**2. The biochemical mechanisms transpiring in case of epileptic seizures**

Epilepsy should be considered not only as a single disease, but also common symptomatic symptoms of brain abnormalities involving central nervous system infections, traumatic brain injuries, genetic syndromes or brain lesions such brain tumors are present. The relationship of inflammation in the pathophysiology of epilepsy is implied in various clinical studies [5,6]. The dysregulated homeostasis in the peritumoral tissue may cause to seizure somethesia as the tumor cells create an intrinsic epileptogenicity. The most vital mechanism inducing tumor related seizures is the alteration of amino acid neurotransmission where also an alteration in the extracellular ions is involved. These mechanisms should be enlightened to provide guidance for improving new strategies in the surgical and medical treatment for tumor associated epilepsy.

is an important deterministic of epileptic seizures. Due to the decreased intratumoral perfusion and increased metabolism, hypoxia occurs causing acidosis through metabolic requirements of the proliferating tissue and the disrupted oxidative energy metabolism, both inducing glial cell swelling and damage effecting the surrounding tissue [2]. It was implied that derangement between the excitatory and inhibitory balance leads to glioma associated seizures as there is an intimate relationship between seizure activity and increased extracellular glutamate levels in tumor related epilepsy. The involvement of tumor growth is not clear yet. Glutamate levels are shown to increase reaching neurotoxic levels during seizures. Epileptic activity is implied to be originating within the peritumoral border distant from the tumor tissue and it was shown that the glutamate levels were higher in peritumoral cortex when compared with health brain tissue parts in glioma patients. GABA receptor activity is thought to be an inhibitor as receptor down regulation seems causing hyperactivity in the surrounding microenvironment. There is also a close relationship between immunological and inflammatory changes with a diminished risks of glioma and epileptic seizures related to tumor presence as proinflammatory cytokines seem to be involved in epilepsy pathogenesis [3,4]. On the other hand, patients having epileptic seizures with brain tumors were reported having increased levels of ROS and the antioxidant status was found to be decreased. This seems to be recovered after treatment with antiepileptic drugs favoring the so called damaging effect of oxidative stress in epilepsy flashing the estimated possibility of preventing the seizures via antioxidant treatment. Alleviation of the oxidative damage utilizing antioxidant substances in epilepsy was shown experimentally. These knowledge may highlight the possible future strategies in the medical treatment of tumor associated epilepsy. In terms of surgical aspects, removing the tumor to stop epileptic seizures might not assure a prosperous result alone considering that the neurons surrounder the tumor form an epileptogenic area [2]. On the other hand, when the lesion is removed, surrounding neurons may stop exciting aberrantly, returning to normal status. Thus the neurosurgeons are suggested to minimize the residual tumor volume where applicable. The conservation of the mitochondria and eventually decreasing oxidative stress related events seems to be reasonable therapeutic approach. Not only resecting the tumor but also combining an appropriate postoperative treatment should be the main aim in seizure control. As men‐ tioned, therapy with antioxidants having a potential neuroprotective effect, should be intended to lower the conferred oxidative damage in epilepsy treatment where ketogenic diets were also shown to have beneficial effects in treating epileptic seizures as they seem to increase glutathione levels in mitochondria. It is clear that developing a mitochondria targeted antioxidant therapy would be promising approach in epilepsy, hopefully resulting in seizure

106 Tumors of the Central Nervous System – Primary and Secondary

control withdrawing treatment with antiepileptic drugs in long term.

**2. The biochemical mechanisms transpiring in case of epileptic seizures**

Epilepsy should be considered not only as a single disease, but also common symptomatic symptoms of brain abnormalities involving central nervous system infections, traumatic brain injuries, genetic syndromes or brain lesions such brain tumors are present. The relationship of inflammation in the pathophysiology of epilepsy is implied in various clinical studies [5,6].

The tumor tissue might be epileptogenic due to excreting some molecules itself or the peritu‐ moral tissue might be transformed into an epileptogenic zone as the microenvironment of brain tumors is considerably different from that of healthy brain tissue which is demonstrated via contemporary imaging techniques. On the other hand, the peritumoral tissue might turn into an epileptogenic zone because of the mechanic restrainment of the tumor as a result of hypoxia and ischemia. These lead to epileptic seizures following the alterations in neurotrans‐ mitters and their receptors, metabolic changes and inflammatory responses. Structural epileptogenic abnormalities in the cortex might also be attended as low levels of N-acetylas‐ partate which is a marker for the survival and functionality of the neurons, was shown in the epileptogenic cortex via magnetic resonance spectroscopy [7]. It was shown that damage in the subcortical network affecting the electrical transmission is effectuated mostly by high grade brain tumors [8] while a partial deafferentation in cortical regions is induced by low grade tumors causing an epileptogenic stage [9,10]. Inflammatory changes and gliosis in the peritumoral tissue also contribute. Derangements in the neurovascular entirety also cause hypersynchronization leading to epileptogenity. The emerge of decreased expression of junctional transmembrane proteins [11] and increased vascular endothelial growth factor (VEGF) release which aggrevates the edema in the surrounding of the lesion [12] is due to the impaired blood brain barrier through molecular alterations in brain tumors and hypoxia and acidosis, appearing sequentially, occur because of the enhanced metabolism and the dimin‐ ished perfusion in the intratumoral tissue. Definitely, an adequate blood supply is obligatory for brain tumor growth [13] and in case of inadequate blood supply, acidosis followed by interstitial hypoxia appears extending to the surrounding tissue, as a consequence of both elevated metabolic requirements of the proliferating tissue and impaired oxidative energy metabolism. Also, peritumoral hypoxia comes out because of direct restrainment through large sized tumors. In either case, damage sequential to glial cell swelling occurs [14] where the membranes of the cells are vulnerable for inward sodium currents augmenting the risk of epilepsy [15]. In consequence of hypoxia, glucose catabolism picks up culminating excess lactate production which leads to acidosis and in tumor tissues increased lactate levels were also shown [16]. In the peritumoral area the increase in sodium and calcium levels contribute to neuronal hyperexcitability [17] and the change in the gating of calcium channels have been reported in epileptic tissue where calcium influx is blocked via NMDA receptor channels through stabilizing the neuronal excibility by magnesium. Also, mutations in the potassium channels were implied and the extracellular potassium concentrations are known to play a role in membrane potential [18,19].

Glutamate is an excitatory neurotransmitter which acts on postsynaptic membranes through interacting with ionotropic and metabotropic glutamate receptors [20]. There is a relationship 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 causing antiepileptogenic effects were reported [23].

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

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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

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‐

bring about a serious infliction and therefore to a neuronal death [40].

to increased mitochondrial superoxide radical production [44].

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.
