**8. Preventing oxygen stress in human AED treated epilepsy**

#### **8.1. Melatonin**

Numerous studies of melatonin conducted over the last 30 years have confirmed that this neurohormone is susceptible to circadian rhythms, has anti-oxidant properties and modulates immunological activity (Harderland et al., 2006). Melatonin affects the blood platelets and prolongs their life. It is transported by the platelets to all the body tissues. Thanks to its 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.

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 (Fauteck et al., 1999).

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 properties in the central nervous system.

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 conditions of oxidative stress.

#### **8.2. Selenium**

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*

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

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

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

Numerous studies of melatonin conducted over the last 30 years have confirmed that this neurohormone is susceptible to circadian rhythms, has anti-oxidant properties and modulates immunological activity (Harderland et al., 2006). Melatonin affects the blood platelets and prolongs their life. It is transported by the platelets to all the body tissues. Thanks to its

**8. Preventing oxygen stress in human AED treated epilepsy**

*ROS levels was reverted by the mood stabilizer valproic acid.*

22 Pharmacology and Nutritional Intervention in the Treatment of Disease

altered than the anti-oxidant systems of children taking CBZ.

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

**7.7. Valproic acid and carbamazepine**

found in SOD levels.

effectively than CBZ or PB.

**8.1. Melatonin**

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 EEG recordings and normalized liver activity.

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 in patients with epilepsy (Naziroglu, 2009).

## **8.3. Plants**

Assuming that AEDs can trigger free radical production and lipid peroxidation, Hung-Ming et al. (2002) studied TW970, a modified version of the Chinese herbal specific chaihu-longumuli-tang which has antiepileptic and antioxidant properties. The TW 970 was administered for 4 months to 3 groups of adults: 1) 20 patients with drug-resistant epilepsy (at least 4 seizures a month); 2) 20 patients with mild epilepsy (fewer than 4 seizures a month), and 3) a control group of 20 healthy adults matched for age. The patients were tested prior to the introduction of TW970 and four months after introduction. In the resistant group, seizure frequency dropped from 13.4 ± 3.4 to 10.7 ± 2.5 a month but the difference was not significant (p=0.084). Prior to TW970 introduction, the resistant epilepsy group had significantly higher lipid peroxidation, increased MDA and CuZn-SOD activity, including reduced GSH, compared with the healthy control group. After 4 months of TW970 treatment, levels of MDA and CuZn-SOD normalized in the resistant epilepsy group whereas no significant changes in parameters were found in the mild epilepsy group, either prior to or following TW970 therapy. The authors suggest that TW970 may reduce seizure frequency in resistant epilepsy and that anti-oxidants may be responsible for this effect.

torial. Moreover, the results, usually are not conducted according to rules of evidence based

Epilepsy Treatment and Nutritional Intervention

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

25

Drug-resistant seizures force physicians to use polytherapy with various AEDs. Polytherapy increases the production of free radicals and disturbs mineral balance to a greater extent than monotherapy, leading to increased oxygen stress. Both, increased free radical production and inhibition of the enzymes which remove scavengers, lead to adverse reactions and aggravation

Patients with chronic epilepsy and long-term AED therapy are at greater risk of atherosclerotic changes in the arteries through complex molecular mechanisms that promote atherogenesis (Hamed and Nabeshima, 2005). Metabolic dysfunctions in these patients have been attributed

In relevant study, relationship between the carotid artery intima-media thickness (CA-IMT) and lipid profile (MDA, oxidised LDL, total anti-oxidant capacity, GSH-Px and uric acid) were assessed in 225 adult patients with epilepsy (and 60 control subjects) (Hamed et al., 2007). Compared to the control group, the CA-IMT of treated and untreated patients common carotid artery, bifurcation area and internal carotid arteries were significantly thickened in 51.1%, 73.3% and 43.6% of patients, respectively. The study supports the opinion that in patients with epilepsy, various risk factors and CA-IMT become worse, which could be attributed to epilepsy itself and/or AEDs. According to the authors, these dysfunctions are indications for routine anti-oxidant multivitamin supplementation (folic acid, vitamins B12, B6, C, E, and betacarotene). The protective, anti-atheromatic effect of vitamins is based on their anti-oxidant and anti-inflammatory properties. Tupeev et al. (1993) found a positive effect of prolonged vitamin E treatment (600 mg/day) in patients with generalized seizures: seizure frequency was

In other research highlighted earlier, increased lipid hydroperoxidase concentrations were weakly correlated with the risk factors for vascular changes (triglyceridemia, cholesterolemia)

**10. The effects of surgery on oxygen stress in AED-resistant temporal lobe**

López et al. (2007) studied the activity of anti-oxidant enzymes (SOD, catalase and GSH-Px) and markers of oxygen stress induced molecular neuronal injury (MDA and ROS) before and at various times after epileptic focus resection in 9 therapy resistant patients; a control group consisted of 32 healthy individuals. All the studied variables normalized postoperatively

**9. Drug-resistant epilepsy and polytherapy**

of the morbid process (Maertens et al., 1995; Hamed et al., 2004).

reduced, EEG improved and anti-oxidant activity increased.

(Mahle and Dasgupta, 1997).

**epilepsy**

except SOD activity.

to altered homocysteine, lipid and lipoprotein metabolism and uric acid.

medicine.

Japanise kampo (TJ-960) traditional herbal medicine was used for treatment of epilepsy (Hamada et al., 1993). The authors identified baicalein as one of the several components the most potent scavenger for radicals in FeCl3-induced epilepsy model in rats. It is suggested that baicalein action is based upon radical quenching and anti-oxidant effects.

Many Native American plants are valued by local medical practitioners for their positive effects on health and a number of diseases, including epilepsy. *Celastrus paniculatus L.* (CP), *Picrorhiza kurroa (PK)* and *Withania somnifera L. (WS)* were investigated for their free radical scavenging capacity (Russo et al., 2001). It has been observed that methanolic extracts of these plants are dose-dependent free radical scavengers, and that they prevent DNA injury due to oxygen stress. PK extract had a more powerful effect than CP or WS. These favourable biological properties, reported in clinical and animal studies, have been attributed, at least in part, to their anti-stress, immune-modulating, anti-inflammatory and anti-aging effects. A similar anti-oxidant effect was observed using another plant in Ayurvedic medicine, *Bacopa monniera L.* (BM), which has free radical scavenging capacity (Russo et al., 2003).

#### **8.4. Nootropics and anti-oxidants**

It was reported that nootropics (phenotropil) and antioxidants (mexidol) potentiate AEDs in posttraumatic epilepsy treatment (Savenkov et al., 2013).The authors observed in 75 patients significant reduction of epileptic seizure frequency, decrease of epileptic changes in the EEG, improvement of cognitive function and quality of life. Coherent indicators of slow waveactivity were observed after treatment. The authors recommended to use mexidol and phenotropil with AEDs for complex treatment of posttraumatic epilepsy.

When interpreting clinically, these and the highlighted earlier results, one needs to be careful because the relationships in disease as heterogeneous as epilepsy are complex and multifac‐ torial. Moreover, the results, usually are not conducted according to rules of evidence based medicine.
