Abstract

Since the last edition of this volume, there have been major advances in our understanding of redox mechanisms in epilepsies. The brain’s architecture, cell types, and function make it uniquely susceptible to oxidative damage. Animal models of acquired epilepsy have revealed reactive oxygen species generated by multiple cellular sources; oxidant damage to cellular lipids, proteins, and deoxyribonucleic acid; and an altered thiol redox status. Preclinical studies have identified several redox-based therapeutic strategies to improve epilepsy and/or its comorbidities. This chapter provides an overview of the role of redox dysregulation in epilepsy with emphasis on therapeutic targets.

Introduction

The epilepsies comprise a spectrum of complex and heterogeneous neurological disorders characterized by an enduring predisposition to generate recurrent, unprovoked seizures. Globally, greater than 65 million people suffer from epileptic seizures and associated neurobiological, cognitive, and psychological comorbidities (Fisher et al., 2014). From a clinical perspective, the ever-evolving and dynamic etiologic classification of epilepsy is critical for (a) an accurate diagnosis, (b) identification of potential seizure triggers, (c) prediction of the likely occurrence of other seizure types and disease prognosis, (d) guiding the selection of antiseizure therapies, and (e) development of novel therapeutics. The International League Against Epilepsy (ILAE) classification of the epilepsies encompasses three levels: (1) diagnosis of seizure type, (2) diagnosis of epilepsy type, and (3) diagnosis of a specific epilepsy syndrome (Scheffer et al., 2017). At each level, significant consideration is given to etiologies such as structural, metabolic, immune, genetic, infectious and unknown (England et al., 2012). There are certain molecular, pathological, and circuit-level alterations that predispose a normal brain to uncontrolled seizure activity. Extensive evidence from surgically resected brain tissue and animal seizure models highlights the following key processes in the development/pathogenesis of epilepsy: neuronal loss, oxidative/nitrosative stress, mitochondrial dysfunction, neuroinflammation, axonal and dendritic sprouting, and neurogenesis (Dichter, 2009; Loscher and Brandt, 2010). Specifically, the role of oxidative/nitrosative stress in epilepsy has garnered sustained attention for the following reasons: (1) recurrent seizure activity-induced production of reactive oxygen species (ROS) from various cellular sources (Kovac et al., 2014; Patel et al., 2005; Puttachary et al., 2015; Rojas et al., 2014); (2) a chronically perturbed glutathione (GSH) redox status and alterations in antioxidant enzyme (catalase, glutathione peroxidase [GPx], superoxide dismutase [SOD]) activities observed in patients and rodent models with seizures (Freitas et al., 2005; Lopez et al., 2007; Ristic et al., 2015; Rumia et al., 2013; Yuzbasioglu et al., 2009); (3) seizure-induced oxidative damage to cytosolic and mitochondrial proteins, nuclear and mitochondrial DNA, ion channels and neurotransmitter transporters, and hippocampal phospholipids (Cantu et al., 2009; Liang and Patel, 2004; Patel et al., 2001; Trotti et al., 1998); (4) antioxidant and dietary treatment strategies (that elevate/replete GSH levels, target mitochondrial and nicotinamide adenine dinucleotide phosphate reduced [NADPH] oxidase mediated ROS production) decreased oxidative stress and neuroinflammation, afforded neuroprotection, and rescued cognitive deficits (Barros et al., 2007; Klomparens and Ding, 2019; Pauletti et al., 2019; Singh et al., 2018, 2019); (5) rodent models and human patients genetically deficient in mitochondrial superoxide dismutase (SOD2) or thioredoxin 2 (TXN2) exhibited spontaneous seizures and seizure-related neuropathology (Liang and Patel, 2004; Holzerova et al., 2016). Conversely, overexpression of SOD2 or thioredoxin attenuated kainic acid (KA)-induced oxidative stress, neuronal damage, and seizure severity (Liang et al., 2000). (6) In the Theiler’s murine encephalomyelitis virus (TMEV) model of temporal lobe epilepsy (TLE), a significant increase in certain oxidative stress markers were observed at time points that coincided with acute seizures A significant decrease in reduced/oxidized glutathione (GSH/GSSG) ratio and an increase in 3-nitrotyrosine (3NT) levels were observed in the hippocampi of mice injected intra-cortically with TMEV. This study highlighted the changes in redox status as a consequence of seizure activity in a model of infection-induced epilepsy (Bhuyan et al., 2015). Traumatic brain injury (TBI) often resulting from blunt force trauma to brain parenchyma can cause neuropsychiatric/neurological impairments including posttraumatic epilepsy (PTE). At 6 and 24 h after TBI, a significant increase in 8-epi prostaglandin F_2α, (a lipid biomarker of oxidative stress) derived from peroxidation of arachidonic acid was observed in ipsi- and contralateral cortical brain regions. Also, at the same time points, significant decreases in protein sulfhydryl thiols and GSH levels were observed in these brain regions. Interestingly, these effects were less pronounced in hippocampal brain regions in this model (Tyurin et al., 2000). Collective evidence from epilepsy patients and various animal models highlights the integral involvement of excessive reactive species (RS) production in the etiology of epilepsy and associated comorbidities (Pearson-Smith and Patel, 2017). Physiological concentrations of ROS and reactive nitrogen species (RNS) are integral for balanced neurotransmission, neuroplasticity, and cellular redox homeostasis. Excess oxidative burden, however, can damage cellular macromolecules, disrupt thiol redox circuits in signal transduction pathways, and lead to bioenergetic failure and ultimately cell death. In disorders such as epilepsy, recurrent seizures place a huge energy demand on the cell owing to metabolic alterations between ictal and interictal phases (Duffy et al., 1975). This bioenergetic fluctuation coupled with oxidative distress can cause metabolic dysfunction and severely disrupt cellular homeostatic mechanisms, thereby becoming the “perfect concoction” for further seizure propagation.

