In recent years, the role of oxidative stress in diseases of the CNS has been attracting increasing attention. In such diseases, and particularly in refractory epilepsy, FR, mitochondrial DNA (mtDNA) mutation, decreased mitochondrial respiration, mitochondrial calcium dysregulation, lipid oxidation, protein modification, mitochondrial permeability transition, among other factors, are frequently observed, although to different degrees. In this review, we show that, in epilepsy, an imbalance exists in the antioxidant defense system. The decrease in oxidative stress using antioxidants could be a therapeutic option leading to the reduced administration and adverse effects of some anticonvulsants agents.
Experiments conducted in animals and cellular models, as well as observations of patients, all suggest the benefit of protection against oxidative damage for attenuation of neuronal degeneration [107
]. Thus, it has been proposed that therapeutic approaches target oxidative stress in the treatment of diseases of CNS, including refractory epilepsy. For example, therapeutic benefits from antioxidant treatment with agents such as N
-acetylcysteine (NAC) may be due to their capacity to stop or slow the process of neuronal cell death. There is a need for further studies in clinical trials with specific patient groups that have drug-resistant epilepsy. NAC should mainly function as a precursor of glutathione (a powerful antioxidant). This is important because it indicates that the NAC effect is more general and can improve the condition of people not genetically linked [103
]. In addition, natural antioxidants (polyphenols, isoflavones, ginsenosides and flavonoids), extracted from plants have a proven antioxidant function and protective effect on mitochondrial function. For example, green tea and polyphenols are believed to be a strong antioxidant against hydroxyl radicals, nitric oxide and lipid oxidation [112
However, due to the limited studies to date, the efficacy and side effects of natural antioxidants for the treatment of CNS diseases have yet to be determined. Molecules, such as vitamins C and E, glutathione, and coenzyme Q10 (CoQ10), lipoic acid and melatonin, play an important role in the endogenous defensive strategy against oxygen FR [114
]. Mitochondrial gene therapy (studies targeting the amelioration of mtDNA lesion) [130
], and substitution of defective mtDNA using gene-carrying vectors to send recombinant mtDNA into cells, are other approaches for mitochondrial gene therapy. Novel methodologies for manipulation of mitochondrial drugs are needed for mitochondria-targeted treatment [133
]. To date, there is little progress in the study of gene therapy for preventing oxidative damage, and therefore clinical trials are necessary for further exploration of this question.
In patients with refractory epilepsy, current treatments include surgical resection of areas affecting epilepsy [139
] and the ketogenic diet or other alternative diets used since the 1970s [143
]. However, the refractoriness of epilepsy continues to be an unresolved problem. Some human studies, although still in the experimental phase and without definitive data, suggest that the administration of some antioxidant agents can be used as adjuvants in the treatment of refractory epilepsy. These antioxidant agents include melatonin [147
], vitamin E [148
], selenium [149
] and allopurinol [151
]. It is urgent to shed more light on the mechanisms of refractory epilepsy and find new treatments that could improve the quality of life of patients.