Evidence suggests that glutathione homeostasis may be altered due to reactive metabolites and/or ROS produced during treatment with anticonvulsants (Cárdenas-R et al. 2013). Glutathione is an important biomolecule that protects the cell against chemical-induced cytotoxicity by direct or enzymatic (GST) conjugation with electrophilic compounds while demonstrating reactive oxygen teratogenic potential in patients with epilepsy (Ebru et al. 2011).
In the current study, the GST level was significantly decreased in the epileptic patients compared to that in the control group; however, no significant difference was found among the different patient subgroups. These results are consistent with the findings of studies by Michoulas et al. (2006) and Solowiej and Sobaniec (2003). Solowiej and Sobaniec (2003) reported that the intermediate metabolites of VPA and CBZ are detoxified via conjugation with glutathione, leading to the efflux of GST in bile. Thus, depletion of hepatic GST stores as a result of this detoxification might account for the changes observed in the serum GST level. However, Adnan et al. (2001) recorded a decrease in the GST level in patients treated with VPA, while it was not changed in patients receiving CBZ. They stated that CBZ may be a better drug for management of epilepsy, as its metabolic intermediates were more stable and thus resulted in less free radical injury than VPA.
Children with idiopathic epilepsy treated with VPA and/or CBZ have a disrupted oxidant-antioxidant balance and thus require an adequate supply of antioxidants for brain protection and prevention of neurological disturbances. In addition, long-term use of valproate could lead to a lack of selenium, copper, and zinc, which are cofactors of GST activity. Thus, long-term administration of AEDs in epileptic children leads to decreased GST levels (Adnan et al. 2001).
Graf et al. (1998) suggested that deficits in antioxidant activity enhance susceptibility to the adverse effects of VPA therapy. Moreover, another study reported no change in the glutathione peroxidase level in erythrocytes during treatment with VPA (Yiş et al. 2009).
In contrast to our results, Kürekçi et al. (1995) found that serum GST levels were increased in patients on VPA therapy. They reported that this increase might be due to an induction of hepatic synthesis of glutathione.
Lipid peroxidation is an indicator of free radical metabolism and oxidative stress in humans and other organisms. Free radicals have a short half-life, and the estimation of MDA, which is an end product of lipid peroxidation formed during the non-enzymatic oxidation of polyunsaturated fatty acids, is both simple and convenient for determining lipid peroxidation and thereby oxidative stress in human subjects (Waldbaum and Patel 2010).
Excess oxidative stress may be a final common pathway through which AEDs exert their teratogenic potential in epilepsy patients (Ebru et al. 2011).
Our results showed that the MDA level was significantly higher in the patients with idiopathic epilepsy than in the controls. This finding is consistent with that of Michoulas et al. (2006). No significant difference in the MDA level was detected among our patient subgroups. Zhang et al. (2011) and Bindu et al. (2012) reported an increased MDA level in epileptic patients receiving VPA compared to that in the control group. Solowiej and Sobaniec (2003) reported a decreased MDA level in patients treated with CBZ monotherapy, while the MDA level was elevated in patients treated with VPA. This might be due to the decreased activities of the antioxidant enzymes associated with VPA therapy, whereas these enzymes showed normal activity during CBZ therapy (Ebru et al. 2011). Yiş et al. (2009) reported that the MDA levels were significantly increased but did not reach pathological levels in epileptic patients receiving VPA.
In contrast to our results, Yüksel et al. (2000) detected no significant difference in serum MDA levels between epileptic children treated with VPA and healthy controls. Changes in the antioxidant defense mechanisms and the resulting lipid peroxidation are involved in the pathogenesis of epilepsy. However, research findings concerning these processes are very conflicting (Solowiej and Sobaniec 2003).
In the present study, the serum GST level was significantly lower in the poor seizure control group (for at least 6 months) than in the controlled seizure group. However, the serum MDA level was significantly higher in the patients with poor seizure control than in the patients who were controlled. Our results were consistent with those of Graf et al. (1998) who reported a normal GST level in children showing good clinical tolerance and a decreased level in patients with repeated seizures. Their study showed that antioxidant enzymes including GST were saturated when the free radical load of the body increased. They also demonstrated that when these enzymes failed to compensate for the excessive repeated free radical load due to repeated seizures, the antioxidant enzyme level started to decrease, while damage occurred within the cell membranes. They added that VPA especially increased the oxygen-associated tissue damage due to its toxic metabolites in the body.
The duration of drug intake was negatively correlated with the GST level and positively correlated with the MDA level in the three groups of epileptic patients. Zhang et al. (2011) reported a positive correlation between the plasma MDA level and the duration of VPA treatment. Additionally, Martinc et al. (2012) found that erythrocyte GST activity was markedly decreased after long-term administration of VPA. Liu et al. (1998) correlated long-term use of various AEDs to deficiencies in magnesium and serum zinc, which play a critical role in neuronal excitability, in red blood cells.
A limitation of this study is the small size of the patients.