In this chapter, the different sources of ROS production and their role in the etiology of epilepsy and associated comorbidities are broadly discussed. In addition, we discuss impairment in redox-signaling leading to dysregulation of critical redox-sensitive signaling pathways. Finally, attenuation and/or mitigation of excessive RS production from diverse cellular sources using dietary therapies and small-molecule antioxidants strategies is discussed.

Neuron-Glial Interactions and Their Role in Metabolic Dysfunction Associated with Seizures

Although astroglia expend only a small proportion (~5%) of total adenosine triphosphate (ATP) in the brain (Attwell and Laughlin, 2001), astroglia play a number of critical roles in regulating neuronal metabolism and neurotransmitter synthesis; indeed, these two processes are linked, as the synthesis of glutamate depends upon tricarboxylic acid (TCA) cycle intermediaries and conversely can “feed” into the TCA cycle. Of relevance to epilepsy and seizures, astroglia provide intermediaries for the neuronal TCA cycle, the antioxidant glutathione, and a neuronal energy source during excessive activity.

Neurons lack pyruvate carboxylase (Yu et al., 1983), an enzyme that is necessary for replenishment of oxaloacetate in the TCA cycle. As a result of this, the synthesis of glutamate would rapidly deplete TCA cycle intermediaries in neurons. Replenishment of these intermediaries in neurons can, however, occur from direct transport of these intermediaries from astroglia to neurons.

Astroglia are also a major producer of GSH from glutamate, cysteine, and glycine, and provide the intermediaries necessary for glutathione synthesis in neurons (Dringen et al., 1999). GSH provides one of the major antioxidant defenses in the central nervous system. GSH is readily oxidized by glutathione peroxidase to glutathione disulfide (GSSG), thereby neutralizing ROS and hydrogen peroxide (H₂O₂) in the brain (Dringen, 2000).

Astroglia are the main regulators of extracellular glutajmate concentrations via the Glutamate aspartate transporter 1 GLAST (EAAT1) and Glutamate transporter 1 GLT1 (EAAT2) (Danbolt, 2001). Glutamate taken up by astroglia is then converted to glutamine for transport back to neurons. Glutamate can, however, also enter the TCA cycle and therefore acts as an energy substrate. Astroglial glutamate uptake also activates the sodium-potassium ATPase, increasing glucose uptake, glycolysis, and glial lactate production (Pellerin and Magistretti, 1994); the consequent lactate surge provides a rapid metabolic response to increases in neuronal activity, such as occurs during seizures (Bittner et al., 2011). Astroglial lactate can then be shuttled to neurons to act as an energy substrate during seizures.

How does epilepsy impact upon these metabolic functions? Importantly, astrocytic metabolism seems to be unaffected in animal models of epileptogenesis (Melo et al., 2005), and astrocytic mitochondrial function seems to be maintained during prolonged seizure activity, at a time when neuronal mitochondria depolarize and fail (Kovac et al., 2012). Indeed, astroglia may play a role in maintaining seizure activity through sustaining the energy substrates necessary for continued neuronal activity (Kovac et al., 2012). Moreover, astrocytic lactate production can depolarize neurons, increasing network excitability (Sada et al., 2015). Thus, the preservation and maintenance of astroglia bioenergetics may have a pro-seizure effect. What about the production of glutathione in epilepsy? Most animal studies demonstrate an acute reduction in glutathione following prolonged seizures but a return to normal levels thereafter (Shekh-Ahmad et al., 2018; Cock et al., 2002). These suggest a maintenance of glial antioxidant defence systems in epilepsy.

Role of Oxidative and Nitrosative Stress in Epilepsy

The brain, despite occupying a small fraction of total body mass, has a high metabolic rate accounting for ~20% of total oxygen metabolism (Hyder et al., 2013). The majority of the energy generated (~80%) is utilized by neurons for neurotransmitter synthesis, restoration of neuronal membrane potentials, vesicle recycling, and axoplasmic transport (Attwell and Laughlin, 2001; Harris et al., 2012; Pathak et al., 2015). Neuronal energy metabolism predominantly relies on mitochondrial oxidative phosphorylation as compared to astrocytic glycolytic metabolism (Kasischke et al., 2004). During the sequential univalent reduction of oxygen to water, ~0.1% to 1% (Fridovich, 2004) of electrons leak from electron transport chain (ETC) complexes I (CI) and III (CIII) (Jastroch et al., 2010) leading to the formation of superoxide anion radical (O₂^.–). Through enzymatic or spontaneous dismutation reactions, superoxide gets converted to H₂O₂ (a nonradical with high transmembrane diffusability), which, in the presence of certain transition metal ions (Iron[II] or Cu[I]), decomposes to form the highly reactive hydroxyl (OH^.) radical species (Fenton’s reaction). Superoxide can react with nitric oxide (NO) to form the reactive nonradical species, peroxynitrite (ONOO^–) (Calabrese et al., 2004). Another important and emerging source of reactive oxygen species generation in the brain is the NOX (NADPH oxidase) family of enzymes, initially identified to play a role in phagocytic “oxidative bursts” (Franchini et al., 2013). The NOX enzymes comprise different subunits that interact upon stimulation to form transmembrane protein complexes that generate superoxide using NADPH as the primary substrate. Seven isoforms (NOX1, 2, 3, 4, and 5 and dual oxidases [DUOX] 1, and 2) of NADPH oxidase have been identified with various tissue distributions and activation mechanisms (Panday et al., 2015). In the brain, isoforms 1, 2, and 4 having varied subcellular localizations across different cell types have been identified (Nayernia et al., 2014). In addition to these critical sources, reactive species produced by xanthine oxidases, cytochrome P450s, certain peroxidases, cyclooxygenases, and lipoxygenases (Di Meo et al., 2016) not only participate in physiological signaling, synaptic plasticity, and neuromodulation (Massaad and Klann, 2011) but in excess can impair redox homeostasis/signaling (Schieber and Chandel, 2014) and trigger neuroinflammation, hyperexcitability, and neurodegeneration (Gandhi and Abramov, 2012).

