**4. Aging and anti-oxidants of omega-3 fatty acid**

*Omaga-3 fatty acids supplementation* was added to standard laboratory food for 6 weeks to aged 24 months old Wistar rats (Avramovic et al., 2012). The results showed befeneficial effects of omega-3 fatty acid on the brain cortex with increased SOD activity and decreased lipid peroxidation in contrast to the control grup. The changes in oxidative/antioxidative balance are due to effects of eicosapentanoic acid (EPA) and decosahexanoic (DHA) on lipids and enzyme of anti-oxidative system. Aging as a biophysiological process could be influeced by EPA and DHA.

in the serum was reduced, suggesting that different anti-oxidants have different activities in this epileptic group. It was found that some nutrients may have a positive effect on the reduction of seizure frequency and may improve cognitive functioning in patients with epilepsy (vitamin B1, B6, vitamin E, Mg, Mn, taurine, glycine, omega-3 fatty acids). In order to prevent the negative effects of AEDs, prophylactic or therapeutic replenishment of folic acid, vitamin B6, vitamin D, and L-carnitine may be advisable. In some cases melatonin may reduce seizure frequency. However, supplementation can very seldom substitute AEDs completely (Gaby, 2007). Casuistic reports may be observed e.g. in pyridoxine (vitamin B6) deficiency

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It has been shown CBZ-induced toxic effects in erythrocytes in epilepsy treated patients (Ficcara et al, 2013). However, some beneficial effects of CBZ has been evident as an increased release of ATP and NO derived metabolites from erythrocytes to lumen, leading to an

Bolayir et al. (2004) studied the effect of OXC on anti-oxidative processes in 13 adult patients with epilepsy prior to monotherapy and after 1 year of OXC monotherapy; 15 healthy controls were included in the study. Lipid peroxidation activity, SOD, GSH-Px and catalase in the red blood cells were measured. The patients had significant differences in level of GSH-Px and SOD after 1 year of treatment compared with pre-treatment levels. MDA level was also significantly different compared with the control group and the pre-treatment assessment. These findings suggest that the anti-oxidation systems in patients treated with OXC were

Mahle and Dasgupta (1997) found a significant increase in blood serum concentration of lipid hydroperoxydase in PHT monotherapy compared with the control group. Total blood serum anti-oxidant capacity was lower in patients than in healthy controls. These authors found a weak correlation between lipid hydroperoxidase concentration, triglyceridemia and choles‐

The negative consequences of oxygen stress in serum were significantly larger in women with epilepsy treated with PHT monotherapy (N=20), than in healthy women (N=20) and women with untreated epilepsy (N=12) (Liu et al., 1997). For PHT treated epileptic woman, the MDA serum level was significantly increased (p< 0.05), and GSH level – significantly decreased (p< 0.005). This was not observed in untreated epilepsy and in healthy control women. The abnormal metabolism of S-Cu, CuZn-SOD, and GSH was highly involved in the PHT-mediated toxicity. According to the authors, addition of glutathione to PHT treatment – resulting in modification of the activity of CuZn-SOD enzymes and reduction of copper absorption during

pregnancy, may prevent the incidence of the foetal phenytoin syndrome.

seizures, usually, in neonates and infants.

increased NO pool in the vasculature.

negatively affected after 1 year of treatment.

terol levels in the serum of patients with epilepsy.

**7.1. Carbamazepine**

**7.2. Oxcarbazepine**

**7.3. Phenytoin**

#### **5. Course of seizures and oxygen stress**

An interesting effect of *prolonged seizures* (PS) versus *repeated-seizures* (RS) in one day old chicken *in pilocarpine-induced status epilepticus* has been reported (Tsai et al., 2010). In the PS group excessive levels of ROS and MDA, and lower activities of SOD and catalase were found when compared to the RS group (p< 0.05). This was associated with neuronal death in the PS group (p < 0.01). ROS, mitochondrial dysfunction and DNA damage played important roles in pathophysiology of the immature brain to PS-induced damage. The authors suggest that replenishment of SOD and catalase activities might be useful in protecting neurons against seizure-induced damage.

