Effects of Add‐on Melatonin Administration on Antioxidant Enzymes in Children with Epilepsy Taking Carbamazepine Monotherapy: A Randomized, Double‐blind, Placebo‐controlled Trial

Abstract

Summary:Purpose: Melatonin has been shown to exhibit antioxidant, antiexcitotoxic, and free radical-scavenging properties in various animal models. The study was designed to assess its effects on the blood levels of antioxidant enzymes in children with epilepsy receiving carbamazepine (CBZ).Methods: In a double-blind, randomized, parallel-group, placebo-controlled trial, we assessed the effect of add-on melatonin (6-9 mg/day for 14 days) on the antioxidant enzymes glutathione peroxidase (GPx) and glutathione reductase (GRd) in 31 children with epilepsy receiving CBZ monotherapy, who were seizure free at least for the last 6 months. The interaction of melatonin with CBZ and its active metabolite, carbamazepine-10, 11-epoxide (CBZ-E), also was studied.Results: An increase in GRd activity was noted in the melatonin group as compared with a decrease of the same enzyme in the placebo group. Changes in GPx activity failed to reach statistical significance. No significant changes were found in the serum levels of CBZ and CBZ-E in either group.Conclusions: The study suggests that melatonin exerts antioxidant activity in patients with epilepsy receiving CBZ therapy. Key Words: Melatonin-Carbamazepine-Carbamazepine-10,11-epoxide-Antioxidant enzymes.Evidence has accumulated about the involvement of reactive oxygen species (ROS) in epilepsy (1). The free radicals generated cause a cascade of neurochemical events leading to neurodegeneration and cell death. Free radicals also are produced by antiepileptic drugs (AEDs) like carbamazepine (CBZ) (2).The neuromodulator melatonin has been shown to reduce oxidative stress in various animal models, because of its antioxidant as well as free radical-scavenging properties (3), and to antagonize a mutagenic effect of CBZ in some systems (4). Melatonin also exhibits anticonvulsant activity in different seizure models (5), and at least No randomized controlled trials have assessed the effect of add-on melatonin on antioxidant enzymes in pediatric epilepsy. The objectives of the present study were (a) to compare the effect of add-on melatonin with placebo on antioxidant enzymes in children with epilepsy receiving CBZ monotherapy; and (b) to study the pharmacokinetic interaction between melatonin and CBZ and its active metabolite carbamazepine-10,11-epoxide (CBZ-E).

Redox Processes in Neurodegenerative Disease Involving Reactive Oxygen Species

“…Treatments designed to prevent lipid peroxidation may be more effective for epilepsy prophylaxis than administration of antiepileptic drugs that mask convulsive seizures while brain injury continues [20]. Melatonin exhibits AO, antiexcitotoxic and radical scavenging abilities [21]. Data indicate that the compound exerts AO activity in epileptic patients.…”

The effects of agomelatine and melatonin on ECoG activity of absenceepilepsy model in WAG/Rij rats

“…Generation of absence seizures is thought to be associated with excessive thalamic oscillations, due to abnormal intrinsic neuronal properties under the control of an inhibitory GABAergic mechanism (Steriade et al, 1993;Manning et al, 2003;Kovacs et al, 2015). On the other hand, melatonin shows anticonvulsant activity due to its antioxidant, antiexcitotoxic, and free radical-scavenging properties in various experimental epilepsy models and human studies (Floreani et al, 1999;Srivastava et al, 2002;Gupta et al, 2004;Lima et al, 2011;Nazıroğlu et al, 2013;Yürüker et al, 2015). However, absence seizures do not cause serious excitotoxic damages as seen in convulsive seizures, because of less free radical generation.…”

Neuronal plasticity: implications in epilepsy progression and management

“…The severe stress induced by repeated or prolonged seizures alters homeostasis between endogenous free radical sequestrants/antioxidants and excitotoxic potentials resulting in the exhaustion of endogenous protective capabilities, membrane lipid peroxidation and excitotoxicity [Gupta et al, 2004;. CBZ was better in controlling free radical related seizures than VPA and PHT [Yù ksel et al, 2000;.…”

“…Future antiepilepogenic neuroprotective strategies should extend beyond the available medications to involve other AEDs with safer pharmacological profile and with multiple mechanisms of action, including free radical scavengers/antioxidant and multivitamins [Gupta et al, 2004;: mitochondrial uncouplers [Hemingway, 2001] antiapoptotic/ antinecrotic substances [Verhagen et al, 2000], glutamate receptor blockers [Moldrich et al, 2003], and neurotrophic factors [Yang et al, 1996]. Modulation of the receptors and cell signaling processes involved in the excitotoxicity cascade should be among the targets as well [Sankar, 2005].…”