Redox Homeostasis

The definition of “oxidative and nitrosative stress” has undergone many revisions with our growing understanding of the complexities of redox biology. Early definitions oversimplified the concept by considering only the imbalance in oxidants and antioxidants (Sies, 1997), akin to the early definition of hyperexcitability and excitation-inhibition balance. A later definition incorporated the disruption in redox circuitry into the concept of oxidative stress “as an imbalance between pro-oxidants/antioxidants (Halliwell, 2007) along with disruption in redox signaling and control (Jones, 2006) caused by excessive reactive species (including free radicals and nonradicals) production.” Although antioxidant defenses are abundant and overlapping in biological systems, it is also recognized that depletion and/or diminished antioxidant defenses such as GSH, SOD2, or certain dietary constituents can lead to oxidative stress. More recently the term “oxidative stress” was further subjected to context-related states accounting for the wide ranges of prooxidant and antioxidant cellular components as “physiological oxidative stress or eustress” and “toxic oxidative stress or distress” (Sies et al., 2017). Within this new framework, epileptogenic insults can result in acute and repetitive oxidative stress as well as enhancement of physiological oxidative eustress. For example, increased steady-state levels of ROS observed shortly following single isolated seizures may activate redox signaling pathways and a physiological oxidative stress, whereas prolonged status epilepticus (SE) initiates “oxidative distress” resulting in macromolecular oxidant damage and repair (Dizdaroglu, 1991; Jarrett et al., 2008a; Kudin et al., 2002; Patel et al., 2008; Ryan et al., 2014). The brain is uniquely susceptible to these stressors, given its high metabolic rate, limited antioxidant capacity, presence of redox-active transition metals, and enrichment in polyunsaturated fatty acids (Cobley et al., 2018; Halliwell, 2006). Failure to detoxify excess ROS/RNS by enzymatic and nonenzymatic antioxidant defenses can lead to inactivation of certain metabolic enzymes (e.g., mitochondrial aconitase; Cantu et al., 2009), irreversible protein oxidation of ion channels (voltage-gated calcium and potassium channels; Bogeski and Niemeyer, 2014), lipid peroxidation and ferroptosis-induction (Conrad et al., 2018), and DNA damage (presence of 8-hydroxy-2’-deoxyguanosine [8-OHdG] in mitochondrial and nuclear DNA; Kowalska et al., 2020; Mecocci et al., 1993) that can ultimately result in cellular dysfunction and/or death. In an energy-expensive neurological disorder such as epilepsy, increased oxygen consumption to meet acute energy demand, increase in second messengers like calcium, decrease in ATP levels, and liberation of free fatty acids during seizures are all potential factors that could contribute to reactive species production and propagation.

Sources of Reactive Oxygen Species Production

There are several potential sources for ROS, and it is likely that their contribution varies according to the length of a seizure. In addition, there are other key variables that need to be factored in: (a) type of model (chemoconvulsant or SE models that recapitulate human acquired epilepsy [e.g., temporal lobe epilepsy, TLE]) versus ex vivo slice preparations, primary cortical cultures; (b) timing of RS occurrence (“snapshot” of RS vs. continuous monitoring); (c) indirect (indices of oxidative stress) versus direct (real-time “capture” of ROS/RNS species) measurement of RS; and (d) method/technique of RS measurement (fluorescence probes/dyes vs. electron paramagnetic resonance [EPR]). Mitochondria have been proposed to play a major role in seizure-induced RS production. The electron transport chain within mitochondria contains redox units, some of which (in particular complex I and complex III) can “leak” electrons, generating superoxide, which then gets converted to hydrogen peroxide (Turrens, 2003). When there is a high metabolic demand, such as during seizures, there is an increase in ROS production, which has been proposed to be predominantly generated by mitochondria (Malinska et al., 2010). Mitochondrial ROS production requires functioning mitochondria with a hyperpolarized mitochondrial membrane potential preferably without ATP production (Adam-Vizi and Chinopoulos, 2006). Mitochondrial calcium accumulation, depolarization and failure will prevent mitochondrial ROS and consequently hydrogen peroxide production (Komary et al., 2008). Mitochondria may therefore contribute to ROS production during brief seizure activity but not during more prolonged seizure activity, which leads to depolarization of the mitochondrial membrane potential and mitochondrial failure (Kovac et al., 2012). Since ROS production has been shown to increase during prolonged seizures at a time, when neuronal mitochondria are “failing” (Williams et al., 2015; Kovac et al., 2014), other potential sources must be at play. Because of the difficulties in dissecting out these sources in in vivo models during prolonged seizure activity, acute in vitro models have been used. Such acute seizure models (e.g., in vitro [glioneuronal culture] low-magnesium model) have identified a calcium/mitochondria-independent, neuronal NADPH oxidase mediated seizure-induced ROS production during prolonged seizure-like activity. However, these models may not fully recapitulate the temporal and spatial activation of different sources of ROS across different cell types in a hyperexcitable circuit that occurs during the “development of epilepsy.” Moreover, accurate identification of ROS sources in epilepsy is further confounded by redox signaling and ensuing ROS-mediated cross-talk between various cellular compartments (Go et al., 2018). RS, particularly superoxide production, may vary during acute, latent, chronic phases of epileptogenesis and during ictal/interictal periods (Rowley and Patel, 2013). Thus although prolonged in vitro seizure-like activity generates ROS predominantly through mitochondria-independent mechanisms, there is considerable evidence that mitochondria are a key source in chronic epilepsy such as: (a) In the rat kainate model, just 16 h after SE, mitochondrial aconitase (and not cytosolic aconitase) is inactivated preceding hippocampal neuronal loss. (b) Biphasic (acute and chronic phases) inhibition of mitochondrial CI by ROS-mediated posttranslational modification (carbonylation). Interestingly, CI inhibition coincided with periods of high seizure activity in the rat kainate model (Ryan et al., 2012). (c) Chronic impairment of the mitochondrial redox status (measured by coenzyme A [CoA] reduced/oxidized [CoASH/CoASSG]) coinciding with increases in mitochondrial H₂O₂ was observed in the rat lithium-pilocarpine model (Waldbaum et al., 2010). Similar dysfunction of mitochondrial redox status was observed in the rat kainate model (Liang and Patel, 2006). (d) Transient lowering of pO₂ shortly after SE (~6 h) was observed in the kainate model. After ~16 h, pO₂ levels became normal and this coincided with increased ROS production (Liang et al., 2000; Liang and Patel, 2006). Inactivation of mitochondrial aconitase, a TCA cycle enzyme (containing a labile Fe motif susceptible to superoxide-mediated oxidative damage), may lead to the release of iron (Gardner, 1997; Gardner et al., 1995) that may lead to more ROS production (ROS-induced-ROS) via the Fenton’s reaction. Excessive ROS may posttranslationally modify specific amino acid side chains in protein complexes, causing their inactivation (e.g., CI inhibition). This may lead to mitochondrial bioenergetic failure, excess ROS accumulation, changes in mitochondrial thiol redox status, and oxidative damage (e.g., mitoDNA 8-OHdG formation; Dizdaroglu, 1991). Furthermore, transient ischemia-reperfusion events that occur during epilepsy development may lead to excess mitochondrial ROS production via the oxidation of succinate (a TCA cycle substrate) accumulated during ischemia (Chouchani et al., 2014). Other than mitochondria, there are other important sources, in particular NADPH oxidase, that have been shown to be the main contributors to ROS production during more prolonged seizure activity (Kovac et al., 2014; Shekh-Ahmad et al., 2019b). In a landmark study by Patel et al. (2005), the involvement of NADPH oxidase-mediated superoxide production (in the extracellular compartment) in rat and mice kainic-acid models was demonstrated. Interestingly, temporal activation of NADPH oxidase coincided with hippocampal microglial activation. Furthermore, extracellular superoxide dismutase (EC-SOD which scavenges extracellular superoxide) overexpressing mice treated with kainate showed decreased hippocampal neuronal loss compared to EC-SOD-deficient mice treated with kainate.

