**1. Introduction**

### **1.1. Epilepsy**

Epilepsy is the most common chronic brain condition with epileptiform neuronal discharg‐ es, characterized by recurrent unproved seizures with at least two and at least 24 hrs apart. Epileptiform patterns in electroencephalogram (EEG) should confirm the diagnosis. It is the most expensive chronic neurological brain disorder in Europe (Andlin-Sobocki et al. 2005; Majkowski and Majkowska-Zwolińska, 2010). According to the World Health Organisa‐ tion and the World Bank, the costs of epilepsy constitutes 0.5% of all diseases (Leonardi and Ustrun, 2002).

The incidence of epilepsy in the whole population is estimated as about 50-60 cases per 100.000 persons per year, and it is aged depending. In elderly, above 65 yrs old, it is increasing and about 80 yrs old is about 200 cases /100.000/year and in young preschool age children 100-150 / 100.000/year (Forsgeren, 2004). Worldwide prevalence of epilepsy is about 1% (in whole world about 50 millions of persons). However, according to Poter (1988), 45 to 100 million people worldwide were estimated to have epilepsy. Prevalence, like incidence, is age related; in age above 70 yrs it is highest (about 2%), and a little lower in infants. Extremes of life in humans are associated with increased incidence of epilepsy and increased susceptibility to oxygen stress in the developing immature brain (Lafemina et al., 2006) and in aged animals (Liang and Patel, 2004; Avramovic et al., 2012). It is an open question if there is a causal relation between these two events.

Occurrence of the first seizure, at any age, does not necessary mean epilepsy and a need for antiepileptic drug (AED) administration. It may be symptomatic and diagnostic procedure should be implemented to exclude or confirm an etiological cause. In the whole life of a person, from birth to death, at least one epileptic seizure may occur − including febrile convulsions − in about 8% of otherwise healthy population. In about one of them epilepsy will develop.

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Once diagnosis of epilepsy, as defined, is established AED treatment should be started, and in majority of seizure free patients should be continued for several years after the last seizure. In at least 1/3 of epileptic patients with pharmaco-resistant epilepsy, their seizures tend to recur despite of using more than one AED. This group of patients may require life long administra‐ tion of AEDs. However, a patient's drug resistancy does not imply that the patient will never become seizure-free on further adjustment of AED therapy or other treatment intervention (Kwan et al., 2010; Fröscher, 2012). Introduction of so called new generation of AEDs, while substantially better tolerated, as far as adverse events are concerned, did not make break‐ through in control of pharmaco-resistant form of epilepsy.

seizure control and prevent adverse events, in particular, long term ones affecting cognitive functions. Ideas of various brain disorders, including epilepsy, are teleologicaly explicitly associated with the oxygen toxicity paradigm (Atroshi et al., 2007). Consequently, anti-oxidant interventions are logical procedure with a hope for better health care for these groups of patients. Rational for use of these essential compounds to stay healthy is that they cannot be synthesized in human body. Thus, anti-oxidant supplements could have a potential role in preventing diseases. However, in a normal diet, in high-income countries, sufficient amounts of anti-oxidants may be provided Despite of that more than one third of adults regularly take anti-oxidant supplements (Bjelakovic et al., 2013). The authors assessed whether different doses of beta-carotene, vitamin A and vitamin E affect mortality in primary or secondary prevention randomized clinical trials low risk of bias (53 trials, 241,883 persons aged 18-103 years, 44% women). The study was based on Cochrane systematic review analyzing beneficial and harmful effect of the anti-oxidant supplements in adult. Meta-regression analysis showed that the dose of vitamin A was significantly positively associated with all cause mortality. Vitamin A in a dose above recommended daily allowance (RDA) (>800 µg) did not significantly influence mortality. Beta-carotene in dose above 9.6 mg, and vitamin E in dose above the RDA

