Status epilepticus results in persistent overproduction of reactive oxygen species, inhibition of which is neuroprotective

Williams, Sarah; Hamil, N.; Abramov, Andrey Y.; Walker, Matthew C.; Kovač, Stjepana

doi:10.1016/j.neuroscience.2015.07.005

Cited by 53 publications

(40 citation statements)

References 16 publications

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“…Inhibition of NADPH oxidase can neuroprotect in in vivo models of status epilepticus [82][83][84]. As previously described ROS and consequent peroxynitrite formation can contribute to cell death though lipid peroxidation, inactivation of enzymes, mPTP opening and DNA damage.…”

Section: Reactive Oxygen Speciesmentioning

confidence: 72%

Pathophysiology of status epilepticus

Walker¹

2018

Neuroscience Letters

109

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Status epilepticus (SE) is the maximal expression of epilepsy with a high morbidity and mortality. It occurs due to the failure of mechanisms that terminate seizures.Both human and animal data indicate that the longer a seizure lasts, the less likely it is to stop. Recent evidence suggests that there is a critical transition from an ictal to a post-ictal state, associated with a transition from a spatio-temporally desynchronized state to a highly synchronized state, respectively.As SE continues, it becomes progressively resistant to drugs, in particular benzodiazepines due partly to NMDA receptor-dependent internalization of GABA (A) receptors. Moreover, excessive calcium entry into neurons through excessive NMDA receptor activation results in activation of nitric oxide synthase, calpains, and NADPH oxidase. The latter enzyme plays a critical part in the generation of seizuredependent reactive oxygen species. Calcium also accumulates in mitochondria resulting in mitochondrial failure (decreased ATP production), and opening of the mitochondrial permeability transition pore. Together these changes result in status epilepticus-dependent neuronal death via several pathways. Multiple downstream mechanisms including inflammation, break down of the blood-brain barrier, and changes in gene expression can contribute to later pathological processes including chronic epilepsy and cognitive decline.

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Section: Reactive Oxygen Speciesmentioning

confidence: 72%

Pathophysiology of status epilepticus

Walker¹

2018

Neuroscience Letters

109

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“…There are two potential sources of ROS that are produced from SE which could be contributing to the inflammatory responses – mitochondrial ROS and extracellular ROS from activation of NADPH oxidase (Nox2) (Liang et al, 2000; Patel et al, 2005; Williams et al, 2015). Mitochondria have been shown to be a source of seizure-induced ROS formation based on evidence that mitochondrial, but not whole tissue, cytosolic or nuclear targets are disproportionately oxidized following SE (Liang et al, 2000; Jarrett et al, 2008; Liang et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…The importance of ROS and redox status in epilepsy comes from several lines of evidence. First, studies have demonstrated that prolonged seizure activity can cause an increase in superoxide (O 2 .− ) and hydrogen peroxide from both mitochondria and extracellular sources such as NADPH oxidases (Nox2), leading to oxidative damage to cellular macromolecules and ultimately neuronal damage (Liang et al, 2000; Liang and Patel, 2006; Patel et al, 2005; Williams et al, 2015). Secondly, oxidative stress and alterations to the glutathione redox status have been shown to occur throughout the course of epileptogenesis in experimental models of TLE (Rowley et al, 2015; Ryan et al, 2014; Waldbaum et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation

McElroy

Liang

Day

et al. 2017

Experimental Neurology

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Inflammation has been identified as an important mediator of seizures and epileptogenesis. Understanding the mechanisms underlying seizure-induced neuroinflammation could lead to the development of novel therapies for the epilepsies. Reactive oxygen species (ROS) are recognized as mediators of seizure-induced neuronal damage and are known to increase in models of epilepsies. ROS are also known to contribute to inflammation in several disease states. We hypothesized that ROS are key modulators of neuroinflammation i.e. pro-inflammatory cytokine production and microglial activation in acquired epilepsy. The role of ROS in modulating seizure-induced neuroinflammation was investigated in the pilocarpine model of temporal lobe epilepsy (TLE). Pilocarpine-induced status epilepticus (SE) resulted in a time-dependent increase in pro-inflammatory cytokine production in the hippocampus and piriform cortex. Scavenging ROS with a small-molecule catalytic antioxidant decreased SE-induced pro-inflammatory cytokine production and microglial activation, suggesting that ROS contribute to SE-induced neuroinflammation. Scavenging ROS also attenuated phosphorylation of ribosomal protein S6, the downstream target of the mammalian target of rapamycin (mTOR) pathway indicating that this pathway might provide one mechanistic link between SE-induced ROS production and inflammation. Together, these results demonstrate that ROS contribute to SE-induced cytokine production and antioxidant treatment may offer a novel approach to control neuroinflammation in epilepsy.