Microglia are resident macrophages of the central nervous system (CNS) (Illes et al., 2020) that are critical for surveillance, mounting inflammatory responses, maintaining the spatial organization of neuronal and non-neuronal cell types, phagocytosis/removal of debris, and synaptic pruning (Crapser et al., 2021). Among the CNS cell types, microglia are one of the major producers of ROS/RNS and inflammatory mediators. Microglial activation and the subsequent release of ROS/RNS and pro-inflammatory mediators has been observed in experimental animal models and human epileptic brain tissue (Crapser et al., 2021; Crespel et al., 2002; Ravizza et al., 2008; Dube et al., 2010; Morin-Brureau et al., 2018). Microglial ROS/RNS production occurs predominantly via NOX2 and NOX4 (Simpson and Oliver, 2020). Genetic ablation of certain NOX2 subunits or inhibition of NOX2’s enzymatic activity by diphenyleneiodonium (DPI) attenuated microglial activation and the release of multiple proconvulsive cytokines, and decreased susceptibility to pentylenetetrazol (PTZ)-induced seizures in mice (Huang et al., 2018). Microglial ROS/RNS production following acute or recurrent seizures can cause oxidative stress (often in other CNS cell types), potentially alter/degrade components in the extracellular matrix (ECM) and cause neuronal damage. A study by Pauletti et al. (2019) reported a significant decrease in GSH/GSSG ratio and glutathionylated proteins in the hippocampi of electrical SE-induced rats at 4 and 14 days post SE. This was reversed in SE-exposed rats by treatment with antioxidants such as N-acetyl cysteine (NAC) or sulforaphane (SFN) or both. Interestingly, certain biomarkers of oxidative stress (like inducible nitric oxide [iNOS], the cysteine transporter [xCT], the transcriptional nuclear factor erythroid-derived 2-like 2 [Nrf2]) were significantly increased in neurons and astrocytes but not in microglia. Additionally, upregulation of these markers was also observed in neurons and astrocytes from resected and autoptic hippocampal tissue obtained from human patients with chronic epilepsy. Another critical aspect to consider is the GSH redox tone of activated microglia which can regulate inflammatory cytokine production. A study by McElroy et al. (2017a) showed that the improvement of the GSH redox tone by a novel posttranslational mechanism attenuated bacterial lipopolysaccharide (LPS)-induced pro-inflammatory cytokine production from murine microglial cells. Additionally, scavenging of ROS/RNS by a SOD mimetic significantly attenuated SE-mediated microglial activation (assessed by staining for ionized calcium binding adaptor molecule 1, Iba-1) and pro-inflammatory cytokine production in hippocampi of rats treated with pilocarpine (McElroy et al., 2017a). This strongly suggests that the redox tone of microglia is critical for regulating neuroinflammatory responses which can subsequently impact neuronal excitability and seizure generation.

