**3.9. Zonisamide (ZNS)**

**3.7. Topiramate**

16 Pharmacology and Nutritional Intervention in the Treatment of Disease

some hepatocytes.

**3.8. Valproic acid**

al., 2004).

TPM with its many mechanisms of action has undoubted effectiveness in the treatment of epilepsy in children. However, TPM administered to rat stomach for 3 months may lead to such adverse effects as toxic liver dysfunction (Huang et al., 2007). In a study of young rats it was found that small doses of TPM (40 mg/kg a day) may reduce total antioxidant capacity in the organism and lead to minor liver pathology. Large doses of TPM (80 mg/kg a day) or a combination of TPM (40 mg/kg) and VPA (300 mg/kg a day) significantly increased the risk of such adverse effects. GSH levels in the liver were significantly lower in the group taking large doses of TPM and the TPM+VPA group compared with the group taking small doses of TPM and the control group which was only given distilled water. Histopathological examination also revealed disseminated punctual necrosis, and as well lipid and degenerative changes in

TPM (40 and 80 mg/kg i.p.) had no effect on either rats' KA-induced status epilepticus or mortality but larger doses significantly reduced KA-produced lipid peroxidation (Kubera et

Treatment of diabetic mice with TPM, a potent mitochondrial carbonic anhydrazes (CA) inhibitor, prevented the oxidative stress caused by diabetes (Price et al., 2012). The authors studied the effects of pharmacological inhibition of mitochondrial CA activity on *streptozotocin induced-oxidative stress* and pericytes loss in the mouse brain. Pericytes are in immediate contact with endothelial cells and are vital for blood-brain barier integrity. These results provide for the first time evidence that inhibition of mitochondrial CA activity reduces diabetes-reduced oxidative stress in the mouse brain and rescuses cerebral policytes dropout. Mitochondrial CA may provide a new therapeutic targed for oxidative stress related impairments of the brain. Anti-oxidant activity of TPM was shown also in vitro study (Cardenas-Rodrigues et al., 2013a). The results show that TPM displays scavenging capacity of superoxide, hydroxyl radical, hypochlorus acid, hydrogen peroxide, signled oxygen but not to peroxynitrite. Although TPM was less efficient than *nordihydroguaiaretic acid*, *dimethylthiourea, ascorbic acid, sodium pyruvate and glutathione* in its scavenging capacity. The authors conclude that anti-

In model of rat *cortical cell culture*, VPA was found to protect against the negative effects of oxygen stress (Wang et al., 2003). Administration of VPA for 7 days prevented lipid and protein oxidization anomalies and accumulation of free radicals. Short-term administration of VPA

Several mechanisms were suggested for VPA hepatotoxicity, however, most of them are associated with oxygen stress resulting in mitochondrial dysfunction. Rat liver mitochondria were obtained by differential ultra centrifugation and then incubated with different concen‐ tration of VPA (25-200µM) (Jafarian et al., 2013). The results showed that VPA could induce oxidative stress via rising in mitochondrial ROS, lipid peroxidation, mitochondrial membrane potential collapse, mitochondrial swelling and release of Cytochrome C. The authors found

oxidant properties of TPM could explain it's the neuroprotective effect.

affects one or more of the neuroprotective processes.

The major mechanisms of antiepileptic ZNS are inhibition of voltage-gated Na(+) channel, Ttype voltage sensitive Ca(2+)channel, Ca(2+) relasing system and neuronal depolarizationinduced glutamate release, and increased release of inhibitory neurotransmitters.

*In the KA convulsion model* in rats, pretreatment with ZNS led to increased anti-oxidant level in the hippocampus (Ueda et al., 2005). The study was performed in freely moving rats using in vivo microanalysis and electron paramagenetic resonance spectroscopy. In the authors' opinion, ZNS has neuroprotective properties against free radicals.

Neuroprotective properties of ZNS also have been shown *in iron-induced epileptogenic foci* in the rat brain (Komatsu et al., 2000). The authors found that the level of 8-hydroxy-2. deoksy‐ guanosine (8-OHdG), which is used as a marker for oxidative DNA damage, increased 15 min after ferric chloride solution injections reaching maximum after 30 min. ZNS prevented the increase of the 8-OHdG within 30 min after iron solution injection. This effect may be due to the ZNS antioxidant activity and might be interesting to use it in prevention of posttraumatic epilepsy development due to blood extravasation and epileptogenic affect of free ferrum.

#### **3.10. Old and new AEDs**

Pavone and Cardile (2003) studied effects of AEDs on oxygen stress in an *astrocyte culture from rats.* Selected list of studied variables includes: lactate dehydrogenase (LDH) and glutamine synthtase (GS) levels, ROS production, lipid peroxidation and DNA fragmentation. Drugs such as CBZ, TPM and OXC caused oxygen stress whatever their dose. Gabapentin (GBP), LEV, LTG, tiagabine (TGB) and ZNS on the other hand, caused no significant metabolic changes in large or small doses. Cortical astrocytes seem to tolerate this latter group of AEDs better than the former ones.

Animal models of seizures, in particular, epilepsy and oxidative processes are useful for developing antiepileptic drugs (Majkowski et al., 2011; Rowles and Olsen, 2012). However, one of the main problems in transferring animal-based data to humans is to define effectiveness of a dose.