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Within the last three decades interest in oxygen stress and its role in the development of oxygen pathology has been considerably increasing and the importance of this phenomenon − increasingly recognized not only in the brain disorders e.g. epilepsy (Azam et al., 2012), headache (Vurucu et al., 2013) but also in other organ function e.g. heart, vascular disorders, diabetes, nasal polyps (Bozkus et al., 2013; Büyükkaya et al., 2013; Chalghoum et al., 2012; Kim et al., 2013; Madmani et al., 2013). Moreover, for the first time the pathophysiological conse‐ quences of L-ferritin deficiency in a human helped to define the concept for new disease entity − halmarked by idiopatic generalized seizures and atypical restless leg syndrome − in 23 yrs old female (Cozzi et al., 2013). The syndrome was accompanied with diminished levels of cytosolic catalase, superoxide dismutase (SOD) 1 protein levels, enhanced reactive oxygen

Oxygen stress means that the production of free radicals and ROS has exceded physiolog‐ ical the anti-oxidant defence mechanism capacity (Sies, 1985; Mahle and Desgupta, 1997). In Bartosz (2006) opinion, oxygen stress research may be the key to better understanding of certain biochemical, physiological and pathological aspects of living organisms and suggests that such understanding could be applied in clinical practice. Free radicals, the product of oxygen stress, may play an important role as physiological markers which control cell process signals. However, when produced in excess, or when anti-oxidant defense system is not efficient, the free radicals may lead to cell damage. Under physiologic circumstances, the brain has sufficient anti-oxidant defense mechanisms, including GSH-Px which converts potentially harmful H2O2 to oxygen and water at the expense of reduced

(>15 mg) significantly increased mortality.

glutathione (GSH) (Wang et al., 2003).

species (ROS) production and higher level of oxidized proteins.

**1.2. Oxygen stress**

All AEDs, with various mechanisms of actions, can to some extent control frequency and severity of epileptic seizures, but not to prevent epileptogenesis (will be discussed in some detail later in this text) which may start after any kind of inborn or acquired brain pathology. However, AEDs may to some extent prevent secondarily cortical epileptization due to epileptic seizures and epileptiform patterns in EEG by reducing or inhibiting occurrence of seizures and/or epileptiform discharges and their spreading to various parts or whole brain structures. On the other hand some AEDs can produce oxygen stress.

In patients with AED therapy resistance, other treatment e.g. neurosurgery may be beneficial in the patients with epileptogenic focus which is precisely localized and is not in eloquent cortical areas. Vagus nerve stimulation is used in addition to AEDs in patients if their seizures are not adequately controlled and there is no possibility to perform neurosurgery (e.g. diffuse brain pathology). Ketogenic diet (KD) may be helpful in some infants and young children with severe epilepsy. Protective modulation of oxidative stress and mitochondrial function by the KD was recently reviewed (Milder and Patel, 2012). The authors highlighted potential mechanism of the KD which can ultimately result in increased production of anti-oxidants and detoxification enzymes with the protective effects of the KD. The diet in Wistar rats revealed an increase in anti-oxidant activity in hippocampus (glutathione peroxidase (GSH-Px) about 4 times) and no changes in lipoperoxidation levels (Ziegler et al., 2003). Cerebral cortex was not affected by the KD, and in cerebellum was a decrease in anti-oxidant capacity. The authors conclude that KD might contribute to protect the hippocampus from neurodegenerative sequelae of seizures. Using organotypic hippocampal slice cultures, it was shown that ketone bodies abolished hippocampal network hyperexcitability following metabolic insult (hypoxia) (Samoilova et al., 2010). The study demonstrated a direct link between metabolic resistance and better control of excessive synchronous abnormal electrical activity. Chronic in vitro ketosis has neuroprotective but not anticonvulsant activity.

However, both methods neurosurgery and KD − are used in rather small percentage of drug resistant epilepsy patients. There is a number of intervention procedures which are at exper‐ imental level, still.