NADPH oxidases are membrane-bound enzymes that catalyze the production of superoxide from NADPH and oxygen. They play a physiological role in generating ROS, necessary for CNS development and cellular signaling. However, N-methyl-D-aspartate (NMDA) receptor activation results in excessive ROS production by NOX, leading to neuronal death (Kovac et al., 2014; Williams et al., 2015). Of the various NOX isoforms, it is likely that NOX2, which can be activated by NMDA receptor activation (Brennan et al., 2009; Girouard et al., 2009), is the isoform that plays a prominent role in seizure-induced neuronal death. In a mouse model of TBI (controlled cortical impact model), the temporal (biphasic) activation of NADPH oxidase with a concomitant increase in superoxide in both cortical and hippocampal regions was reported. One hour after TBI, neuronal NOX2 activity was significantly elevated, whereas at 24–96 h post TBI, microglial NOX2 was elevated. Pre or post treatment with apocynin (inhibitor of NADPH oxidase assembly) markedly inhibited microglial activation, oxidative damage, and conferred neuroprotection in cortical and hippocampal brain regions (Zhang et al., 2012). This highlights the role of ROS in epilepsy of cortical origin. Other examples in which ROS have been studied in epilepsies of cortical origin include the ferrous/ferric chloride model of recurrent seizures and a SOD2 knockout model of spontaneous seizures. Injection of ferrous or ferric chloride into rat sensorimotor cortex resulted in chronic recurrent focal paroxysmal electroencephalographic discharges as well as behavioral convulsions and electrical seizures. Also, at the site of the epileptic foci, hypertrophied astrocytes, iron-filled macrophages and fibroblasts, and neuronal loss (next to injection site) were observed. Based on these observations, this study suggested that metallic ions (especially iron) found in whole blood could propagate recurrent, focal epileptiform discharges in posttraumatic epilepsy (Willmore et al., 1978). Later, a study by Mori et al. (1990) highlighted the involvement of superoxide and hydroxyl radical (after ferric chloride injection into rat cortex) in causing neuronal lipid peroxidation and the formation of guanidine compounds (Hiramatsu, 2003), both of which can propagate seizures. The formation of the highly reactive hydroxyl radical could be attributed to the Fenton’s reaction involving hydrogen peroxide (formed from super oxide dismutation) and iron. Treatment of rats with hydroxyl radical scavengers like epigallocatechin (EGC) or the phosphate diester of vitamins E and C (EPC) significantly attenuated the ferric-chloride mediated formation of malondialdehyde and epileptiform discharges (Mori et al., 1990). The deletion of SOD2 in excitatory principal neurons in mice forebrain (cortex and hippocampus) resulted in a severe epileptic phenotype predominantly arising from the retrosplenial, motor, and somatosensory regions in the cortex that corresponded with necrotic neuronal death. Deletion of mitochondrial SOD that enzymatically detoxifies superoxide resulted in oxidative stress evidenced by mitochondrial aconitase inactivation, increase in 2-hydroxyethidium (2-OHDE, the gold-standard method for detecting superoxide), and Nrf2 upregulation in the cortex of 2-month-old mice. Another deleterious consequence of neuronal SOD2 deletion was the upregulation of astrocytic glial fibrillary acidic protein (GFAP) observed in SOD2 knockout mice, which is reminiscent of a cell-nonautonomous astrocytic response. Taken together, this study critically highlights the role of neuronal mitochondrial superoxide in mediating a unique pattern of cortical neurodegeneration, cell nonautonomous astrocytic response, and a severe epileptic phenotype (score of 4.5 on the Racine scale coupled with significant impairments in locomotion and behavior; Fulton et al., 2021).

Although NOX is likely to be the dominant source of seizure-induced ROS, there are several other potential ROS sources, including xanthine oxidase, monoaminoxidase, cyclooxygenase, and lipoxygenase (Kovac et al., 2014; Baran et al., 1994; Ueda et al., 1997). During very prolonged seizure activity, a situation of high metabolic demand, ATP depletion results in increased adenine and, consequently, hypoxanthine and xanthine production; these are substrates for xanthine oxidase, the activity of which generates reactive oxygen species.

The precise sequence of activation of different cellular sources of ROS/RNS in epilepsy is yet to be delineated and remains controversial. With data stemming from a variety of in vitro, in vivo, and ex vivo seizure models and human patients with epilepsy, it is quite evident that there can be several sources of RS production which can be regulated by metabolic alterations, redox signaling circuits, external signals such as inflammatory mediators, and intracellular signal transduction pathways.

Redox-Mediated Cellular Pathway Disruption in Epilepsy

Redox Regulation of Nrf2 in Epilepsy

Nrf2 is a key, redox-sensitive transcription factor that responds to oxidative/electrophilic stress by orchestrating the transcription of genes encoding antioxidant/phase II detoxification enzymes, anti-inflammatory mediators, signaling proteins and genes involved in the regulation of calcium homeostasis, and mitochondrial biogenesis, thereby mounting a protective response to restore cellular homeostasis. Nrf2 is ubiquitously expressed at varying levels in different tissues and belongs to the cap ‘n’ collar basic region-leucine zipper (CNC-bZip) family of transcription factors (Ryoo and Kwak, 2018). Under unstressed/physiological conditions, Nrf2 is localized within the cytosol, where it is tethered to two molecules of its negative regulator protein, Kelch-like ECH associated protein 1 (Keap1). Nrf2 is short-lived in the cytoplasm as it is continuously targeted for ubiquitination and proteasomal degradation by Keap1, a substrate adaptor protein for Cullin3-based Cullin-RING E3 ubiquitin ligase (CRL) (Cullinan et al., 2004; Sekhar et al., 2002). An increase in oxidative/electrophilic stress inactivates Keap1, allowing for nuclear translocation of Nrf2 where it forms a heterodimer with small masculoaponeurotic fibrosarcoma (sMaf) proteins and binds to antioxidant (ARE 5′-TGACXXXGC-3′) or electrophile response elements (EpREs) in the promoters of target genes. Nrf2 can be activated by different mechanisms, but here we will focus on how RS can activate Nrf2 through direct interactions (reversible, covalent binding) with reactive cysteine residues in Keap1. Keap1 is a cysteine-rich protein containing 27 cysteines with different degrees of reactivity. Importantly, residues C151 and C288 are “discrete” sensors of specific RS and inducers which are exogenous small molecules. Most notably, the C151 residue senses sulforaphane (SFN), dimethyl fumarate (DMF), and nitric oxide; and the C288 residue responds to prostaglandin A2 and 4-hydroxynonenal (4-HNE]) (Zhang and Hannink, 2003; Dinkova-Kostova et al., 2017; Wakabayashi et al., 2004; McMahon et al., 2010; Takaya et al., 2012).

