Effects of Valproate Monotherapy on the Oxidant‐Antioxidant Status in Mexican Epileptic Children: A Longitudinal Study

Abstract

Epilepsy is a neurological disorder that can produce brain injury and neuronal death. Several factors such as oxidative stress have been implicated in epileptogenesis. Valproic acid (VPA) is a widely used drug for the treatment of epilepsy, but the mechanisms underlying these benefits are complex and still not fully understood. The objective of this study was to evaluate, for the first time, the effects of VPA on the oxidant-antioxidant status in Mexican epileptic children before and after 6 or 12 months of treatment with VPA by determining the activities of several plasmatic antioxidant enzymes (glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT)) and oxidant marker (malondialdehyde (MDA), hydrogen peroxide (H2O2), 8-hydroxy-2-deoxyguanosine (8-OHdG), and 3-nitrotyrosine (3-NT) levels) profiles. The possible relationships between these markers and some clinicopathological factors were also evaluated. Plasma samples were obtained from the peripheral blood of 16 healthy children and 32 patients diagnosed with epilepsy, and antioxidant/oxidant markers were measured spectrometrically. Significant decreases in all antioxidant enzyme activities, with the exception of GPx, and increases in all oxidant markers in epileptic subjects versus healthy children were observed. Interestingly, all these effects reverted after VPA monotherapy, although the results were different depending on the treatment period (6 or 12 months). These changes were contingent upon brain imaging findings, type of epilepsy, etiology of epilepsy, and the efficacy of 6 months of VPA monotherapy. Significant and positive correlations of GPx and SOD activities and H2O2 and 8-OHdG levels with the age of children at the beginning of treatment were observed. H2O2 levels were also positively correlated with number of seizures before VPA monotherapy. VPA showed significant antioxidant effects decreasing seizure activity, possibly depending on the presence of cerebral structural alterations, treatment time, and age.

Dose-Dependent Behavioral and Antioxidant Effects of Quercetin and Methanolic and Acetonic Extracts fromHeterotheca inuloideson Several Rat Tissues following Kainic Acid-InducedStatus Epilepticus

“…In addition, the number of seizures was significantly positively correlated with the levels of these oxidative stress markers. Furthermore, in this work, we showed that carbonyl levels are significantly negatively correlated with latency in the brain prefrontal cortex of rats treated with KA, consistent with the findings of another study on humans where we showed, for the first time, that protein oxidation (measured as 3-nitrotyrosine plasmatic levels) is significantly increased in epileptic children in comparison with the control children [20]. In another rat model, the authors also showed that PC content and lipid peroxidation levels are increased in the brain prefrontal cortex in the context of iron-induced epilepsy and that administration of dehydroepiandrosterone (DHEA), a corticosteroid hormone with antioxidant 13 Oxidative Medicine and Cellular Longevity properties, attenuates these effects, suggesting that the antioxidant improved performance on cognitive tasks and prevented behavioral alterations [61].…”

Role of oxidative stress in epileptogenesis and potential implications for therapy

“…In contrast, 6-and 12-month valproate monotherapy increased activity of antioxidant enzymes (glutathione reductase, glutathione peroxidase, superoxide dismutase, and catalase) in 32 pediatric patients. Simultaneously, reduced levels of oxidative markers, such as malondialdehyde, hydrogen peroxide, 8-hydroxy-2-deoxyguanosine and 3-nitrotyrosine, were observed [1].…”

“…First-generation ASDs occurred rather disappointing in the aspect of neuroprotection and prevention of epileptogenesis, valproate showing some antiepileptogenic potential [1][2][3][4][5]. Moreover, this class of ASDs often enhances epilepsy aftermaths, impairing cognition and decreasing mood [32,33,38].…”

“…In both experimental and clinical conditions, antiseizure drugs (ASDs) were generally found disappointing in the aspect of neuroprotection and prevention of epileptogenesis [1][2][3][4][5]. Therefore, searching for not only antiseizure but also anti-epileptogenic strategies may become a new promising possibility to overcome problems associated with the treatment of drug-resistant epilepsy.…”

Seizure-Induced Oxidative Stress in Status Epilepticus: Is Antioxidant Beneficial?

“…Topiramate can inhibit free radical production, attenuate lipid peroxidation, and supporting the antioxidant redox system to protect pentylenetetrazol-induced brain injury [ 187 ]. In a recent study, it was shown that children with valproic acid monotherapy has significant antioxidant effects and decreases seizure activity [ 188 ]. Valproic acid may increase levels of glutathione and exert its neuroprotective effect [ 189 ].…”