In short, currently, AED administration in great majority of patients is the most successfully used symptomatic treatment of seizures but not epilepsy itself. However, long-term treatment, in particular, when polytherapy is used, may result in adverse events including cognitive function impairments, and in turn in decrease the patients' quality of life. Thus, continuous search and trials are needed to find compounds of antiepileptogenesis prevention, to improve seizure control and prevent adverse events, in particular, long term ones affecting cognitive functions. Ideas of various brain disorders, including epilepsy, are teleologicaly explicitly associated with the oxygen toxicity paradigm (Atroshi et al., 2007). Consequently, anti-oxidant interventions are logical procedure with a hope for better health care for these groups of patients. Rational for use of these essential compounds to stay healthy is that they cannot be synthesized in human body. Thus, anti-oxidant supplements could have a potential role in preventing diseases. However, in a normal diet, in high-income countries, sufficient amounts of anti-oxidants may be provided Despite of that more than one third of adults regularly take anti-oxidant supplements (Bjelakovic et al., 2013). The authors assessed whether different doses of beta-carotene, vitamin A and vitamin E affect mortality in primary or secondary prevention randomized clinical trials low risk of bias (53 trials, 241,883 persons aged 18-103 years, 44% women). The study was based on Cochrane systematic review analyzing beneficial and harmful effect of the anti-oxidant supplements in adult. Meta-regression analysis showed that the dose of vitamin A was significantly positively associated with all cause mortality. Vitamin A in a dose above recommended daily allowance (RDA) (>800 µg) did not significantly influence mortality. Beta-carotene in dose above 9.6 mg, and vitamin E in dose above the RDA (>15 mg) significantly increased mortality.

#### **1.2. Oxygen stress**

Once diagnosis of epilepsy, as defined, is established AED treatment should be started, and in majority of seizure free patients should be continued for several years after the last seizure. In at least 1/3 of epileptic patients with pharmaco-resistant epilepsy, their seizures tend to recur despite of using more than one AED. This group of patients may require life long administra‐ tion of AEDs. However, a patient's drug resistancy does not imply that the patient will never become seizure-free on further adjustment of AED therapy or other treatment intervention (Kwan et al., 2010; Fröscher, 2012). Introduction of so called new generation of AEDs, while substantially better tolerated, as far as adverse events are concerned, did not make break‐

All AEDs, with various mechanisms of actions, can to some extent control frequency and severity of epileptic seizures, but not to prevent epileptogenesis (will be discussed in some detail later in this text) which may start after any kind of inborn or acquired brain pathology. However, AEDs may to some extent prevent secondarily cortical epileptization due to epileptic seizures and epileptiform patterns in EEG by reducing or inhibiting occurrence of seizures and/or epileptiform discharges and their spreading to various parts or whole brain structures.

In patients with AED therapy resistance, other treatment e.g. neurosurgery may be beneficial in the patients with epileptogenic focus which is precisely localized and is not in eloquent cortical areas. Vagus nerve stimulation is used in addition to AEDs in patients if their seizures are not adequately controlled and there is no possibility to perform neurosurgery (e.g. diffuse brain pathology). Ketogenic diet (KD) may be helpful in some infants and young children with severe epilepsy. Protective modulation of oxidative stress and mitochondrial function by the KD was recently reviewed (Milder and Patel, 2012). The authors highlighted potential mechanism of the KD which can ultimately result in increased production of anti-oxidants and detoxification enzymes with the protective effects of the KD. The diet in Wistar rats revealed an increase in anti-oxidant activity in hippocampus (glutathione peroxidase (GSH-Px) about 4 times) and no changes in lipoperoxidation levels (Ziegler et al., 2003). Cerebral cortex was not affected by the KD, and in cerebellum was a decrease in anti-oxidant capacity. The authors conclude that KD might contribute to protect the hippocampus from neurodegenerative sequelae of seizures. Using organotypic hippocampal slice cultures, it was shown that ketone bodies abolished hippocampal network hyperexcitability following metabolic insult (hypoxia) (Samoilova et al., 2010). The study demonstrated a direct link between metabolic resistance and better control of excessive synchronous abnormal electrical activity. Chronic in vitro

However, both methods neurosurgery and KD − are used in rather small percentage of drug resistant epilepsy patients. There is a number of intervention procedures which are at exper‐

In short, currently, AED administration in great majority of patients is the most successfully used symptomatic treatment of seizures but not epilepsy itself. However, long-term treatment, in particular, when polytherapy is used, may result in adverse events including cognitive function impairments, and in turn in decrease the patients' quality of life. Thus, continuous search and trials are needed to find compounds of antiepileptogenesis prevention, to improve

through in control of pharmaco-resistant form of epilepsy.

2 Pharmacology and Nutritional Intervention in the Treatment of Disease

On the other hand some AEDs can produce oxygen stress.

ketosis has neuroprotective but not anticonvulsant activity.

imental level, still.