In the brain, Nrf2 is widely expressed and is critical for antioxidant response and regulation of neuroinflammation. In animal models of stroke and TBI, Nrf2-deficient mice exhibited extensive cortical damage, larger infarct size, and exacerbated immune responses when compared to Nrf2-expressing mice (Shih et al., 2005; Shah et al., 2007; Jin et al., 2009). A battery of cytoprotective genes regulated by Nrf2 include the enzymes involved in production, utilization, and regeneration of GSH (glutamate-cysteine ligase catalytic and modifier subunits: gclc, gclm; cystine/glutamate antiporter: xCT), thioredoxin (Thioredoxin: Txn; Thioredoxin reductase I: Txnrd1), peroxiredoxin 3 (Prx3), NADPH regeneration (Glucose-6-phosphate dehydrogenase: G6pd; Isocitrate dehydrogenase: Idh1), heme breakdown (hemeoxygenase 1: HO-1), and xenobiotic detoxification (NADPH quinone dehydrogenase: NQO1). This highlights how the Nrf2 pathway controls two intricately interconnected processes: redox signaling and metabolism/energy producing pathways (Tonelli et al., 2018). In epilepsy, a complex disorder characterized by metabolic/bioenergetic alterations, a disrupted redox status, and neuroinflammation, understanding the role of the Nrf2 pathway is critical and targeting it may potentially have “disease-modifying” effects (Patel, 2018). Interestingly, patients deficient in G6pd or TXNRD1 exhibited seizures, and patient fibroblasts were less resistant to oxidant challenge (Merdin et al., 2014; Westring and Pisciotta, 1966; Kudin et al., 2017). Furthermore, chemoconvulsant (kainate or lithium-pilocarpine) treated rats showed significant dysregulation of tissue and compartment-specific GSH/GSSG redox status in the hippocampus and neocortex that persisted throughout the latent and chronic phases of epileptogenesis (Ryan et al., 2014; Waldbaum et al., 2010). Also, impairment of the GSH system was observed in the parietooccipital region of both brain hemispheres in patients with epilepsy (Mueller et al., 2001). The tripeptide glutathione is the most abundant antioxidant thiol synthesized in the cytosol by a two-step ATP dependent process. The downstream targets of Nrf2 (gclc and gclm), although expressed separately, associate in the cytosol to form the heterodimer glutamate-cysteine ligase (GCL), the rate-limiting enzyme in GSH biosynthesis (Lee et al., 2006; Franklin et al., 2009). The GSH/GSSG redox couple are a versatile and indispensable antioxidant system especially in the brain (Aoyama, 2021) for the following reasons: (1) thiol-disulfide exchange reactions especially under oxidative stress (e.g., reversible protein S-glutathionylation); and (2) astrocyte-neuronal “GSH shuttle” to replenish the neuronal GSH pool and protect against neurotoxicity. Additionally, in the tripartite synapse, increased neuronal firing activates astrocytic Nrf2, thereby leveraging antioxidant/cytoprotective effects (Habas et al., 2013; Sagara et al., 1993; Dringen, 2000). (3) Glutathione/Glutaredoxin antioxidant system acting in concert with Thioredoxin/Peroxiredoxin systems detoxify excess H₂O₂ in mitochondria (Ren et al., 2017), regulate ATP production, apoptosis (Yin et al., 2012), and mitochondrial dynamics (trafficking to axonal segments, fusion and number) (Smith et al., 2019). Recently, Cvetko et al. (2020) showed that disruption of mitochondrial thiol status (not just superoxide alone) activates cytosolic Nrf2, via a Keap-1 dependent mechanism that involves specific cysteine residues (C151, C226/C613 sensors). (4) Glutathione can act as a neuromodulator and a reservoir for glutamate (Sedlak et al., 2019). (5) X_c–/glutathione/glutathione peroxidase 4 (Gpx4) axis controls ferroptosis (Conrad and Friedmann Angeli, 2015) and is essential for protecting the brain from iron/heme-induced excess lipid hydroperoxide accumulation (Chen et al., 2020). See Figure 31–1 for more details.

Figure 31–1.

Sources and role of reactive species (RS) in epilepsy.

Studies from acquired and genetic epilepsy models have reported temporal activation of Nrf2. In the mouse pilocarpine model, Nrf2 activation along with increased expression levels of downstream targets HO-1 and NQO-1 in the hippocampus peaked at about 3 days after SE and then declined. In this model, animals overexpressing Nrf2 (using adeno-associated virus vector, AAV) had fewer seizures and decreased microglial activation (Mazzuferi et al., 2013). In the kainate model, Nrf2 activation was highest 3–7 days after SE. Nrf2-deficient mice treated with kainate were more susceptible to seizures, had greater neuronal injury/loss, and increased microglial activation (Kraft et al., 2006). In a genetic model of epilepsy where SOD2 was selectively deleted in mice forebrain excitatory principal neurons, Nrf2 gene expression (~1.87-fold change) and protein levels in the nucleus were significantly increased in 2-month-old mice. Interestingly, at this time point, mitochondrial NADPH oxidase 4 (Nox4) was upregulated, suggesting an intricate interplay between mitochondrial redox signaling and cytosolic Nrf2 activation (Fulton et al., 2021). In human TLE patients, a 2-fold increase in Nrf2 mRNA was observed in surgically resected hippocampal tissue (Mazzuferi et al., 2013). These studies accentuate the neuroprotective role of Nrf2 activation and its therapeutic potential. Current therapeutic strategies focus on increasing Nrf2 transcriptional activation using dietary therapies (ketogenic diet [KD]), small-molecule/synthetic activators (dimethyl fumarate [DMF], RTA 408)), antioxidants (NAC), plant-derived compounds (sulforaphane, curcumin), and certain long noncoding RNAs (LncRNAs). KD (high fat and low protein/carbohydrate diet), the earliest nonpharmacological dietary intervention significantly reduced seizure burden in >60% pediatric patients with intractable childhood epilepsy, although the mechanism of action was largely unknown (Misiewicz Runyon and So, 2012; Hartman and Vining, 2007). The KD is known to induce nutritional ketosis, which may induce mild oxidative stress and trigger a mitohormetic response which can be defined as the induction of a reduced amount of mitochondrial stress that can ultimately lead to an increment in vitality and health of the cell/tissue/organism (Miller et al., 2018; Barcena et al., 2018). In a study by Jarrett (2008b), KD-fed rats showed an increase in de novo GSH synthesis evidenced by an increase in GCL enzyme activity. Furthermore, these rats showed an increase in hippocampal mitochondrial GSH and GSH/GSSG ratio. Interestingly, the study by Milder et al. (2010) further showed that the KD activates the Nrf2 pathway through acute induction of mild oxidative (mitochondrial H₂O₂) and electrophilic stress (4-HNE). Sulforaphane pre-treatment had anticonvulsant effects in three murine acute seizure models (6Hz, fluorothyl, and pilocarpine models) and improved respiration and ATP production in hippocampal mitochondria (Carrasco-Pozo et al., 2015). Another phytochemical curcumin increased latency to myoclonic seizures and exhibited a dose-dependent antiseizure effect in the PTZ-induced kindling model in rats. Additionally, curcumin treatment decreased oxidative stress and reversed cognitive impairment in this model (Mehla et al., 2010). In the same model, Nrf2 activator DMF conferred neuroprotection to hippocampal neurons by increasing GSH levels and decreasing lipid peroxidation and pro-inflammatory cytokine levels (Singh et al., 2018, 2019). Chronic treatment with the antioxidant NAC exhibited dose-dependent anticonvulsant effects in the mouse PTZ model (Zaeri and Emamghoreishi, 2015). Interestingly, a combination therapy of NAC and sulforaphane administered during epileptogenesis delayed the onset of epilepsy, reduced frequency of spontaneous seizures, protected hippocampal neurons, and reversed cognitive deficits in a rat model of electrical SE (Pauletti et al., 2019). Another promising approach to activate Nrf2 involves Keap-1 inhibition using RTA-408. Acute treatment with RTA-408 after SE increased GSH and ATP levels and decreased spontaneous seizures in the rat kainate model (Shekh-Ahmad et al., 2018). By targeting (blocking) an important source of ROS production (NOX) and activating the Nrf2 pathway parallelly, Shekh-Ahmad et al. (2019b) achieved greater seizure control and modified the severity of epilepsy in kainic acid–treated rats. Since Nrf2 can be regulated posttranscriptionally, Geng et al. (2018) reported the potential of a specific LncRNA UCA1 (urothelial carcinoma associated 1, UCA1) in suppressing microRNA (miR-495)-mediated inhibition of Nrf2 in the rat pilocarpine model. UCA1 and Nrf2 were downregulated and miR-495 was upregulated in the hippocampus of these rats. Overexpression of UCA1 (using pcDNA- UCA1 vector construct) upregulated Nrf2, prevented hippocampal neuronal apoptosis, and decreased seizure frequency.