#### **6. Sleep deprivation and oxygen stress**

It is well known that *sleep deprivation* in epileptic patients may provoke seizures. The mecha‐ nism underlying this relation is unknown. Hirotsu et al. (2013) investigated changes in gene expression related to reactive oxygen species and NO production in the frontal cortex of a rodent model of temporal lobe epilepsy (PILO) in rats with *pilocarpine-induced status epilepti‐ cus* after paradoxidal sleep deprivation (PSD 24h) and total sleep deprivation (TSD 6h). The data show that PILO rats had increased NOX-2 expression and decreased SOD expression independent of sleep. Higher NOX-2 expression was observed only in PILO rats subjected to the control condition and TSD 6h. CAT expression in the frontal cortex of PILO rats submitted to PSD 24 h was reduced compared to that of PILO rats that were not sleep-deprived. In the authors opinion, the molecular changes in the frontal cortex following sleep deprivation suggest a machanism via oxidative stress.

#### **7. Oxygen stress and AEDs in human epilepsy**

AEDs have various and equivocal effects on the oxidization processes (Hamed and Abdellach, 2004; Hamed et al., 2004; Devi et al., 2008; Ounjaijean et al., 2011; Rowles and Olsen, 2012; Azam et al., 2012; Naziroglu and Yürekli, 2013;Rodriguez et al., 2013). Generally, epilepsy and prolonged AED treatment (CBZ, PHT and VPA) results in increased Zn, Ca, Na, MDA and GSH-Px. Usually, anti-oxidant trace elements' levels such as Se, Cu, Zn, Mg, and total antiox‐ idant capacity and ceruloplasmine are low in the blood of epileptic patients. New AEDs are more prone to restore anti-oxidant system in brain. In untreated patients with epilepsy, uric acid (a powerful free oxygen radical scavenger) was elevated but the total anti-oxidant capacity in the serum was reduced, suggesting that different anti-oxidants have different activities in this epileptic group. It was found that some nutrients may have a positive effect on the reduction of seizure frequency and may improve cognitive functioning in patients with epilepsy (vitamin B1, B6, vitamin E, Mg, Mn, taurine, glycine, omega-3 fatty acids). In order to prevent the negative effects of AEDs, prophylactic or therapeutic replenishment of folic acid, vitamin B6, vitamin D, and L-carnitine may be advisable. In some cases melatonin may reduce seizure frequency. However, supplementation can very seldom substitute AEDs completely (Gaby, 2007). Casuistic reports may be observed e.g. in pyridoxine (vitamin B6) deficiency seizures, usually, in neonates and infants.

### **7.1. Carbamazepine**

are due to effects of eicosapentanoic acid (EPA) and decosahexanoic (DHA) on lipids and enzyme of anti-oxidative system. Aging as a biophysiological process could be influeced by

An interesting effect of *prolonged seizures* (PS) versus *repeated-seizures* (RS) in one day old chicken *in pilocarpine-induced status epilepticus* has been reported (Tsai et al., 2010). In the PS group excessive levels of ROS and MDA, and lower activities of SOD and catalase were found when compared to the RS group (p< 0.05). This was associated with neuronal death in the PS group (p < 0.01). ROS, mitochondrial dysfunction and DNA damage played important roles in pathophysiology of the immature brain to PS-induced damage. The authors suggest that replenishment of SOD and catalase activities might be useful in protecting neurons against

It is well known that *sleep deprivation* in epileptic patients may provoke seizures. The mecha‐ nism underlying this relation is unknown. Hirotsu et al. (2013) investigated changes in gene expression related to reactive oxygen species and NO production in the frontal cortex of a rodent model of temporal lobe epilepsy (PILO) in rats with *pilocarpine-induced status epilepti‐ cus* after paradoxidal sleep deprivation (PSD 24h) and total sleep deprivation (TSD 6h). The data show that PILO rats had increased NOX-2 expression and decreased SOD expression independent of sleep. Higher NOX-2 expression was observed only in PILO rats subjected to the control condition and TSD 6h. CAT expression in the frontal cortex of PILO rats submitted to PSD 24 h was reduced compared to that of PILO rats that were not sleep-deprived. In the authors opinion, the molecular changes in the frontal cortex following sleep deprivation

