Altered Antioxidant Enzyme Activities in Children with a Serious Adverse Experience Related to Valproic Acid Therapy

Abstract

Specific oxidative metabolites of valproic acid (VPA) have been associated with the clinically defined toxicity of the drug. To investigate the role of enzymatic detoxification in clinical toxicity, we compared activities of five antioxidant enzymes in 15 patients with a serious adverse experience (SAE) related to VPA therapy, to enzyme activities measured in 35 patients with good clinical tolerance of VPA, and 50 healthy, age-matched subjects. These enzymes included glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glutathione transferase, superoxide dismutase, and catalase in erythrocytes; and GSH-Px in plasma. We also determined levels of Se, Cu, and Zn, trace elemental cofactors for these enzymes, in plasma from each individual. In patients with a VPA-associated SAE, GSH-Px was significantly depressed and GSSG-R was significantly elevated relative to values for the other groups. Selenium and zinc concentrations were lower in SAE patients than in controls. These findings may indicate a role for selenium dependent antioxidant activity in individual susceptibility to an SAE related to VPA therapy.

Relationship of antioxidant enzyme activities with myelomeningocele

“…Only a few articles describing abnormal FRSE activities in infants with MM have been published (6,7,8,10). Previous studies measured FRSE activities, especially GSH-related reported a similar observation.…”

“…Numerous studies have shown the relationship between FRs and neural tube defects (7, 8, 9, 10, 20, 29). The antiepileptic drugs producing FRs increase FR-mediated cellular damage and may result in neural tube defects (8,21,25,27). Exposure of rat embryos to a high concentration of oxygen (20%) during early neurulation (day 9 to 10) significantly increased the incidence of neural tube defects when compared with control embryos (12).…”

“…These enzymes play an active role in the detoxification of H 2 O 2 for the protection of cell against oxidative stress. The impaired responsiveness of the FRSE system plays a crucial role in oxygen-induced embryopathy and might result in MM (7,8,9,10,12,15,21). Erythrocyte FRSE are the most important enzymes in prevention of FRmediated neurological disease (6).…”

The Role of Reactive Species in Epileptogenesis and Influence of Antiepileptic Drug Therapy on Oxidative Stress

“…Erythrocyte GPX [91, 92], GR [93] and serum Se [94], uric acid and albumin [80], which are considered endogenous enzymatic and non-enzymatic antioxidant molecules, were found to be reduced in children and adults treated with VPA. Furthermore, in studies in patients with epilepsy, treated with VPA, increased levels of oxidative macromolecular damage markers, such as MDA [76, 86, 90, 91] and 15F-2t-isoP [95], which are markers of enhanced lipid peroxidation and increased levels of 8-OHdG [90, 96], which is a marker of nucleic acid damage, were observed.…”

The role of the melatoninergic system in epilepsy and comorbid psychiatric disorders

“…Increased oxidative stress and disturbance of the endogenous antioxidant system can aggravate seizure activity (Yüksel et al, 2000). On the other hand, data has shown that the metabolites of several AEDs behave as pro-oxidant agents with toxic effects (Graf et al, 1998;Niketic et al, 1995;Yüksel et al, 2000). Experiments have confirmed the potent antioxidant activity of melatonin in different pathological states: chronic melatonin infusion (10 mg/kg/day), as well as a cumulative dose of 10 mg/kg, suppressed KA-induced oxidative stress in the hippocampus (Chung and Han, 2003) without preventing the development of SE .…”