**5. Contributing mitochondrial alterations**

portionally with tumor malignancy, decrease of SOD activity with the increasing grades of

The GSH redox cycle is one of the most important antioxidative systems. GSH is a primary endogenous neuroprotectant for the brain. GSH protects neuron cells from lipid peroxidation and brain cells from peroxynitrite mediated oxidative damage. GSH is prevalantly seen in brain tissue, thus highly expressed in various primary brain tumors. GSH content was shown to be related to tumor response to nitrogen mustard therapy in human brain neoplasms. When glutathione-S-transferase (GST) isoenzymes in neoplastic and non-neoplastic astroglia were compared, GST3 isoenzyme was seen to be significantly higher in tumors. It is said that GST expression levels in brain tumors seems in association with the tumor histology as some tumor types express enhanced levels but some show only slight rise or decrease when compared to normal cells. GST was found to be active in high levels in benign tumors such as meningioma but only two-three folds higher compared to normal tissue but it was slightly increased in astrocytoma. In glioblastomas, GSH levels were found significantly lowered compared to normal tissue and merely elevated in meningioma. It has been reported that GPx and gluta‐ thione reductase (GR) enzyme activities decrease and protein oxidation levels increase in patients with glioblastoma multiforme and transitional meningioma; the two kinds of tumors which represent specially one of the most malignant and most benign tumors respectively and it was shown that there is a complex relationship between pro-and anti-apoptotic molecules in glioblastoma multiforme pathogenesis, thus targeting multiple pathways with advanced chemotherapeutic agents or radiotheraupetic regimens following total resections might be helpful in patients with glioblastoma multiforme and consistent differences in the levels of antioxidants in different types of brain tumors were emphasized in different studies. The decreased antioxidant levels in brain tumor patients reflect the enhanced oxidative damage and increased cancer developing possibility, stating the role of antioxidants in cancer preven‐ tion and role of oxidative injury as the of cancer. It was seen that β-carotene and α-tocopherol levels decreases when malignancy grade increases and the decrease was found significant for

oligodendroglioma grade I-II, glioblastoma multiforme and medulloblastoma [45,46].

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‐

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

malignancy in brain tumors were implied [45,46].

110 Tumors of the Central Nervous System – Primary and Secondary

Seizure activity is considered to be inducing energy failure and leading to neuronal injury. Neuronal mitochondria, moving along axons and dendrites, are substantially dynamic [61]. Ca2+regulation, redox signaling, developmental and synaptic plasticity are among the func‐ tions of mitochondria [62].The triggering influence of several mutations in the genes affecting oxidative phosphorylation in epilepsy implies the importance of mitochondria for neurons. The related mutations were demonstrated in the mitochondrial DNA polymerase γ (POLG1) [63,64], mitochondrial tRNALys (MT-TK) [65,66] and tRNAPhe (MT-TF) [67] genes in different phenotypes of epilepsy. Epilepsy is also appelled as a nonsyndromic mitochondrial disorder (MID) due to a novel classification and has a genetic or metabolic ground through a cerebral lesion or dysfunction [68]. Depending on the selection of MID patients, the prevalence seems to be lower in adulthood and the generalized seizures are remarkably more often compared to focal seizures.

Decreased ATP levels, changes in neuronal calcium homeostasis and modifications of ion channels and neurotransmitter transporters due to ROS damage are the main causes of impaired mitochondrial function and the increased neuronal excitability leading to epilepto‐ genesis. In many studies, ATP depletion during seizures was indicated [69-71] entailing a decrease in neuronal plasma membrane potential leading to an increase in neuronal excitability as the major source of ATP for sodium potassium ATPase is the mitochondrial oxidative phosphorylation in neurons [72,73]. The interneurons, being mithochondria rich, expose a decreased synaptic transmission in inhibitory synapses, thereby the increased excitability in epilepsy due to mitochondrial dysfunction could be explained accordingly.

Mitochondria have a substantial role in intracellular Ca2+sequestration in neurons so can be named as major calcium buffers [74,75]. Attributing to remarkable calcium flow in neuronal excitability, through ligand gated and voltage gated ion channels, cyclic calcium elevations are seen during epileptic activity. Referring to this, mitochondria can attenuate the altered neuronal excitability and synaptic transmission in epilepsy [76]. Yet another reason for the increased excitability encountered in epilepsy is, astroglial and neuronal glutamate transport‐ ers' being quite sensitive to oxidative damage which are known to be crucial for the mainte‐ nance of low synaptic glutamate levels [77]. and it was indicated that complex I activity induces the excess release of glutamate [78]. So it can be concluded by stating that oxidative stress has direct effects on neuronal excitability in the same time.
