Temporal and spatial increase of reactive nitrogen species in the kainate model of temporal lobe epilepsy

Abstract

Steady-state levels of reactive oxygen species (ROS) and oxidative damage to cellular macromolecules are increased in the rodent hippocampus during epileptogenesis. However, the role of reactive nitrogen species (RNS) in epileptogenesis remains to be explored. The goal of this study was to determine the spatial and temporal occurrence of RNS i.e. nitric oxide levels in a rat model of temporal lobe epilepsy (TLE). Rats were injected with a single high dose of kainate and monitored by video for behavioral seizures for 6 weeks to determine the onset and severity of chronic seizures. RNS and tissue/mitochondrial redox status (glutathione redox couple and coenzyme A:glutathione redox couple) were measured in the hippocampus at 8 hr, 24 hr, 48 hr, 1 wk, 3 wk and 6 wk following kainate to assess the level of reactive species in subcellular compartments. We observed a biphasic increase in RNS levels with a return to control values at the 48 hr time point. However, both tissue and mitochondrial redox status showed permanent and significant decreases during the entire time course of epilepsy development. 3 nitrotyrosine (3NT) protein adducts were found to gradually increase throughout epileptogenesis, conceivably as a result of the local environment under oxidative and nitrosative stress. Colocalization of 3NT immunostaining with neuron- or astrocyte-specific markers revealed neuron-specific localization of 3NT in hippocampal principal neurons. Persistent and concurrent glutathione oxidation and nitrosative stress occurs during epileptogenesis suggesting a favorable environment for posttranslational modifications.

Mitochondrial respiration deficits driven by reactive oxygen species in experimental temporal lobe epilepsy

“…In studies of patients with TLE, the role of mitochondria has been suggested by inhibition of complex I of the electron transport chain (ETC) and reduction in N-acetyl aspartate levels in the hippocampus (Kunz et al, 2000; Vielhaber et al, 2008). Recent work from our group has shown increases in production of mitochondrial ROS, reactive nitrogen species (RNS), oxidative damage to oxidant-sensitive mitochondrial proteins (aconitase and complex I) and glutathione depletion in animal models of TLE (Jarrett et al, 2008; Waldbaum et al, 2010; Ryan et al, 2012, 2013). Increased mitochondrial ROS and oxidative damage to ETC enzymes suggests that mitochondrial respiration may be impaired in TLE.…”

TLR1 expression in mouse brain was increased in a KA-induced seizure model

“…Temporal lobe epilepsy (TLE), the most common form of acquired epilepsy, is characterized by recurrent seizures that originate from the hippocampus, amygdala or entorhinal cortex (EC) and is initiated by an injury, such as head trauma, hypoxia, complex febrile seizures or status epilepticus (SE) [1,2]. Epilepsy involves several processes, such as neuronal loss, gliosis, gene regulation, axonal sprouting, inflammation and neurogenesis [1].…”

“…Epilepsy involves several processes, such as neuronal loss, gliosis, gene regulation, axonal sprouting, inflammation and neurogenesis [1]. However, the molecular mechanism of epileptogenesis is not clearly understood.…”

Ultrastructural changes to rat hippocampus in pentylenetetrazol- and kainic acid-induced status epilepticus: A study using electron microscopy

“…In many cases it closely mimics the clinical manifestations of mesial temporal lobe epilepsy in humans, the most common type of epilepsy in adults (Sharma et A c c e p t e d M a n u s c r i p t proposed that only severe neuronal damage cannot explain the consequential epileptic activity, so, subcellular structural, molecular and nano modifications, facilitating abnormal firing and seizure episodes should be present (Ryan et al 2014, Otahal et al 2014). Different approaches could be used to reveal such fine modifications.…”