Despite the therapeutic potential of these strategies, there are still some caveats associated with them. Most of them rely on transcriptional Nrf2 upregulation: Nrf2 inducibility (by compounds like sulforaphane) decreases over time due to increased expression of Nrf2 transcriptional repressors like BTB domain and CNC homolog 1 (Bach1) and cellular myelocytomatosis oncogene (c-Myc) (Pomatto et al., 2018; Zhou et al., 2018; Ungvari et al., 2011). Hence, there is a need to develop/identify compounds that do not solely rely on Nrf2 transcriptional upregulation. McElroy et al. (2017b) reported the use of an FDA-approved dithiol compound, Dimercaprol (DMP), to increase GSH levels by a novel (Nrf2-independent) mechanism: posttranslational activation of the GSH biosynthetic enzyme GCL in a variety of CNS cell types. DMP increased GCL holoenzyme formation/activity and intracellular GSH levels. This increase in GSH dampened bacterial LPS-induced release of proinflammatory mediators and protected against paraquat (PQ)-induced neuronal injury in vitro. Whether DMP could have antiseizure and/or antiepileptogenic effects is currently being investigated in our lab.

Biomarkers

Given the occurrence of oxidative stress in preclinical models and human epilepsies, redox-based biomarkers can have many potential uses, including their ability to predict the development of epilepsy following a brain injury and/or genetic predisposition, disease progression, or pharmacoresistance. Additionally, they can be used to determine target engagement for (pre)clinical trials of antioxidant therapies. Several peripheral and brain biomarkers that reflect the redox status have been identified in human epilepsies as well as preclinical models. Arachidonic acid–derived F2-isoprostanes, a gold standard oxidative stress biomarker (Roberts and Morrow, 2000), are increased in the brains of animals following seizures (Patel et al., 2008). Thiol redox couples such as GSH/GSSG and cysteine (Cys) and its disulfide (Cyss) have been used to report redox status of tissue and plasma in a variety of preclinical models and human disease states (Mannery et al., 2010). In preclinical models of acquired epilepsy, brain GSH/GSSG and plasma Cys/Cyss ratios have been shown to be significantly decreased in a manner sensitive to antioxidant therapy, suggesting their utility as useful biomarkers for redox status (Liang and Patel, 2016; Pauletti et al., 2019). A proinflammatory cytokine such as High-mobility group box-1 (HMGB1) is one of the first mediators released due to damage or inflammation, particularly following epileptogenic injuries, and chronic seizures (Maroso et al., 2010). The activity of HMGB1 is known to be regulated by posttranslational oxidative modifications of two cysteine residues that result in pro-inflammatory effects through activation of redox-sensitive NF-kB and toll-like receptor 4 (TLR4) (Frank et al., 2016; Schiraldi et al., 2012; Zurolo et al., 2011). In fact, plasma and brain HMGB1 levels are correlated with disease progression in preclinical models of epilepsy and sensitive to antioxidant treatment (Pauletti et al., 2019). The deleterious and modulatory roles played by inflammatory and redox biomarkers suggest that they may be important in the pathogenesis of epilepsy occurring as a result of brain injury. Elevated miRNA levels such as miRNA-23a, miRNA-34, miRNA-132, miRNA-146, and miRNA-4521 have been observed in epilepsy and of note miRNA-134 may serve as a peripheral biomarker (Henshall et al., 2016; Wang et al., 2017). Several miRNAs are responsive to redox status alterations and may be useful as peripheral biomarkers of oxidative stress (see for more details, (Kobylarek et al., 2019).