AEDs have various and equivocal effects on the oxidization processes (Hamed and Abdellach, 2004; Hamed et al., 2004; Devi et al., 2008; Ounjaijean et al., 2011; Rowles and Olsen, 2012; Azam et al., 2012; Naziroglu and Yürekli, 2013;Rodriguez et al., 2013). Generally, epilepsy and prolonged AED treatment (CBZ, PHT and VPA) results in increased Zn, Ca, Na, MDA and GSH-Px. Usually, anti-oxidant trace elements' levels such as Se, Cu, Zn, Mg, and total antiox‐ idant capacity and ceruloplasmine are low in the blood of epileptic patients. New AEDs are more prone to restore anti-oxidant system in brain. In untreated patients with epilepsy, uric acid (a powerful free oxygen radical scavenger) was elevated but the total anti-oxidant capacity

EPA and DHA.

seizure-induced damage.

**5. Course of seizures and oxygen stress**

18 Pharmacology and Nutritional Intervention in the Treatment of Disease

**6. Sleep deprivation and oxygen stress**

suggest a machanism via oxidative stress.

**7. Oxygen stress and AEDs in human epilepsy**

It has been shown CBZ-induced toxic effects in erythrocytes in epilepsy treated patients (Ficcara et al, 2013). However, some beneficial effects of CBZ has been evident as an increased release of ATP and NO derived metabolites from erythrocytes to lumen, leading to an increased NO pool in the vasculature.

#### **7.2. Oxcarbazepine**

Bolayir et al. (2004) studied the effect of OXC on anti-oxidative processes in 13 adult patients with epilepsy prior to monotherapy and after 1 year of OXC monotherapy; 15 healthy controls were included in the study. Lipid peroxidation activity, SOD, GSH-Px and catalase in the red blood cells were measured. The patients had significant differences in level of GSH-Px and SOD after 1 year of treatment compared with pre-treatment levels. MDA level was also significantly different compared with the control group and the pre-treatment assessment. These findings suggest that the anti-oxidation systems in patients treated with OXC were negatively affected after 1 year of treatment.

#### **7.3. Phenytoin**

Mahle and Dasgupta (1997) found a significant increase in blood serum concentration of lipid hydroperoxydase in PHT monotherapy compared with the control group. Total blood serum anti-oxidant capacity was lower in patients than in healthy controls. These authors found a weak correlation between lipid hydroperoxidase concentration, triglyceridemia and choles‐ terol levels in the serum of patients with epilepsy.

The negative consequences of oxygen stress in serum were significantly larger in women with epilepsy treated with PHT monotherapy (N=20), than in healthy women (N=20) and women with untreated epilepsy (N=12) (Liu et al., 1997). For PHT treated epileptic woman, the MDA serum level was significantly increased (p< 0.05), and GSH level – significantly decreased (p< 0.005). This was not observed in untreated epilepsy and in healthy control women. The abnormal metabolism of S-Cu, CuZn-SOD, and GSH was highly involved in the PHT-mediated toxicity. According to the authors, addition of glutathione to PHT treatment – resulting in modification of the activity of CuZn-SOD enzymes and reduction of copper absorption during pregnancy, may prevent the incidence of the foetal phenytoin syndrome.

#### **7.4. Phenytoin and carbamazepine**

Comparative studies of the effects of PHT and CBZ monotherapies found a significant increase in the blood serum level of MDA and CuZn-SOD, and a significant reduction of glutathione in a patients treated with PHT compared with a healthy control group and a group with untreated epilepsy (Liu et al., 1998). No differences were found for CBZ except for a slight increase in CuZn-SOD activity. All in all, CBZ caused fewer interferences with antioxidant activity, lipid peroxidation and the level of trace elements (Cu, Zn).

concentration of 114 ± 9.7 µg/ml, peroxidation was significantly higher than in a control group of children with a mean VPA concentration of 81.0 ± 8 µg/ml. Free radicals caused DNA oxygen injury due to significant increase in the serum level of 8-OHdG. In the authors' opinions, 8- OHdG may be a good biological indicator of increased risk of VPA-related cell degeneration. Other authors have also found a linear relation between lipid peroxidation and VPA levels in the plasma of patients with epilepsy (Martinez-Ballesteros et al., 2004). They measured lipid peroxidation spectrofluorometrically, before and after Fenton reaction evocation, in 76 patients and 4 healthy controls. Interestingly, lipid peroxidation was higher in patients with partial epilepsy than in patients with generalized epilepsy, and higher in women than in men. *The same sex-related differences in oxygen stress effects were found in PHT-treated epilepsy (Liu et al., 1997), in hyppocampal slices in patients (Li et al., 2005), in the mouse PTZ-seizure model (Oztas et al., 2007). In PTZ-seizure model in Wistar rats, seizure were more severe in females; moreover pretreatment by a nitric oxide syntase (NOS) inhibitor N-omega-nitro-L-arginine-methylester, completely prevented seizures in male rats, whereus increased severity frequency and duration in female rats, on the other hand, pretreatment by NO precursor sodium-nitroprusside increased seizure severity in male, and*