Within the last three decades interest in oxygen stress and its role in the development of oxygen pathology has been considerably increasing and the importance of this phenomenon − increasingly recognized not only in the brain disorders e.g. epilepsy (Azam et al., 2012), headache (Vurucu et al., 2013) but also in other organ function e.g. heart, vascular disorders, diabetes, nasal polyps (Bozkus et al., 2013; Büyükkaya et al., 2013; Chalghoum et al., 2012; Kim et al., 2013; Madmani et al., 2013). Moreover, for the first time the pathophysiological conse‐ quences of L-ferritin deficiency in a human helped to define the concept for new disease entity − halmarked by idiopatic generalized seizures and atypical restless leg syndrome − in 23 yrs old female (Cozzi et al., 2013). The syndrome was accompanied with diminished levels of cytosolic catalase, superoxide dismutase (SOD) 1 protein levels, enhanced reactive oxygen species (ROS) production and higher level of oxidized proteins.

Oxygen stress means that the production of free radicals and ROS has exceded physiolog‐ ical the anti-oxidant defence mechanism capacity (Sies, 1985; Mahle and Desgupta, 1997). In Bartosz (2006) opinion, oxygen stress research may be the key to better understanding of certain biochemical, physiological and pathological aspects of living organisms and suggests that such understanding could be applied in clinical practice. Free radicals, the product of oxygen stress, may play an important role as physiological markers which control cell process signals. However, when produced in excess, or when anti-oxidant defense system is not efficient, the free radicals may lead to cell damage. Under physiologic circumstances, the brain has sufficient anti-oxidant defense mechanisms, including GSH-Px which converts potentially harmful H2O2 to oxygen and water at the expense of reduced glutathione (GSH) (Wang et al., 2003).

Excessive free radical production is related to various physiological and pathological states, including aging, epileptic seizures or the use of xenobiotics, including fat-soluble drugs (Nikietic et al., 1995; Martinez-Bellesteros et al., 2004; Patel, 2004); this also applies to old and to some new AEDs (Hamed and Abdellah, 2004; Kaipainen et al., 2004; Sobaniec et al., 2006; Atroshi et al, 2007; Avcicek and Iscan, 2007; Płonka-Półtorak et al., 2011). A number of nonspecific factors as well as dietary habits affect the state of anti-oxidants in the healthy elderly (Anlasik at al., 2005). This suggests that at the current level of understanding, oxidation and anti-oxidation processes are rather ubiquitous and hence non-specific for particular disorder.

lipophylic metalloporphyrin catalytic anti-oxidant was reported (Liang and Patel, 2004; Liang et al., 2012). This effect correlated with chronic mitochondrial oxygen stress (aconi‐ tase enzyme deactivation) and reduced oxygen use. According to the authors, oxygen stress caused by free radical peroxides increases seizure susceptibility in this subgroup of mice. This susceptibility increases with age (corresponding to high incidence of epilepsy in elderly) and also with increased environmental stimulation and use of stimulants. It is interesting and worthwile to emphesize that **oxygen stress and mitochondrial dysfunc‐ tion may both cause and be caused by epileptic attacks** (Heinemann et al., 2002; Patel, 2004; Sullivan et al., 2004; Waldbaum and Patel, 2010b). At present, an increasing atten‐ tion is paid to the possible interaction between oxidative stress, resulting in disturbance of physiological signaling roles of calcium and free radicals in neurones, and mitochondrial

Epilepsy Treatment and Nutritional Intervention

http://dx.doi.org/10.5772/57484

5

According to Dubenko and Litovchenko (2002), application of energy metabolism activators improves the clinical and electroencephalographic course of epilepsy. This has been demon‐ strated experimentally by positive histological changes. According to these authors, this treatment prevents neuronal harm and development of encephalopathy with its cognitive function impairments. Relation between epileptiform discharges and serious cognitive function impairments was shown in kindling animal model of epilepsy (Majkowski, 1981, 1990) and in young children without seizures but with continous spike and wave during sleep − so called electrical status epilepticus described by S.A. Tussinari (Patry et al., 1971). Thus, it was also shown that **not only epileptic seizures but also EEG discharges may cause complex metabolic neuronal lesions and oxidant/anti-oxidant disequilibrium** (Freitas et al., 2004;

