Role of oxidative stress in epileptic seizures

Abstract

Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of epilepsy. Therefore, antioxidant therapies aimed at reducing oxidative stress have received considerable attention in epilepsy treatment. However, much evidence suggests that oxidative stress does not always have the same pattern in all seizures models. Thus, this review provides an overview aimed at achieving a better understanding of this issue. We summarize work regarding seizure models (i.e., genetic rat models, kainic acid, pilocarpine, pentylenetetrazol, and trimethyltin), oxidative stress as an etiologic factor in epileptic seizures (i.e., impairment of antioxidant systems, mitochondrial dysfunction, involvement of redox-active metals, arachidonic acid pathway activation, and aging), and antioxidant strategies for seizure treatment. Combined, this review highlights pharmacological mechanisms associated with oxidative stress in epileptic seizures and the potential for neuroprotection in epilepsy that targets oxidative stress and is supported by effective antioxidant treatment.

Introduction

Epilepsy has plagued humanity for centuries. It was probably first described in ancient Egyptian writings around 2000 BC and was a popular topic of the Greek and Roman scholars. The “sacred disease” or “falling sickness”, as it was frequently called, was closely identified with supernatural forces and was considered a manifestation of the gods and spirits. The modern era of epilepsy began with the writings of Jackson in the late 1870s (Jackson, 1879). His extensive treatise established the neuroanatomic basis for epileptic phenomena. Since the introduction of electroencephalography in the 1930s (Gastaut, 1950), the understanding of the basic neurophysiology of the disorder has greatly expanded. Improved understanding has resulted in the development of a large number of potent and specific drugs for various seizure types and has been the basis for rational therapeutics and patient monitoring. Despite the increasing number and variety of anti-epileptic drugs, more than 30% of cases of epilepsy are medically intractable (Kwan and Brodie, 2000), with temporal lobe epilepsy (TLE) having one of the worst prognoses among epileptic disorders. There is usually a latent period of several years between the initial precipitating injury and the emergence of chronic TLE characterized by spontaneous recurrent motor seizures originating from temporal lobe foci (Devinsky, 2004). Furthermore, TLE is frequently associated with hippocampal sclerosis, mainly exemplified by significant neurodegeneration in the dentate hilus and the CA1 and CA3 regions (Sloviter, 2005). Moreover, anti-epileptic drugs merely provide symptomatic treatment without having any influence on disease course. Thus, there is a pressing need to develop alternative therapeutic approaches that prevent epileptogenesis after status epilepticus (SE).

In the modern era, epilepsy is the most frequent neurodegenerative disease after stroke. It afflicts more than 50 million people worldwide (Strine et al., 2005). At least 6% of the population is said to suffer one isolated seizure episode during their lifetime. Over 90% of epileptics suffer from generalized tonic–clonic seizures, and many suffer from multiple forms of the disorder.

Brain injury resulting from seizures is a dynamic process that comprises multiple factors contributing to neuronal cell death. These may involve genetic factors, excitotoxicity-induced mitochondrial dysfunction, altered cytokine levels, and oxidative stress (Ferriero, 2005). Seizure-like activity at the cellular level initiates significant influx of calcium via voltage-gated and N-methyl-d-aspartate (NMDA)-dependent ion channels (Van Den Pol et al., 1996). Elevated intracellular ions lead to biochemical cascades, which trigger acute neuronal death after SE (Fujikawa et al., 2000). In addition, high levels of intracellular calcium can induce reactive oxygen species (ROS).

ROS, including superoxide radical $({}^{}{\text{O}}_2^{-})$, hydrogen peroxide (H₂O₂), hydroxyl radical (OH), and singlet oxygen (¹O₂), are generated during normal cellular metabolism (Kontos, 1989, Beit-Yannai et al., 1997). Physiological levels of ROS can be scavenged by enzymatic (e.g., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and peroxiredoxins (Prxs)) and non-enzymatic (e.g., vitamin C, vitamin E, and reduced form of glutathione (GSH)) antioxidant defense systems. However, excessive ROS levels due to increased ROS production, decreased antioxidant defense ability, or both leads to oxidative stress (Winyard et al., 2005). In addition, excess ROS further reacts with nitric oxide (NO) to generate reactive nitrogen species (RNS) such as peroxynitrite (ONOO⁻; Brown and Borutaite, 2001).

The brain is particularly susceptible to oxidative stress because it utilizes the highest amount of oxygen compared with other bodily organs. The brain also contains high concentrations of polyunsaturated fatty acids that are prone to lipid peroxidation, is rich in iron, which can catalyze hydroxyl radical formation, and is low in CAT activity (e.g., 10% that of the liver; Halliwell, 1999, Mariani et al., 2005, Jellinger, 2003). Oxidative stress results in functional cellular disruption and cellular damage and may cause subsequent cell death via oxidation of biomolecules such as proteins, lipids, and nucleotides. Protein oxidation leads to functional changes or deactivation of various enzymes (Stadtman, 2001). Lipid peroxidation causes membrane structure alterations that affect membrane fluidity and permeability and membrane protein activity (Wong-ekkabut et al., 2007). Oxidative stress is involved in the pathogenesis of a number of neurologic conditions and neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and epilepsy (Perry et al., 2002, Migliore et al., 2005, Ashrafi et al., 2007).

However, the role of oxidative stress in epilepsies has only recently begun to be recognized (Ashrafi et al., 2007). Studies have focused on elucidating whether prolonged seizure activity in animals results in increased ROS production and whether oxidative injury contributes to seizure-induced brain damage. ROS formation occurs when unpaired electrons escape the electron transport chain and react with molecular oxygen, thus generating superoxide. Superoxide can react with DNA, proteins, and lipids and plays an important role in many physiological and pathophysiological conditions. The maintenance of low ROS levels is critical to normal cell function, and therefore, prolonged increases in ROS carry an inherent risk of increasing neurodegeneration such as that seen in epilepsy.

This review outlines studies supporting the emerging recognition of the role of oxidative stress in epileptic conditions. Evidence for the production and consequences of acute and chronic oxidative stress in various animal models of epilepsy are reviewed, and damage to proteins, lipids, and antioxidant defenses is considered. Oxidative stress in relation to cell death or consequences of epileptic seizures is given attention because neuronal cells are considered vulnerable to oxidative damage and a contributing factor in epileptogenesis. In addition, regulation of oxidative stress with natural and chemical treatments as a means of attenuating epileptogenesis and seizure initiation is discussed.