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The alteration of iron homeostasis and oxygen stress in 24 young adult epileptic patients treated with VPA monotherapy revealed a significant decrease of serum anti-oxidant levels while anti-oxidant enzyme activities increased (Ounjaijean et al., 2011). An interesting association was found between the daily dose of VPA and the concentration of non-transferrin bound iron (NTBI) (p=0.009), MDA (p=0.022) and Zn (p=0.009). Thus, the study has shown that VPA treatment in epilepsy patients contributes to the metabolism of iron, leading to the formation of NTBI and increase of oxidative stress. The alteration of iron homeostasis and oxygen stress product were not observed in the control group comprising of 24 sex and age-

In a recent study, Plonka-Półtorak et al. (2011) found that in long-term VPA monotherapy in adult young epileptic patients (and 21 healthy controls) frequency of seizures and duration of VPA therapy (7-14 years) were associated with changes of oxidative/antioxidative balance. The activity of erythrocyte SOD was higher in patients treated for a longer period (7-14 years) in comparison to controls (p=0.001) and patients with a short period of time (p < 0.001). Patients with uncontrolled epilepsy exhibited higher serum Zn than seizure-free patients (p=0.041). The most relevant parameters for anti-oxidative defence mechanism were plasma SOD, ferric

It is interesting that commonly reported VPA oxidative stress effect occurs in overweight children (Verrotti et al., 2008). The study was performed on 31 epileptic children before and after 1 year of therapy with VPA. The control group consisted of 31 sex-, age-and BMI-matched healthy controls. In the authors' opinion, increase in the levels of oxidant markers (MDA) (p < 0.001) and lower level of antioxidant (vit. E, p< 0.001), probably caused by obesity, might

Very interesting effect of the mood stabilizing VPA on decrease of ROS in schizophrenic patient was reported (Paulsen Bda et al., 2012). Studies on schizophrenia have shown altered cell respiration and oxidative stress response, however this knowledge is acquired mainly from

contribute to endothelial dysfunction and arteriosclerosis in later life.

*decreased in females (Uzum et al., 2005).*

matched healthy volunteers.

reducing ability of plasma, uric acid and Zn.

#### **7.5. Topiramate and Selenium**

Neuroprotective effects of TPM and Se deficiency play a important role in pathophysiology of seizures in epileptic patients. Demirci et al., (2013) studied effect of Se and TPM in neural PC 12 cell by evaluating Ca(2+) mobilization, lipid peroxidation and anticonvulsant levels. The results showed that Se induced protective effects on oxidative stress in PC12 cells by modu‐ lating cytosolic Ca(2+) influx and anti-oxidant levels. TPM modulated also lipid peroxidation and glutathione and vitamin C concentrations in the cell system.

#### **7.6. Valproic acid**

VPA is frequently used in epileptic patients, mainly, in young children. In some forms of idiopathic epilepsy (myoclonic and absences) is the most effective drug, however, its use is limited due to adverse events related to dose and duration of treatment. Recently, Zhang et al. (2011) studied the VPA influence on neutrophils' oxidative metabolism and oxidant status. The study were performed on 26 newly diagnosed epileptic children with idiopathic epilepsy and 30 healthy children were included as control group. The authors performed the study before, after 6 and 12 months of VPA treatment. MDA, superoxide dismutase, catalase and glutathione peroxidase were measured in plasma. The results showed that VPA may activate neutrophils and cause oxidative stress, moreover, prolonged treatment may aggravate it. Multiple regression analysis showed that the time of treatment and the activation rates of neutrophils were indicator which has positive correlation with the levels of plasma MDA and that SOD activities were inversely correlated with MDA levels.

