**1. Introduction**

Oxidative stress appears when prooxidant-antioxidant balance is altered in the direction of the former, causing neuronal cell death and dysfunction, so resulting in oxidative damage lending to disease pathogenesis. Brain tissue have a very high metabolic rate as it consumes approximately 20% of the inhaled oxygen due to the fact that neurons need high amounts of ATP for sustaining ionic gradients across cell membranes and so as for neurotransmission and as most of the ATP is produced via oxidative metabolism, neurons are dependant on mito‐ chondrial function supremely. Oxidative stress is known to act a part in mitochondrial dysfunction and brain damage associated with epileptic seizures. In recent studies it is implied that epileptic status alters the redox potential and diminishes ATP levels creating a break down in brain energy production and a damage to cellular targets such as protein, lipids and DNA is seen following persistent seizures. Thus a consecutive cell damage emerges after persistent seizures with an increase in mitochondrial oxidative stress status in epilepsy patients.

Brain tumours typically cause epileptic seizures. The life quality of patients with brain tumors having epileptic seizures are seriously effected owing to the factors not being clear and the problems confronted in the treatment. Antiepileptic treatment culminates with limited success due to drug interactions, adverse effects and pharmacoresistance frequently.The mechanism of epileptogenesis in patients having a brain tumour is not clarified obviously yet. Seizures are conferred as the initial symptom in around 30-50% of patients particularly with slow growing primary brain tumors [1]. Seizures are mostly seen in patients having low grade tumors while in patients with high grade brain tumors the insidance is lower. Also, the location of the tumor

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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.

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

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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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

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

associated epilepsy.

role in membrane potential [18,19].

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 control withdrawing treatment with antiepileptic drugs in long term.