Therapeutic Strategies

Based on the current knowledge of ROS involvement in the epilepsies, redox signaling pathways and oxidative stress are potentially viable therapeutic targets to attenuate seizures, disease progression, and comorbidities of epilepsy. Please see Table 31–1. However, much of the accumulated knowledge has been limited to preclinical studies. While the bulk or stoichiometric oxidant scavengers such as vitamin E have been shown to attenuate oxidative stress and seizures in some animal models and human studies (Barros et al., 2007; Levy et al., 1990, 1992; Mehvari et al., 2016; Ogunmekan and Hwang, 1989; Xavier et al., 2007), this remains controversial. In many such studies there may be problems with penetration of scavengers across the blood–brain barrier and “exhaustion” of their oxidant scavenging potential, as many will not be regenerated through reduction enzymes; this contrasts to glutathione disulfide (the oxidized form of glutathione), which is reduced to glutathione by glutathione reductase, leading to a regeneration of its oxidant scavenging potential. Boosting the endogenous antioxidant signaling pathways as outlined above with compounds such as NAC and sulforaphane can elevate glutathione levels and attenuate disease progression and cognitive deficits (Pauletti et al., 2019). NAC treatment, in particular, has been shown to exert beneficial effects in patients suffering from different types of progressive myoclonic epilepsies (EPM) characterized by myoclonic jerks, convulsive seizures, and a progressive decline in cognitive function and motor skills. Unverricht–Lundborg disease (ULD or EPM1) is an autosomal recessive neurodegenerative disorder characterized by myoclonus and tonic-clonic seizures, dysarthria, cognitive dysfunction, and ataxia and is often refractory to medications. Moreover, the involvement of oxidative stress and neuroinflammation in the pathogenesis of ULD has been reported by previous studies (Crespel et al., 2016). ULD patients (young, 4–6 years; old, 40 years) treated with NAC (4–6 g/day) showed a remarkable improvement in walking, daily functioning, and a reduction in myoclonus and generalized seizures (Deepmala et al., 2015; Hurd et al., 1996; Ben-Menachem et al., 2000). There is also evidence that glutathione levels are increased by the KD (Jarrett et al., 2008b; Milder et al., 2010). Levels of endogenous antioxidant defenses can be increased by the activation of specific transcription factors. Nrf2 is a transcription factor that promotes the expression of antioxidant proteins but is kept in check by Keap1. Keap1 inhibition protects against reactive oxygen species and has also been shown to prevent epileptogenesis and, in combination with NADPH oxidase inhibitors, can modify established epilepsy (Shekh-Ahmad et al., 2018). Peroxisome proliferator-activated receptor gamma (PPAR-gamma) also promotes the expression of catalase and glutathione peroxidase, and its activation may contribute to the antioxidant effects of the KD. Direct scavengers of ROS such as catalytic antioxidants (that act enzymatically and target free radicals) delivered for short periods of time following SE can confer neuroprotection and inhibit seizure-induced cognitive dysfunction (Liang et al., 2012; Pearson et al., 2015). Finally, scavengers of lipid peroxidation by-products that ultimately cause oxidative damage such as the gamma-ketoaldehyde scavenger salicylamine also show neuroprotection and inhibit cognitive dysfunction rather than modify epilepsy in SE models (Pearson et al., 2017). Therefore, following severe SE or brain trauma, these types of compounds may serve as adjunctive therapies to current antiseizure drugs. Inhibition of sources of ROS such as NOX inhibitors have been shown to attenuate seizure-induced cell death (Kim et al., 2013; Kovac et al., 2014). Another mechanism to target seizure-induced ROS production is breaking the cycle between oxidative stress and neuroinflammation. Catalytic antioxidant therapy and specific inhibition of inflammatory pathways/receptors such as prostaglandin E2 receptor (EP2) can achieve this (Fu et al., 2015; McElroy et al., 2017a). However, while targeting ROS in epilepsy or any neurological disease for that matter, treatment with antioxidants should carefully take into account the type of ROS to be targeted, timing of treatment with respect to the oxidative stress, physiological roles of the ROS in normal cell signaling, and brain exposure.

Table 31–1

Therapeutic Interventions and Their Molecular Targets in Epilepsy.

Critical consideration should be given to the timing of intervention to achieve maximum treatment efficacy (e.g., adequate control of seizures and comorbidities) and possibly disease modification with limited adverse effects. It is important to be aware of the differences in treatment initiation timings between experimental animal models and human patients. In human patients, intervention begins after the onset of the first spontaneous seizure or after the detection of the first electrographic spike or after the appearance of the first prodromic symptom. Factors that can confound the timing of intervention include the variability in epilepsy development across the patient population, risk versus beneficial effects of treatment, and heterogeneity in response to treatment owing to differences in seizure origin (e.g., TBI versus tuberous sclerosis complex). A more reliable approach that could guide timing of intervention is the identification of potential biomarkers that are accessible, less invasive, quantifiable, specific, and reflective of ongoing disease pathogenesis (Engel et al., 2013). The recent identification of blood-based redox and inflammatory biomarkers along with peripheral biomarkers of oxidative stress could pave the way to a more reliable prediction of treatment timing and could potentially guide the development of novel therapeutics in the future.

Conclusions

Since the last edition of this volume, there has been a rapid growth in our understanding of the role of oxidative stress and mitochondrial dysfunction in epilepsy. Oxidant damage to cellular and in many cases mitochondrial macromolecules, that is, lipids, proteins, and DNA, has been observed following seizures. Several sources of ROS relevant to epileptogenic injury that can be therapeutically targeted have been identified: most prominently, the NOX enzymes and mitochondria. Preclinical studies have demonstrated an altered thiol redox status in the brain which is amenable to therapeutic targeting by upregulation or modulation of the Nrf2 pathway. Small-molecule antioxidants have shown promise as neuroprotective agents in models of epilepsy. Several redox-active biomarkers have been developed and tested in preclinical models of epilepsy. In addition to oxidative distress, oxidative eustress in epilepsy has emerged in the form of redox signaling mediated by posttranslational oxidative modifications. Future studies in the field will need to harness these advances to improve the lives of people living with epilepsy.

Acknowledgments

Disclosure Statement

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