A number of experimental studies on animal models and humans have shown that all old and some new AEDs can also produce free radicals and significantly increase the peroxidation of neuronal membrane lipids and reduce the protective effects of anti-oxidants. These changes may lead to increased seizure and idiosyncratic drug effect frequency (Kurekci et al., 1995; Sudha et al., 2001; Hung-Ming et al., 2002; Hamed and Abdellach, 2009; Hamed et al., 2009;

Oxidation stress and resistance to AED effects triggers adaptive mechanisms i.e. production of endogenous anti-oxidants scavengers, which prevent the harmful effects of oxidation (Kawakami et al., 2006). These authors studied NO and endogenous anti-oxidant GSH scavengers, GSH-Px, complete (T) and superoxide dismutase (T-SOD), Mn –SOD and catalase in cerebrospinal fluid of children with various neurological disorders. All the anti-oxidant parameters were highest in children with bacterial meningitis compared with other groups. In the group of epilepsy NO, GSH and GSH-Px were higher than in the group with aseptic meningitis and the control group. In the authors' opinion oxygen stress may be related to seizure pathology and its reduction may lead to better prognosis for the course of epilepsy. Akarsu et al. (2007) came to similar conclusions. The authors studied the state of oxidation in 21 children with febrile convulsion and 21 children without febrile convulsions, assessing the level of arginase and catalase in their red blood cells, malondialdehyde (MDA) – an indicator of lipid peroxidation and NO in the plasma and cerebrospinal fluid. The control group

dysfunction, cell damage and epilepsy (Martinc et al., 2012)

Ilhan et al., 2005a; Sok et al., 2006; Barros et al., 2007).

Dostalek et al., 2007).

In epilepsy, when the number of free radicals in the brain neurons increases, this interferes with respiratory chain in the mitochondria, destabilizes the lysosomal membranes, and lowers the convulsion threshold (Tayarani et al., 1987; Frantseva et al., 1998; Frantseva et al., 2000; Patel 2002; Waldbaum and Patel, 2010a). Neuronal firing associated with prolonged epileptic discharges and seizures may lead to a number of neurochemical changes and cascades of events at the cellular and molecular level. This in turn, results in mitochondrial dysfunction, increased ROS and nitric oxide (NO) which precede neuronal degeneration and death with possible subsequent epileptogenesis and cortical epileptization − secondary epileptogenesis − which may result in cognitive function impairments and with chronic intractable epilepsy.

Experimental data indicate that NO may be involved in various way in pathophysiology of epileptic seizures. One of interesting mechanism was suggested by Cupello et al. (1997). The authors studied the effects of NO donors and L-arginine (NO precursor) on the up-take of GABA in synaptosomes of the rat brain. They found that NO decreases synaptosomal GABA up-take and it could result in a reduced availability of GABA at the synapses – leading to an increase of neuronal firing.

Mitochondria are emerging as key participants in cell death because their association with an over-growing list o apoptosis-related problems (Chang, 2010). Peroxydation of neuro‐ nal membranes modifies their electrophysiological properties and leads to abnormal bioelectric discharges of neurones. Among diseases involving dysfunction in the mitochon‐ drial structures, epilepsy is prominent; it is a sign of energetic anomalies in ATP synthe‐ sis due to ADP phosphorylation (Patel, 2002). Mitochondria have important vital functions such as energy production, cellular harm control, neurotransmitter synthesis and free radical production. It is still not clear which of these functions is affected in epileptic seizures (Rowley and Patel, 2013).

Bilateral intracerebra-venticular infusion of all-homocysteic acid in immature rats, resulting in seizures, demonstrated that the marked decrease (approximately 60%) of mitochondrial complex I activity persisted during up to 5 weeks of survival following these seizures (Fol‐ bergova et al., 2010). This period of survival corresponds the development of spontaneous seizures (epileptogenesis) in this model. The authors assumed that the persisting inhibition of mitochondrial complex I may lead to the enhanced production of ROS and/or nitrogen species. In this way may contribute not only to neural injury in this model of seizures but also to epileptogenesis.

