Effects of antiepileptic drugs on antioxidant and oxidant molecular pathways: focus on trace elements

Abstract

Current reports on trace elements, oxidative stress, and the effect of antiepileptic drugs are poor and controversial. We aimed to review effects of most common used antiepileptics on antioxidant, trace element, calcium ion (Ca(2+)) influx, and oxidant systems in human and experimental animal models. Observations of lower blood or tissue antioxidant levels in epileptic patients and animals compared to controls in recent publications may commonly support the proposed crucial role of antioxidants in the pathogenesis of epilepsy. Effects of old and new antiepileptics on reactive oxygen species (ROS) production in epilepsy are controversial. The old antiepileptic drugs like valproic acid, phenytoin, and carbamazepine induced ROS overproduction, while new epileptic drugs (e.g., topiramate and zonisamide) induced scavenger effects on over production of ROS in human and animals. Antioxidant trace element levels such as selenium, copper, and zinc were generally low in the blood of epileptic patients, indicating trace element deficiencies in the pathogenesis of epilepsy. Recent papers indicate that selenium with/without topiramate administration in human and animals decreased seizure levels, although antioxidant values were increased. Recent studies also reported that sustained depolarization of mitochondrial membranes, enhanced ROS production and Ca(2+) influx may be modulated by topiramate. In conclusion, there is a large number of recent studies about the role of antioxidants or neuroprotectants in clinical and experimental models of epilepsy. New antiepileptic drugs are more prone to restore antioxidant redox systems in brain and neurons.

Fig. 1

Free radical generation and Ca²⁺ uptake induce seizure activity by direct activation of Ca²⁺ channels although topiramate-induced modulator role in Ca²⁺ influx through voltage-gated Ca²⁺ channels (VGGC) and glutamate receptors namely AMPA, kainate, and N-methyl-d-aspartate (NMDA). During the physiological process, superoxide radicals (O₂ ⁻) produces and the radicals converted hydrogen peroxide (H₂O₂) by copper (Cu) and zinc (Zn) superoxide dismutase enzyme. The hydrogen peroxide (H₂O₂) is converted to water (H₂O) by Cu- and Zn-dependent catalase (CAT) and selenium (Se)-dependent glutathione peroxidase enzyme (GSH-Px) enzymes. Mitochondria were reported to accumulate Ca²⁺ provided cytosolic Ca²⁺ rises or provided mitochondrial uptake exceeds mitochondrial Ca²⁺ extrusion, thereby leading to depolarization of mitochondrial membranes. On the other hand, exposure of mitochondria to high free Ca²⁺ was shown to increase formation of ROS. The sustained depolarization of mitochondrial membranes and enhanced ROS production may be modulated by topiramate. Transient potential (TRP) or TRP melastatin 2 (TRPM2) channel activity-induced Ca²⁺ influx increases may be modulated by topiramate. The molecular pathway may be a cause of epileptic seizures and represents a fruitful subject of topiramate for further study. − Decrease, + increase