Reactive oxygen species in status epilepticus

Abstract

It has long been recognized that status epilepticus can cause considerable neuronal damage, and this has become one of its defining features. The mechanisms underlying this damage are less clear. Excessive activation of NMDA receptors results in large rises in internal calcium, which eventually lead to neuronal death. Between NMDA receptor activation and neuronal death are a number of intermediary steps, key among which is the generation of free radicals and reactive oxygen and nitrogen species. Although it has long been thought that mitochondria are the primary source for reactive oxygen species, more recent evidence has pointed to a prominent role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an enzyme localized in cell membranes. There is burgeoning in vivo and in vitro evidence that therapies that target the production or removal of reactive oxygen species are not only effective neuroprotectants following status epilepticus, but also potently antiepileptogenic. Moreover, combining therapies targeted at inhibiting NADPH oxidase and at increasing endogenous antioxidants seems to offer the greatest benefits.

Oxidative Stress and Neurodegeneration in Animal Models of Seizures and Epilepsy

“…ROS and nitric oxide can react to create reactive nitrogen species. Among them is peroxynitrite, particularly toxic for cells, which is created when nitric oxide, produced by nitric oxide synthase, reacts with superoxide [122]. There is strong evidence that peroxynitrite production rises in SE, suggesting that peroxynitrite production may be a primary cause of SE-associated cell death [122].…”

“…Among them is peroxynitrite, particularly toxic for cells, which is created when nitric oxide, produced by nitric oxide synthase, reacts with superoxide [122]. There is strong evidence that peroxynitrite production rises in SE, suggesting that peroxynitrite production may be a primary cause of SE-associated cell death [122]. Indeed, excessive peroxynitrite and hydrogen peroxide generation, as well as failure of protective systems such as glutathione depletion, have been considered important causes of neuronal death in many neurodegenerative diseases [123].…”

“…It has been suggested that brain mitochondrial complex III-dependent superoxide generation can lead to seizure-related ROS formation [124]. Prolonged seizure activity, such as that seen in SE, causes mitochondrial depolarization, mitochondrial malfunction, and energy failure; therefore, although mitochondria are a key generator of ROS during short seizures, their involvement in producing ROS declines as the seizure activity continues [122]. Using robust protocols for real-time in vitro and ex vivo monitoring of ROS production during hyperexcitability, it was established that mitochondria were not the main source of ROS during SE [4].…”

Peripheral and central effects of NADPH oxidase inhibitor, mitoapocynin, in a rat model of diisopropylfluorophosphate (DFP) toxicity

“…Oxygen free radicals are oxygen molecules with an unpaired electron. They are highly reactive, causing lipid peroxidation, protein degradation, and DNA damage in their attempt to “steal” electrons ( Lukaszewicz-Hussain, 2010 ; Walker, 2023 ). In the periphery, excess reactive oxygen species (ROS) increase proinflammatory cytokine production ( Chen et al, 2018 ).…”

“…Although mitochondria are traditionally considered the primary contributors to oxidative stress because of high ATP consumption during OP-induced SE ( Milatovic et al, 2006 ; Lukaszewicz-Hussain, 2010 ), emerging evidence suggests the NADPH oxidase (NOX) is also a significant primary producer of free radicals ( Walker, 2023 ). NOX activation creates a feed-forward mechanism of ROS generation in concurrence with the mitochondria ( Dikalov, 2011 ).…”