An increase in spontaneous and evoked epileptic seizures in a subgroup of mice with partial inherent mitochondrial manganese superoxide dismutnase (MnSOD or SOD2) deficit and lipophylic metalloporphyrin catalytic anti-oxidant was reported (Liang and Patel, 2004; Liang et al., 2012). This effect correlated with chronic mitochondrial oxygen stress (aconi‐ tase enzyme deactivation) and reduced oxygen use. According to the authors, oxygen stress caused by free radical peroxides increases seizure susceptibility in this subgroup of mice. This susceptibility increases with age (corresponding to high incidence of epilepsy in elderly) and also with increased environmental stimulation and use of stimulants. It is interesting and worthwile to emphesize that **oxygen stress and mitochondrial dysfunc‐ tion may both cause and be caused by epileptic attacks** (Heinemann et al., 2002; Patel, 2004; Sullivan et al., 2004; Waldbaum and Patel, 2010b). At present, an increasing atten‐ tion is paid to the possible interaction between oxidative stress, resulting in disturbance of physiological signaling roles of calcium and free radicals in neurones, and mitochondrial dysfunction, cell damage and epilepsy (Martinc et al., 2012)

Excessive free radical production is related to various physiological and pathological states, including aging, epileptic seizures or the use of xenobiotics, including fat-soluble drugs (Nikietic et al., 1995; Martinez-Bellesteros et al., 2004; Patel, 2004); this also applies to old and to some new AEDs (Hamed and Abdellah, 2004; Kaipainen et al., 2004; Sobaniec et al., 2006; Atroshi et al, 2007; Avcicek and Iscan, 2007; Płonka-Półtorak et al., 2011). A number of nonspecific factors as well as dietary habits affect the state of anti-oxidants in the healthy elderly (Anlasik at al., 2005). This suggests that at the current level of understanding, oxidation and anti-oxidation processes are rather ubiquitous and hence non-specific for particular disorder. In epilepsy, when the number of free radicals in the brain neurons increases, this interferes with respiratory chain in the mitochondria, destabilizes the lysosomal membranes, and lowers the convulsion threshold (Tayarani et al., 1987; Frantseva et al., 1998; Frantseva et al., 2000; Patel 2002; Waldbaum and Patel, 2010a). Neuronal firing associated with prolonged epileptic discharges and seizures may lead to a number of neurochemical changes and cascades of events at the cellular and molecular level. This in turn, results in mitochondrial dysfunction, increased ROS and nitric oxide (NO) which precede neuronal degeneration and death with possible subsequent epileptogenesis and cortical epileptization − secondary epileptogenesis − which may result in cognitive function impairments and with chronic intractable epilepsy. Experimental data indicate that NO may be involved in various way in pathophysiology of epileptic seizures. One of interesting mechanism was suggested by Cupello et al. (1997). The authors studied the effects of NO donors and L-arginine (NO precursor) on the up-take of GABA in synaptosomes of the rat brain. They found that NO decreases synaptosomal GABA up-take and it could result in a reduced availability of GABA at the synapses – leading to an

4 Pharmacology and Nutritional Intervention in the Treatment of Disease

Mitochondria are emerging as key participants in cell death because their association with an over-growing list o apoptosis-related problems (Chang, 2010). Peroxydation of neuro‐ nal membranes modifies their electrophysiological properties and leads to abnormal bioelectric discharges of neurones. Among diseases involving dysfunction in the mitochon‐ drial structures, epilepsy is prominent; it is a sign of energetic anomalies in ATP synthe‐ sis due to ADP phosphorylation (Patel, 2002). Mitochondria have important vital functions such as energy production, cellular harm control, neurotransmitter synthesis and free radical production. It is still not clear which of these functions is affected in epileptic seizures

Bilateral intracerebra-venticular infusion of all-homocysteic acid in immature rats, resulting in seizures, demonstrated that the marked decrease (approximately 60%) of mitochondrial complex I activity persisted during up to 5 weeks of survival following these seizures (Fol‐ bergova et al., 2010). This period of survival corresponds the development of spontaneous seizures (epileptogenesis) in this model. The authors assumed that the persisting inhibition of mitochondrial complex I may lead to the enhanced production of ROS and/or nitrogen species. In this way may contribute not only to neural injury in this model of seizures but also to

An increase in spontaneous and evoked epileptic seizures in a subgroup of mice with partial inherent mitochondrial manganese superoxide dismutnase (MnSOD or SOD2) deficit and

increase of neuronal firing.

