**3. Role of trace elements and antioxidant enzymes in epilepsy**

#### **3.1. Iron**

In several neurodegenerative diseases, iron accumulates in brain tissues. Since post-mortem examinations cannot distinguish whether iron accumulation is a cause or consequence of brain damage, it is necessary to manipulate iron to assess its causal role. In the animal model of epilepsy, iron supplementation increased damage in various brain regions, and a tight relationship between iron and zinc in micro gliosis was found [10]. In general, iron is kept safe by binding itself to protein; transported in form of transferrin-bound iron or stored in form of ferritin. The liberation of free iron can augment generation of active free radicals and it appears to play a crucial role in the posttraumatic epilepsy [11]. Iron deposition results in tissue damage by either directly damaging cells or changing the cellular environment so that it is more susceptible to toxins or other pathologic processes. On the other hand, iron is a cofactor of catalase (CAT), which plays a role in antioxidant defence systems by catalysing the decom‐ position of hydrogen peroxide. The proper balance of iron without excessive supplementation is very important for oxidant status.

The surrogate markers of iron status may be non-transferrin bound iron (NTBI). There was found an increase in NTBI in patients treated due to epilepsy with VPA [12].

#### **3.2. Selenium, cooper, zinc**

Oxidative stress is a common pathogenic mechanism in neurodegenerative disorders. The central nervous system is particularly susceptible to reactive oxygen species (ROS) due to high oxygen demands of the brain, low concentration of endogenous antioxidants and concomitant accumulation of reactive iron. Furthermore, the abundance of polyunsaturated fatty acids and excess of predominant neurotransmitter glutamate, favour cell toxicity [5]. ROS can activate a self-accelerating vicious cycle leading to mitochondrial damage and neuronal cell death [6].

In epilepsy, the oxidative/antioxidative balance can have a role in both seizure controls and

There are a large range of antiepileptic drugs with different mechanisms of action, pharma‐ cokinetics, pharmacology, and important side effects. Pharmacotherapy of epilepsy is symp‐

Valproic acid (VPA) which is an eight-carbon branched-chain fatty acid, is one of the most widely used effective antiepileptic drugs. The main mechanism of the action includes a blockade of sodium channels, activating calcium dependent potassium conductance and GABAergic effect [7]. VPA is metabolized by microsomal glucuronide conjugation, mitochon‐ drial beta-oxidation and cytochrome P450-dependent omega-, (omega-1)-and (omega-2) oxidation [8]. Therefore, an involvement of lipid peroxidation seems to be probable during

Serious side effects are relatively rare but include fatal hepatotoxicity and acute haemorrhag‐ ic pancreatitis. They occur mainly in children on polypharmacy and those with organic brain disease. Hyperammonaemic encephalopathy has been reported in patients with urea cycle disorder. Benign elevation of liver enzymes is common during valproate therapy and dose depended. Thrombocytopenia and other haematological abnormalities should be control‐ led. Other troublesome adverse effects are weight gain, gastrointestinal disturbances, hair loss and tremors. Hormonal disturbances with polycystic ovary syndrome and risk of teratogenicity, including a 1 to 3% risk of neural tube defects, make the use of VPA in some

In numerous studies there was found to be an imbalance in oxidative status of the patient with

In several neurodegenerative diseases, iron accumulates in brain tissues. Since post-mortem examinations cannot distinguish whether iron accumulation is a cause or consequence of brain

**3. Role of trace elements and antioxidant enzymes in epilepsy**

side effects of often life-long pharmacotherapy.

266 Pharmacology and Nutritional Intervention in the Treatment of Disease

tomatic.

pharmacotherapy with VPA.

women undesirable [7].

**3.1. Iron**

epilepsy treated with VPA [9].

**2. Pharmacotherapy of epilepsy-Valproic acid**

The trace elements selenium (Se), cooper (Cu) and zinc (Zn) are important cofactors of antioxidant enzymes such as superoxide dismutase (Cu-SOD, Zn-SOD), glutathione peroxid‐ ise (GPX) as well as protein with antioxidant properties, ceruloplasmin (CRL, copper-binding protein). SOD and GPX play a predominant role as free radical scavengers in the brain tissue, whilst CAT is deficient [13]. SOD and GPX are also important for detoxification of xenobiotics, and may be involved in the oxidative injury caused by antiepileptic drugs [14].

Results of various studies on trace elements levels and activities of main antioxidant enzymes during pharmacotherapy of epilepsy are conflicting. A selected bias of patients and different laboratory methods might be responsible, as well as the influence of lifestyle with consumption of natural antioxidants or their supplementation [4, 15, 16].

A decrease in the trace elements selenium and copper was reported in epileptic patients receiving sodium valproate [17]. One of the main selenium status marker is plasma glutathione peroxidise (GPX3). The product of plasma SOD (pSOD) activity, H2O2, is the major substrates for GPX3. An involvement of lipid peroxidation seems to be probable and the elevated activity of pSOD in some studies may be explained by this induction. Significant effects of duration of VPA therapy, activity of seizures and gender were found on Zn, pSOD, and erythrocyte SOD (eSOD) levels [4, 9]. Also in prospective studies [18, 19] were reported increased levels of eSOD in epileptic children after implementation of VPA treatment. Some other authors did not find a significant difference in enzyme activity or even a reduced level of pSOD was found in young people with epilepsy treated using valproate [20].

pSOD is a sensitive index of Cu status, while plasma Cu is not a reliable marker of copper status [21]. Zinc supplements can decrease SOD activity, primarily due to the antagonistic relationship between high zinc intakes and copper absorption [22, 23]. A few authors reported lower or normal Zn concentrations in persons with epilepsy [24, 25]
