**4. The pivotal role of oxidative stress during epileptic seizures**

Epilepsy, being an excitotoxic brain disorder, causes neuronal destruction incrementally. The generation of ROS is distinctly implicated in a number of neurologic diseases including seizure disorders. Oxidative stress and mitochondrial dysfunction are indicated to be having a crucial role in the pathogenesis of epilepsy [47,48], contributing to the neuronal destruction through the activation of proapoptotic transcription factors [49,50]. Neuronal cell damage develops due to recurrent or obstinate seizures and abnormal increases in by products during seizures through the increased metabolic activity producing ROS with damage and leading to disrup‐ tion of electrophysiologic integrity and instability of neuronal membranes. Fe3+induces oxidative damage to neuronal plasma membranes and experimentally it was shown that this is related with the development of epileptic activity. Due to small bleedings, Fe3+levels may increase in tumoral and peritumoral areas which also prospectively contribute to the devel‐ opment of tumor related seizures and this is mostly encountered in high grade gliomas [2]. In an experimental study, intracortical injection of Fe3+induced the formation of epileptic areas in cerebral cortex. Also, increase in the peroxidation of membrane lipids is found to be related with the development of epileptic activity [51].

Mitochondrial dysfunction is associated with epilepsy and this was demonstrated both in humans [52,53] and in several experimental epilepsy models [54,55]. When complex I was inhibited, markers of oxidative damage; 3-nitrotyrosine, 4-hydroxynonenal and protein carbonyl levels were significantly increased and this was alleviated treating with a radical scavenger and an antioxidant enzyme [56,57]. It is suggested that the reduced activity of complex I is due to oxidative modification with an extreme sensitivity to ROS, on the other hand complex I is also an important source of ROS, especially when the enzyme complex is partially inhibited [58,59]. Thereby, when complex I is inhibited, enhanced production of ROS might lead to epileptogenesis [60]. The pivotal role of mitochondrial dysfunction in the pathogenesis of epileptic seizure generation seems to be the main topic appraising oxidative stress.