VPA can sometimes be related to allergic idiosyncratic hepatopathy, a rare condition but more frequent in children under 2 years of age taking more than one AED. The mechanism of toxic hepatopathy is unknown but it has been suggested that it is caused by oxygen stress which leads to excessive ROS production and reduction of total anti-oxidant capacity (Chang and Abbott, 2006; Sabayan et al., 2007). Therefore, specifics which reduce oxygen stress may protect against toxic hepatopathy in patients taking VPA. Sabayan et al. (2007) have hypothesized that garlic (allium) preparations may prevent this liver damage by removing free radicals and preventing the reduction of glutathione activity which accompanies treatment with VPA.

VPA used in monotherapy for 60 days in 50 children with epilepsy (mean age 8.5 ± 3.6 years) led to liver dysfunction and free radicals which seems to produce DNA oxidation injury in the liver cells not excluding neurons (Schulpis et al., 2006). The general oxidation state, measured by the level of 8-OHdG, depended on the VPA dose. A linear relation was found between VPA serum level and degree of lipid peroxidation. In a group of children with a mean VPA concentration of 114 ± 9.7 µg/ml, peroxidation was significantly higher than in a control group of children with a mean VPA concentration of 81.0 ± 8 µg/ml. Free radicals caused DNA oxygen injury due to significant increase in the serum level of 8-OHdG. In the authors' opinions, 8- OHdG may be a good biological indicator of increased risk of VPA-related cell degeneration.

**7.4. Phenytoin and carbamazepine**

20 Pharmacology and Nutritional Intervention in the Treatment of Disease

**7.5. Topiramate and Selenium**

**7.6. Valproic acid**

Comparative studies of the effects of PHT and CBZ monotherapies found a significant increase in the blood serum level of MDA and CuZn-SOD, and a significant reduction of glutathione in a patients treated with PHT compared with a healthy control group and a group with untreated epilepsy (Liu et al., 1998). No differences were found for CBZ except for a slight increase in CuZn-SOD activity. All in all, CBZ caused fewer interferences with antioxidant

Neuroprotective effects of TPM and Se deficiency play a important role in pathophysiology of seizures in epileptic patients. Demirci et al., (2013) studied effect of Se and TPM in neural PC 12 cell by evaluating Ca(2+) mobilization, lipid peroxidation and anticonvulsant levels. The results showed that Se induced protective effects on oxidative stress in PC12 cells by modu‐ lating cytosolic Ca(2+) influx and anti-oxidant levels. TPM modulated also lipid peroxidation

VPA is frequently used in epileptic patients, mainly, in young children. In some forms of idiopathic epilepsy (myoclonic and absences) is the most effective drug, however, its use is limited due to adverse events related to dose and duration of treatment. Recently, Zhang et al. (2011) studied the VPA influence on neutrophils' oxidative metabolism and oxidant status. The study were performed on 26 newly diagnosed epileptic children with idiopathic epilepsy and 30 healthy children were included as control group. The authors performed the study before, after 6 and 12 months of VPA treatment. MDA, superoxide dismutase, catalase and glutathione peroxidase were measured in plasma. The results showed that VPA may activate neutrophils and cause oxidative stress, moreover, prolonged treatment may aggravate it. Multiple regression analysis showed that the time of treatment and the activation rates of neutrophils were indicator which has positive correlation with the levels of plasma MDA and

VPA can sometimes be related to allergic idiosyncratic hepatopathy, a rare condition but more frequent in children under 2 years of age taking more than one AED. The mechanism of toxic hepatopathy is unknown but it has been suggested that it is caused by oxygen stress which leads to excessive ROS production and reduction of total anti-oxidant capacity (Chang and Abbott, 2006; Sabayan et al., 2007). Therefore, specifics which reduce oxygen stress may protect against toxic hepatopathy in patients taking VPA. Sabayan et al. (2007) have hypothesized that garlic (allium) preparations may prevent this liver damage by removing free radicals and preventing the reduction of glutathione activity which accompanies treatment with VPA. VPA used in monotherapy for 60 days in 50 children with epilepsy (mean age 8.5 ± 3.6 years) led to liver dysfunction and free radicals which seems to produce DNA oxidation injury in the liver cells not excluding neurons (Schulpis et al., 2006). The general oxidation state, measured by the level of 8-OHdG, depended on the VPA dose. A linear relation was found between VPA serum level and degree of lipid peroxidation. In a group of children with a mean VPA

activity, lipid peroxidation and the level of trace elements (Cu, Zn).

and glutathione and vitamin C concentrations in the cell system.

that SOD activities were inversely correlated with MDA levels.