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“…Recent evidence shows that oxidative stress plays a key role in SE [26,27]. Under normal circumstances, brain tissue continuously produces ROS, such as NO, hydrogen peroxide, and superoxide.…”

Section: Discussionmentioning

confidence: 99%

“…When ROS increase rapidly, the balance is disturbed, and oxidative damage occured [28]. In animal models, SE can lead to increased oxidative stress in the brain [26]. Oxygen free radicals are produced by the abnormal metabolism in the brain as a consequence of SE, and further aggravate brain injury.…”

Section: Discussionmentioning

confidence: 99%

Thymoquinone attenuates brain injury via an antioxidative pathway in a status epilepticus rat model

Shao

Huang

et al. 2017

Translational Neuroscience

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Status epilepticus (SE) is a common, lifethreatening neurologic disorder characterized by acute, prolonged epileptic seizures. The incidence rate of SE is about 0.05 to 0.1% in the general population and 1.1 to 14% in the epileptic population. SE has a poor prognosis because seizures that cannot be terminated quickly result in irreversible brain injury. It is known that multiple factors are involved in the pathogenesis of brain injury induced by SE, one of which is oxidative stress [1][2]. The generation of excess free radicals and increase in lipid peroxidation that occur during SE damage brain tissue, therefore, antioxidants might be effective for treatment of SE [3][4][5].Thymoquinone (TQ), a bioactive monomer derived from black seed (Nigella sativa) oil, has significant antioxidant effects [6][7][8]. It has been shown to suppress oxidative stress and attenuate seizure activity and lower hippocampal neuronal loss in an epilepsy model and in children with refractory seizures [9][10][11]. We speculate that TQ alleviates the brain injury of SE by modulating oxidative stress. It is thought that the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a key defensive role against oxidative stress in epilepsy [12][13][14]. This study evaluated the protective effects of TQ on brain injury in a status epilepticus rat model, and the underlying mechanism related to antioxidative pathway using biochemistry techniques and behavioral and electrophysiological tests. Materials and methods THYMOQUINONE ATTENUATES BRAIN INJURY VIA AN ANTI-OXIDATIVE PATHWAY IN A STATUS EPILEPTICUS RAT MODEL AbstractAim: Status epilepticus (SE) results in the generation of reactive oxygen species (ROS), which contribute to seizure-induced brain injury. It is well known that oxidative stress plays a pivotal role in status epilepticus (SE). Thymoquinone (TQ) is a bioactive monomer extracted from black cumin (Nigella sativa) seed oil that has anti-inflammatory, anti-cancer, and antioxidant activity in various diseases. This study evaluated the protective effects of TQ on brain injury in a lithium-pilocarpine rat model of SE and investigated the underlying mechanism related to antioxidative pathway. Methods: Electroencephalogram and Racine scale were used to value seizure severity. Passive-avoidance test was used to determine learning and memory function. Moreover, anti-oxidative activity of TQ was observed using Western blot and super oxide dismutase (SOD) activity assay. Results: Latency to SE increased in the TQ-pretreated group compared with rats in the model group, while the total power was significantly lower. Seizure severity measured on the Racine scale was significantly lower in the TQ group compared with the model group. Results of behavioral experiments suggest that TQ may also have a protective effect on learning and memory function. Investigation of the protective mechanism of TQ showed that TQ-pretreatment significantly increased the expression of Nrf2, HO-1 proteins and SOD in the hippocampus. Conclusion: these findings...

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Status epilepticus results in persistent overproduction of reactive oxygen species, inhibition of which is neuroprotective

Cited by 53 publications

References 16 publications

Pathophysiology of status epilepticus

Pathophysiology of status epilepticus

Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation

Thymoquinone attenuates brain injury via an antioxidative pathway in a status epilepticus rat model

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