**7. Potential neuroprotective and therapeutic strategies in tumor related epilepsy**

Epileptic seizures related to brain tumors generally expose kind of focal seizures and around one third of the patients are resistive to medical antiepileptic treatment. Generally, neuronal voltage gated sodium and calcium channels, glutamate receptors and the GABA system are the main targets for antiepileptic drugs (AED) [80] which usually trend to treat through several mechanisms suppressing abnormal neuronal set off, solely none of the medications seems to be exhibiting an alteration neither in the progress of the disease not in the prevention [81] due to a number of reasons involving the biochemical context of the peritumoral zone and the drug drug interactions between the chemotherapeutics and AEDs inspiring an antiepileptic effectiveness revealing some side effects [82]. Also, the overexpression of the multidrug resistance proteins (MRPs) in tumors may restrict medicine diffusion into the brain as increased levels of MRPs were reported in brain tumor cells [82]. AEDs are known to be leading to cognitive impairment [83]. Moreoever, some patients under AED therapy exhibit poor seizure control as well as with undesireable side effects [84] embracing a high risk of terato‐ genicity in women [85], alterations in mood, hepatotoxicity, decrease in the mineral density of the bone, difficulties in weight management, dermal maladies etc. [86], thereby an increased tolerability towards new desiged AEDs should be the main intention in future studies. Currently, development of novel glial specific AEDs is considered to be a potential target promising to improve a good outcome.

Obviously, epileptogenesis is intimately associated with oxidative stress inducing ROS generation thus leading to membrane lipid peroxidation and impairment in the antioxidant defense system which also increase the risk of seizure recurrence [87]. In case, treatment with antioxidants is considered to be very profitable in inhibiting epileptic seizures without any adverse effect [88]. Selenium, an antioxidant protecting against ROS, is known to be causing an alteration in the rate of some neurotransmitters when deficient and depletion in selenium levels was reported to be leading to a failure in response to AEDs which act through GABAer‐ gic receptors due to an increased glutamate receptor activation [89] and utilization of selenium supplements reduce epileptic seizures [90]. Application of resveratrol, a meritorious antioxi‐ dant, was also demonstrated to be useful in seizure management and in reducing seizure incidence [91]. Similar findings were indicated experimentally where the prevention of seizures was concerned [92,93] Thymoquinone, another potent free radical and superoxide radical scavenger, exhibited an antiepileptic effect in children suggesting a lack of adverse effects even at high doses [94]. With respect to this point of view, the antiepileptic effect of curcumin, which is an active polyphenolic component, extracted from *Curcuma longa* called as turmeric, was also investigated being almost ten times more active than vitamin E as an antioxidant [95]. Implementation of curcumin which inhibits the transcription of inflammatory cytokines via nuclear factor kappa B (NF-κB),inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (Cox-2) [96], was demonstrated to be preventing the cognitive decline related to traumatic brain injury [97] and its antiepileptic potential was ascertained with short term treatment. Recently, inhibitors of mammalian target of rapamycin (mTOR), including rapa‐ mycin and its analogs, are pointed out and regular treatment with rapamycin is emphasized in preventing epileptogenesis experimentally [98,99], thereby, research relevant to inhibiting mTOR activity seems appreciable. Curcumin is also suggested as mTOR inhibitor suppressing epileptogenesis in experimental studies [100,101].

**(a) (b)**

**Figure 3.** This picture shows an awake craniotomy and intraoperative electrical cortical stimulation (cortical mapping) for the identification of the motor cortex (white paper marks) which is close to the tumor (black dots depict the tu‐ mor) (**a**). The tumor was removed without any motor deficits (**b**) and the patient is seizure free at 1 year follow up.

The main surgical technique for the removal of these gliomas is "endopial" resection. By doing this technique, vessels running deep in the sulci and neighboring cortices are saved. Since these tumors are surrounded by the pial layers, respecting the pia avoids severe neurovascular

**7. Potential neuroprotective and therapeutic strategies in tumor related**

Epileptic seizures related to brain tumors generally expose kind of focal seizures and around one third of the patients are resistive to medical antiepileptic treatment. Generally, neuronal voltage gated sodium and calcium channels, glutamate receptors and the GABA system are the main targets for antiepileptic drugs (AED) [80] which usually trend to treat through several mechanisms suppressing abnormal neuronal set off, solely none of the medications seems to be exhibiting an alteration neither in the progress of the disease not in the prevention [81] due to a number of reasons involving the biochemical context of the peritumoral zone and the drug drug interactions between the chemotherapeutics and AEDs inspiring an antiepileptic effectiveness revealing some side effects [82]. Also, the overexpression of the multidrug resistance proteins (MRPs) in tumors may restrict medicine diffusion into the brain as increased levels of MRPs were reported in brain tumor cells [82]. AEDs are known to be leading to cognitive impairment [83]. Moreoever, some patients under AED therapy exhibit poor seizure control as well as with undesireable side effects [84] embracing a high risk of terato‐ genicity in women [85], alterations in mood, hepatotoxicity, decrease in the mineral density of the bone, difficulties in weight management, dermal maladies etc. [86], thereby an increased tolerability towards new desiged AEDs should be the main intention in future studies. Currently, development of novel glial specific AEDs is considered to be a potential target