Other authors have also found a linear relation between lipid peroxidation and VPA levels in the plasma of patients with epilepsy (Martinez-Ballesteros et al., 2004). They measured lipid peroxidation spectrofluorometrically, before and after Fenton reaction evocation, in 76 patients and 4 healthy controls. Interestingly, lipid peroxidation was higher in patients with partial epilepsy than in patients with generalized epilepsy, and higher in women than in men. *The same sex-related differences in oxygen stress effects were found in PHT-treated epilepsy (Liu et al., 1997), in hyppocampal slices in patients (Li et al., 2005), in the mouse PTZ-seizure model (Oztas et al., 2007). In PTZ-seizure model in Wistar rats, seizure were more severe in females; moreover pretreatment by a nitric oxide syntase (NOS) inhibitor N-omega-nitro-L-arginine-methylester, completely prevented seizures in male rats, whereus increased severity frequency and duration in female rats, on the other hand, pretreatment by NO precursor sodium-nitroprusside increased seizure severity in male, and decreased in females (Uzum et al., 2005).*

The alteration of iron homeostasis and oxygen stress in 24 young adult epileptic patients treated with VPA monotherapy revealed a significant decrease of serum anti-oxidant levels while anti-oxidant enzyme activities increased (Ounjaijean et al., 2011). An interesting association was found between the daily dose of VPA and the concentration of non-transferrin bound iron (NTBI) (p=0.009), MDA (p=0.022) and Zn (p=0.009). Thus, the study has shown that VPA treatment in epilepsy patients contributes to the metabolism of iron, leading to the formation of NTBI and increase of oxidative stress. The alteration of iron homeostasis and oxygen stress product were not observed in the control group comprising of 24 sex and agematched healthy volunteers.

In a recent study, Plonka-Półtorak et al. (2011) found that in long-term VPA monotherapy in adult young epileptic patients (and 21 healthy controls) frequency of seizures and duration of VPA therapy (7-14 years) were associated with changes of oxidative/antioxidative balance. The activity of erythrocyte SOD was higher in patients treated for a longer period (7-14 years) in comparison to controls (p=0.001) and patients with a short period of time (p < 0.001). Patients with uncontrolled epilepsy exhibited higher serum Zn than seizure-free patients (p=0.041). The most relevant parameters for anti-oxidative defence mechanism were plasma SOD, ferric reducing ability of plasma, uric acid and Zn.

It is interesting that commonly reported VPA oxidative stress effect occurs in overweight children (Verrotti et al., 2008). The study was performed on 31 epileptic children before and after 1 year of therapy with VPA. The control group consisted of 31 sex-, age-and BMI-matched healthy controls. In the authors' opinion, increase in the levels of oxidant markers (MDA) (p < 0.001) and lower level of antioxidant (vit. E, p< 0.001), probably caused by obesity, might contribute to endothelial dysfunction and arteriosclerosis in later life.

Very interesting effect of the mood stabilizing VPA on decrease of ROS in schizophrenic patient was reported (Paulsen Bda et al., 2012). Studies on schizophrenia have shown altered cell respiration and oxidative stress response, however this knowledge is acquired mainly from postmortem brain analyses or from nonneuronal cells. The authors reported very interesting results that neural cells – derived from induced pluripotent stem cell generated from skin fibroblasts of a schizopherenic patient – presented a twofold increase in extra-mitochondrial oxygen consumption as well as ROS elevated levels compared to controls. The difference *in ROS levels was reverted by the mood stabilizer valproic acid.*

lipophilic function, it crosses the cell membranes easily, regulates blood-tissue exchange and interacts with the endothelial cells. Platelets can behave like mobile and wandering seroto‐ nergic and/or melatonergic elements, comparable with cerebral neurotransmitter release (Di Bella and Gualano, 2006). Melatonin is a free radical scavenger devoided of pro-oxidative activity (Tan et al., 2002) and therefore it reduces oxygen stress and prevents excessive excitotoxic effects arousal from injured neurones in various animal and human models.

