Production was accompanied by an increase in intracellular [Na+] through NMDA receptor activation
An increase in Reactive oxygen species (ROS) generation has been identified in acute neurologic disease such as stroke,[5,6] and recent evidence indicates that this may contribute to neuronal damage in seizures and epilepsy.[7,8,9,10]
We have shown that seizure-like activity induces profound changes in the rate of ROS
Summary
Production was accompanied by an increase in intracellular [Na+] through NMDA receptor activation. Reactive oxygen species (ROS) contribute to neuronal damage and have been linked to excitotoxicity.[1,2,3,4] An increase in ROS generation has been identified in acute neurologic disease such as stroke,[5,6] and recent evidence indicates that this may contribute to neuronal damage in seizures and epilepsy.[7,8,9,10] ROS measurements during seizurelike activity were predominantly performed in homogenates, extracellular fluids or brain regions with no clear demonstration of whether the ROS were of neuronal origin.[9,11,12] these studies lacked the necessary temporal resolution to determine accurately the evolution of ROS generation during and after prolonged seizure activity. These pathways involved NMDA receptor activation and upregulation of NMDA receptor subunits NR1 and NR2B
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