Obviously, epileptogenesis is intimately associated with oxidative stress inducing ROS generation thus leading to membrane lipid peroxidation and impairment in the antioxidant

damage during surgery and minimizes postoperative neurological deficits.

114 Tumors of the Central Nervous System – Primary and Secondary

**epilepsy**

promising to improve a good outcome.

The ketogenic diet (KD), a subdued carbohydrate diet, is known to be effective in epilepsy treatment [102-104] being neuroprotective and antiepileptogenic. In children, seizures owing to GLUT-1 and pyruvate dehydrogenase deficiency are treated with KD [105], also a prosper‐ ous outcome is seen with other pediatric epilepsy syndromes [106] as it upregulates the neuronal gene expression of the enzymes in Krebs cyclus, oxidative phosphorylation and glycolysis and increases mitochondria density leading to enhanced brain metabolism [107,108], therefore, stimulating the Krebs cyclus seems to be an attractive strategy in seizure management via direct replenishment of energy substrates [109,110]. β-hydroxybutyrate, being a ketone body, protects against metabolic and excitotoxic insults in organotypic hippocampal cultures [111]. Considering the nutrient and energy sensing ability of mTOR, it has a role in pathophysiologic changes related to epileptogenesis and mTOR activity is increased after epileptic status. KD reducing the insulin levels [112], is expected to be inhibiting mTOR activity through decreasing the PI3K/Akt signaling pathway. Also, ROS have a role in the efficacy of KD as the production of some mitochondrial uncoupling proteins are increased with KD and this eventuates with a reduction in the mitochondrial membrane potential and an increase in mitochondrial respiration rate [113]. Mitochondrial production of ROS is decreased with ketone bodies via increasing NADH oxidation without affecting endogenous antioxidant glutathione levels [114]. It was shown that in rat neocortical neurons, ketones prevent oxidative injury via decreasing mitochondrial ROS production [115]. Recently, pyruvate seems to be a promising substrate on seizure activity due to its dual action as a scavenger of ROS and a substrate of Krebs cyclus, so as a strategy in treatment, this might be taken into consideration in prolonged seizures [116]. Restricted KD was implied to be an alternative approach in brain cancer management also, with the purpose of changing the metabolic environment of the tumor [117], yet further studies are essential in case the glucose levels of the patients are lowered when simultaneously the ketone levels are elevated, in the lack of radiation or drug toxicity.

**Acknowledgements**

seizures.

Turkey

Turkey

**References**

**Author details**

Pinar Atukeren1

, Taner Tanriverdi2

We would like to dedicate this chapter to patients having brain tumors suffering from epilepsy

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

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

117

and M. Ramazan Yigitoglu3

1 Istanbul University, Cerrahpasa Medical Faculty, Department of Biochemistry, Istanbul,

2 Istanbul University, Cerrahpasa Medical Faculty, Department of Neurosurgery, Istanbul,

3 Turgut Ozal University, Faculty of Medicine, Department of Biochemistry, Ankara, Turkey

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Currently, the role of microRNAs (miRNA) is emphasized in the regulation of immune responses. miR-146a, known to be induced via several proinflammatory cytokines such as IL-1β and TNF-α, was shown to be upregulating in experimental epilepsy models [118,119], thereby miRNA is suggested to be a potential target in modulating the inflammatory path‐ ways. Some inflammatory mediators have direct effects on neuronal excitability providing a decrease in seizure threshold which was demonstrated experimentally, so if the activation of inflammatory signalings might be blocked, this may also be appraised as a possible therapeutic approach for epilepsy patients.

Distinctive medications exhibit variable therapeutic approaches for epilepsy patients. Not only improving seizure management but also preventing epilepsy in patients who have high risk should be the main target in the treatment with antiepileptogenics. Future studies are truly required with an acceptable safety profile, especially for herbal and supplemental products as there is an incompetence of relevant clinical results although they are recommended in seizure treatment. Yet, antioxidant compounds, particulary targeting mitochondria, may have beneficial effects on long term consequences of epilepsy.