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In epilepsy patients melatonin is reduced compared with controls and is increased threefold following seizures (Bazil et al., 2000) Single evening dose of 5-10 mg melantion can exert a positive effect on the frequency of epileptic seizures in children with sleep disturbances

The neuroprotective effect of melatonin has been confirmed in a randomized, double blind trial of children with epilepsy receiving VPA monotherapy (Gupta et al., 2004). The authors administered VPA+melatonin to 15 children and VPA+placebo to 14 children for 14 days. Posttest glutathione reductase (GSSG-Rd) levels were significantly higher (p=0.05) in the VPA +melatonin group and the percentile difference in the values of this enzyme was also significant (p=0.005). Thus, melatonin possesses anti-oxidant, antiexcitotoxic and free radical scavenging

Gupta et al. (2006) found that CBZ or VPA administered in monotherapy to 22 children with epilepsy had differential effects on melatonin serum levels. In both groups the endogenous and exogenous melatonin was measured 30 minutes after administration. The serum median level of melatonin was higher in the CBZ group 165 pg/ml (range 50-350) than in the VPA group, it was 78 pg/ml (range 13-260). In the authors' opinion these range differences in level of melatonin could be attributed to the different effects of these two AEDs, additive increase in ROS due to disease combined with CBZ, or possibly to differences in melatonin kinetics in

The neuroprotective effect of selenium in epilepsy is related to selenoproteins which are antioxidants (Atroshi et al., 2007; Naziroglu, 2009). Selenium insufficiency has been found in young children with severe mental retardation and drug-resistant epilepsy (Ramaekers et al., 1994). Oral administration of selenium (3-5 µg/kg m.c.) reduced seizure frequency, improved

In another study, serum level of selenium in 30 patients with intractable epilepsy was also lower (66.88 ng/ml ± 17.58) than in healthy controls matched for age, socio-economic status and place of residence (85.93 ng/ml ± 13.93) (p<0.05) (Ashrafi et al., 2007). However, low selenium levels in serum did not correlate with the measured risk factors for drug-resistant epilepsy: with age of onset, infant seizures, neurological disorder or etiology of epilepsy.

It is suggested that blood GSH-Px activities could be a reliable indicator of selenium deficiency

(Fauteck et al., 1999).

properties in the central nervous system.

EEG recordings and normalized liver activity.

in patients with epilepsy (Naziroglu, 2009).

conditions of oxidative stress.

**8.2. Selenium**

#### **7.7. Valproic acid and carbamazepine**

A comparative study of the effect of two-year VPA and CBZ monotherapies on changes in the antioxidant system in children with epilepsy found significant differences in the effects of both AEDs (Yuksel et al., 2001). The levels of GSH, GSH-Px, red blood cell SOD and serum lipid peroxidation were measured. They studied two groups: 1) 25 healthy children and 2) 27 children with epilepsy untreated prior to the study onset, 14 of whom were treated with VPA and 13 with CBZ. Treatment lasted for 2 years. Laboratory tests were conducted in treatment months 13 and 24. The anti-oxidant systems in children taking VPA for 2 years were more altered than the anti-oxidant systems of children taking CBZ.

Another comparative study of CBZ and VPA in children found no differences in the serum concentrations of Cu, Zn, Mn, Se and Mg (Kurekci et al., 1995). The only difference was found for GSH-Px activity which was significantly higher in the VPA group. No differences were found in SOD levels.

#### **7.8. Valproic acid, carbamazepine and phenobarbital**

A more recent comparative study yielded slightly different results of the effect of VPA, CBZ and PB monotherapies on the oxidation and anti-oxidation systems in 122 children – including healthy controls, untreated epileptic patients and epileptic patients treated with VPA, PHT, PB (Avcicek and Iscan, 2007). The authors found that the level of total anti-oxidant capacity in serum was significantly reduced in the group with untreated epilepsy compared with the healthy group. Level of peroxidation was significantly elevated in both the untreated group with epilepsy and the CBZ treatment group compared with healthy controls. The pattern of results was similar for the children treated with PB and the control group. According to the authors, children with epilepsy are at risk of oxygen stress due to seizures and AEDs. Their oxidation and anti-oxidation processes are unbalanced. VPA restores this balance more effectively than CBZ or PB.