(Rowley and Patel, 2013).

epileptogenesis.

According to Dubenko and Litovchenko (2002), application of energy metabolism activators improves the clinical and electroencephalographic course of epilepsy. This has been demon‐ strated experimentally by positive histological changes. According to these authors, this treatment prevents neuronal harm and development of encephalopathy with its cognitive function impairments. Relation between epileptiform discharges and serious cognitive function impairments was shown in kindling animal model of epilepsy (Majkowski, 1981, 1990) and in young children without seizures but with continous spike and wave during sleep − so called electrical status epilepticus described by S.A. Tussinari (Patry et al., 1971). Thus, it was also shown that **not only epileptic seizures but also EEG discharges may cause complex metabolic neuronal lesions and oxidant/anti-oxidant disequilibrium** (Freitas et al., 2004; Ilhan et al., 2005a; Sok et al., 2006; Barros et al., 2007).

A number of experimental studies on animal models and humans have shown that all old and some new AEDs can also produce free radicals and significantly increase the peroxidation of neuronal membrane lipids and reduce the protective effects of anti-oxidants. These changes may lead to increased seizure and idiosyncratic drug effect frequency (Kurekci et al., 1995; Sudha et al., 2001; Hung-Ming et al., 2002; Hamed and Abdellach, 2009; Hamed et al., 2009; Dostalek et al., 2007).

Oxidation stress and resistance to AED effects triggers adaptive mechanisms i.e. production of endogenous anti-oxidants scavengers, which prevent the harmful effects of oxidation (Kawakami et al., 2006). These authors studied NO and endogenous anti-oxidant GSH scavengers, GSH-Px, complete (T) and superoxide dismutase (T-SOD), Mn –SOD and catalase in cerebrospinal fluid of children with various neurological disorders. All the anti-oxidant parameters were highest in children with bacterial meningitis compared with other groups. In the group of epilepsy NO, GSH and GSH-Px were higher than in the group with aseptic meningitis and the control group. In the authors' opinion oxygen stress may be related to seizure pathology and its reduction may lead to better prognosis for the course of epilepsy. Akarsu et al. (2007) came to similar conclusions. The authors studied the state of oxidation in 21 children with febrile convulsion and 21 children without febrile convulsions, assessing the level of arginase and catalase in their red blood cells, malondialdehyde (MDA) – an indicator of lipid peroxidation and NO in the plasma and cerebrospinal fluid. The control group consisted of 41 children divided into two subgroups: 1-with fever without convulsions and 2 – without fever and without convulsions. Both fever and convulsions had a significant effect on the oxidation mechanisms. Febrile and afebrile convulsions differed in their generation of oxygen stress. According to the authors, in afebrile convulsion higher levels of oxygen stress might affect prognosis adversely. This is interpreted in terms of fever as a protective factor preventing neuronal lesion during convulsions. Recently, relation between febrile convulsion and oxygen stress was studied in 32 pediatric patients who within the preceding 8 hrs had experienced respiratory tract infection and had been diagnosed with simple febrile convul‐ sions (Abuhandan et al., 2013). Total oxidant level (TOL) and total anti-oxidant level (TAL) were measured 8 hrs after seizure. The TOL and oxidative stress index were found to be significantly high (p<0.01 and p<0.01, respectively), and TAL was significantly lower (p< 0.03) compared to control group 30 healthy children. The authors conclude that increased oxidative stress may increase the risk of occurrence febrile seizures.

eventually to chronic epilepsy. Brain damage may be followed by immediate (with latency seconds to 1 hr) and/or early (minutes to 1 week) seizure and late (week to dozen of years) recurring seizures. Possible pathomechanism of these seizures, triggering factors, risk factors for development of epilepsy, onset after brain damage, age depending, type of clinical course of seizures, and responsiveness to AEDs are different in these groups (Majkowski, 1990).

