Free radicals, anticonvulsants, and the neuronal ceroid‐lipofuscinoses

Abstract

The relationship between free radicals and scavenger enzymes, and the disorders called the neuronal ceroid-lipofuscinoses, has long been an argumentative one. Recent evidence would seem to support the fact that such a relationship might exist but that it is indirect. The relationship does not seem due to an inborn error of free radical scavenger enzyme metabolism. Anticonvulsants play a role, as they influence free radical generating systems. At this juncture, no one has studied the relationship of anticonvulsant therapy, neuronal ceroid-lipofuscinosis, and the free radical-scavenging enzyme system, and their interplay. We have studied a large number of patients with epilepsy who are on either monotherapeutic or polytherapeutic regimens of most of the common anticonvulsants. We have found excessive free radical production in many of these patients, ranging from minor effects in the simpler anticonvulsants when used monotherapeutically, to more complex changes in polytherapeutic combinations. Likewise, we have found subtle and inconsistent findings in the free radical-scavenging enzyme system in a variety of examples of neuronal ceroid-lipofuscinosis. When refractory seizure disorders stimulate the vigorous use of polytherapy with a variety of free radical-facilitating anticonvulsants, free radical production becomes deleterious. Likewise, in certain types of neuronal ceroid-lipofuscinosis, polypharmacy with anticonvulsants, by enhancing the production of free radicals or suppressing scavenging enzymes, tends to be deleterious and induces a worsening in the disease process.

Blood Levels of Trace Elements, Electrolytes, and Oxidative Stress/Antioxidant Systems in Epileptic Patients

“…Many studies suggest that membrane lipid peroxidation may be causally involved in some forms of epilepsies, and the decrease in free radical scavenging enzyme activity is believed to cause the increased risk of seizure recurrence (4,12,63) and idiosyncratic drug reaction encountered in the management of epilepsy (55,63,64). In addition, Many conventional AEDs are metabolized to generate reactive metabolites with capability of covalent binding to macromolecules (65).…”

“…It has been reported that increased generation of free radicals or reduced activity of antioxidative defense mechanisms can cause some forms of seizures and in addition, increases the risk of seizure recurrence (4,5). Many antiepileptic drugs (AEDs) are metabolized to generate reactive metabolites with the capability of covalent binding to macromolecules as proteins or other vital biomolecules and hence eliciting systemic toxicity (5 -7).…”

“…Many antiepileptic drugs (AEDs) are metabolized to generate reactive metabolites with the capability of covalent binding to macromolecules as proteins or other vital biomolecules and hence eliciting systemic toxicity (5 -7). Peroxidation of membrane lipids caused by an increase of generation of free radicals or decrease in the activities of antioxidant defense systems have been suggested to be critically involved in seizure control (4). Malondialdehyde (MDA) is one of the important aldehydes resulting from membrane lipid peroxidation products.…”

A comparative study on synthesis of some novel α,β-unsaturated carbonyl derivatives and their antioxidant potential

“…Superoxide scavenging activity of the compounds was determined by McCord and Fridovich method [24], which depends on light induced superoxide generation by riboflavin and corresponding reduction of NBT [25][26][27]. The assay mixture contained EDTA (Ethylenediamine tetra-acetic acid) solution (6.6 mM) containing NaCN (3 µg), riboflavin (2 µM), NBT (50 µM), test substances and phosphate buffer (67 mM, pH = 7.8) in a final volume of 3 mL.…”

Prophylactic Effects of Melatonin on Sodium Valproate-Induced Neural Tube Defects and Skeletal Malformations in Rat Embryos

“…Long-term use of antiepileptic drugs has been shown to increase free radical formation and cause oxidative damage within neuronal cells (Maertens et al, 1995). The metabolism of valproate may trigger oxygen dependent tissue injury and elevate the free radicals in the body (Cengiz et al, 2000).…”