**3. The redox status in brain tumors**

Brain is considered to be intensely vulnerable to oxidative damage having a high content of peroxidizable unsaturated fatty acids, high oxygen consumption per unit weight, high content of iron which is a key in lipid peroxidation and a shortage of antioxidant defense systems [39], so a crucial and unique target for both oxidative stress effects compared to other tissues and for metastatic growth being surrounded by the blood brain barrier. Reactive oxygen species (ROS), or free radicals, may exceed the scavenging ability of endogenous antioxidants, resulting in a shift of the redox state of the brain to the oxidative state. Redox balance in neural tissue has an important role in the pathophysiology of neurotoxicity through the free radical generation. ROS are particularly active in the brain and neuronal tissue and very aggressive to glial cells and neurons. Endogenous antioxidant system plays a constitutive role in preven‐ tion of any damage due to free radicals. However, imbalanced defense mechanism of antiox‐ idants, overproduction or incorporation of free radicals from environment to living system bring about a serious infliction and therefore to a neuronal death [40].

between seizure activity and high levels of extracellular glutamate in tumor associated epilepsy. Increased levels of glutamate was shown in glioma patients with epilepsy [15,21]. The number of glutamate receptors are variable depending on the tumor degree. Ionotropic glutamate receptors, which induce intracellular calcium release when activated, are NMDA, AMPA and kainate receptors and with marred activity, in the peritumoral tissue differences in the expression are seen. GABA is also a neurotransmitter which inhibits neuronal discharge and when there is a down regulation in GABA receptors, which are GABAA, GABAB and GABAC, hyperactivity in the peritumoral zone is encountered. Alterations in the functions of GABA receptors in the peritumoral tissue, induce GABAergic neurotransmission alleviation and GABA levels are reported to be increased in tumor tissues [18,19]. GABAergic activity doesn't have a relationship with seizure somethesia directly yet the alterations in the levels seem causal for tumor related epilepsy. Also, in gliomas decreased kynurenic acid levels causing NMDA receptor disinhibition [22] and decreased noradrenaline and serotonin levels

Inflammation, either immune mediated or without infection, also play a crucial role in epileptic seizures and in tumor related epilepsy where proinflammatory cytokines being inflammatory mediators and their receptors are involved in the pathogenesis. High levels of cytokines such as interleukin (IL)-6, IL-1β and the IL-1, tumor necrosis factor (TNF)-α were implied [24]. Cytokine activation depends on both seizure severity and duration in epilepsy patients. [25, 26]. Activation of IL-1β system in glial cells expressing IL-1β and its receptor was reported in studies with chronic epileptic rats [27,28]. IL-4 and IL-6 were shown to be having modulating effects on neurotoxic neurotransmitters which are released during excitation and inflammation [29]. In the peritumoral tissue neurochemical alterations, coupled with the imbalance between stimulatory and inhibitory cytokines, which are immune mediated were shown in glioma [30-32] and reported to be related with tumor associated epilepsy. The activation of toll like receptor (TLR) signaling pathways, which are activated via pathogens or endogenous ligands released by damaged or stressor activated cells called as danger signals, is also a current subject in epilepsy [33,34] and in neurons and astrocytes TLR4 overexpression was demonstrated in chronic epileptic mice [33,35]. The inflammation in the brain tissue is thought to be contributing to the deterioration of the blood brain barrier leading to serum albumin and IgG accumulation. Albumin was reported to be inducing the long lasting hyperexcitability via impairing astrocyte buffering capacity of extracellular potassium and glutamate through activating transforming growth factor (TGF)-β pathway which leads to glutamate transporter downregulation [36-38]. These induced mechanisms through brain inflammation might explain the detention time

occuring between the inflammatory complications and the inception of epilepsy.

Brain is considered to be intensely vulnerable to oxidative damage having a high content of peroxidizable unsaturated fatty acids, high oxygen consumption per unit weight, high content of iron which is a key in lipid peroxidation and a shortage of antioxidant defense systems [39], so a crucial and unique target for both oxidative stress effects compared to other tissues and

causing antiepileptogenic effects were reported [23].

108 Tumors of the Central Nervous System – Primary and Secondary

**3. The redox status in brain tumors**

Tumor cells frequently demonstrate a change in redox status. The alterations in the redox environment enhancing oxidation can induce some of the factors that cause cell proliferation and malignant transformation. Cancer cells display increased glycolysis rate combined with a reduced respiration rate [41]. The enhanced requirements for ATP; generates oxygen free radicals and this causes oxidative stress conditions to come out which eventually promotes cell death. Neurons and cancer cells consume glucose as energy source to respond this issue and glycolytic metabolism rules over in tumor cells. The release of cytochrome c couples with the pentose phosphate pathway and this initiates cytochrome c mediated apoptosis [42]. Caspase activation is initiated by cytochrome c when released from mitochondria during apoptosis. So, the cancer cells and neurons control apoptosis through regulation of cytochrome c release, while utilizing glucose as a source of energy [43]. This marked changes in metabolism have been shown to be related with increased oxidative stress which is emphasized to be due to increased mitochondrial superoxide radical production [44].

Studies have been done to evaluate antioxidant enzyme activities in different types of brain tumors. However, most studies have emphasized decreased levels of antioxidant enzymes and vitamins in diverse malignancies but still the results are inconsistent. Elevated manganase superoxide dismutase (MnSOD) activities were shown in the serum samples of neuroblastoma patients in a study. In recent studies, MnSOD was found to be associated with loss of differ‐ entiation and increased clinical malignancy in neuroepithelial origined brain tumors. MnSOD was found significantly positive in Grade IV astrocytomas and medulloblastomas and negative in normal brain samples. It can be said that MnSOD is overexpressed in most brain tumor types and enhanced MnSOD expression is related with a poor prognosis. MnSOD seems to be a tumor suppressor in the proliferative stage. When tumor progresses more aggressive, MnSOD is upregulated. MnSOD level positively correlates with increased metastasis so MnSOD has an oncogene role. Increase in MnSOD level was seen during the progression of different types of tumors, including brain, to the metastatic stage. Tumorigenesis and metastasis are depend‐ ent on the levels of ROS. A cell having low levels of MnSOD is vulnerable to oxidative stress then it may turn its progression to a tumor cell. Oxidative gene polymorphism and brain tumor risk seems to be associated, the increased risk of glioma and meningioma type brain tumors were found to be related with variants in some antioxidant enzyme genes and in a study, MnSOD tissue expression is said to be a prognostic marker for glioblastoma. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities showed a clear decrease pro‐ portionally with tumor malignancy, decrease of SOD activity with the increasing grades of malignancy in brain tumors were implied [45,46].

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

Biochemical and Surgical Aspects of Epilepsy Related to Brain Tumors — Appraising Redox Biology and Treatments

http://dx.doi.org/10.5772/58343

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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

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

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

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

epilepsy due to mitochondrial dysfunction could be explained accordingly.

with the development of epileptic activity [51].

**5. Contributing mitochondrial alterations**

stress.

to focal seizures.

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].