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Epileptogenic process can be arbitrarily divided into two − overlapping to some extent − stages: cascade of biochemical processes followed by better known electrophysiological stage which precedes epilepsy occurrence. Brain damage initiates a series of non-specific, complex biochemical changes at the neural, synaptic and molecular levels. Among these biochemical changes, oxygen stress resulting in disequilibrium between oxidants and antio-xidants has been postulated in pathogenesis of seizures by many authors (Ueda et al., 1998; Jacobson et al., 1999; Dal-Pizzol et al., 2000, Patel, 2002). Role of oxygen stress has been shown and discussed in experimental animal model of epileptic seizures (Mori et al., 1990; Dakin and Weaver, 1993; de la Pena and Porta-Etessam, 1998; Majkowski, 2007; Rowley and Patel, 2013; Ryan et al., 2012). The latter provided evidence for the occurrence of specific and irreversible oxidative modification of an important mitochondrial enzyme of a protein complex I. The complex is critical for cellular bioenergetics during the process of epileptogenesis. Mechanism of epileptogenesis is not known. However, data from animal models and from patients with temporal lobe epilepsy suggest that steady-state mitochondrial ROS and resulting oxidative damage of neurons occurs during different phases of epileptogenesis (Rowley and Patel, 2013). Epileptogenic substances produce, before seizure occurrence, an increase of free radicals, lipid peroxidation and decrease of GSH-Px – the most important anti-oxidant in brain. Lipid peroxidase correlates with an increase of seizure susceptibility. In turn, occurs dysfunc‐ tion of the mitochondria, neuronal membrane permeability, disturbance of the balance between excessive neuronal activation and inhibition of neuronal transmission which may be due to an increase of glutaminergic or decrease of gabaergic transmitters (Murashima et al., 2005; Narkilati and Pitkanen 2005; Lasoń, 2006). These biochemical changes decrease seizure threshold and lead to epileptic neuronal discharges which may initiate kindling process (electro-epileptogenesis) leading to epileptic attacks (Tayarani et al., 1987; Majkowski, 1993; Frantseva et al., 1998; Frantseva et al., 2000; Liang and Patel, 2004; Waldbaum and Patel; 2010a). These biochemical study, indicating formation of specific protein in process of epileptogenesis, corresponds well with long-lasting synaptic plasticity which is seen in brain modification of sensory evoked potentials and epileptiform potentials development during kindling process of epileptogenesis (Majkowski and Kwast, 1981; Majkowski, 1989). Electrical kindling with its gradual development of epileptiform discharges is the most elegant model of chronic epilepsy which allows to study electrophysiological stage of epileptogenesis. Kindling phenomenon − produced by weak repeated electrical stimulation − described by Goddard et al., (1969), is characterized by widespread and long-lasting neuronal plasticity changes which can be seen in modification of behavior (seizure) and sensory evoked potential changes expressing long-lasting synaptic modification (Majkowski, 1989; 1993). This evoked potentals' modification is of the same kind as during learning processes (Majkowski and Kwast, 1981), what suggests new protein formation in the neurons is involved in epileptogen‐

esis (Hyden, 1980).

Since oxygen stress worsen the course of epilepsy, consistently with those observations, use of anticonvulsants in conventional epilepsy therapy and hence attenuation of oxygen stress could have a positive effect on the course of epilepsy (Costello and Delanty, 2004). Many authors share this opinion. However, these results are not used to inform and guide everyday epilepsy medication.

#### **1.3. Objective**

The chapter is intended to present and discuss current state of knowledge in various animal experimental models of seizures and human epilepsy research related to epileptogenesis and complex interaction between epilepsy, AEDs, and oxygen stress. The effects of various nutritional factors which restore balance in the oxidant/anti-oxidant system, and prevent epileptic attacks and AEDs from causing brain neuronal damages in experimental and human epilepsies will be up-dated.

#### **1.4. Search method**

A literature review was conduced to November 2013. The following search terms were used: oxygen stress, oxidants and antioxidants, animal seizure models, epilepsy and AEDs. It was searched data bases PubMed-line, the Cochrane Epilepsy Group's Specialized Register, indexed and non-indexed citation and relevant papers related to beneficial of antioxidants, and possible harmful effects AEDs and epileptic seizures in animal models and in epileptic patients.
