Reactive oxygen species mediate cognitive deficits in experimental temporal lobe epilepsy

Abstract

Cognitive dysfunction is an important comorbidity of temporal lobe epilepsy (TLE). However, no targeted therapies are available and the mechanisms underlying cognitive impairment, specifically deficits in learning and memory associated with TLE remain unknown. Oxidative stress is known to occur in the pathogenesis of TLE but its functional role remains to be determined. Here, we demonstrate that oxidative stress and resultant processes contribute to cognitive decline associated with epileptogenesis. Using a synthetic catalytic antioxidant, we show that pharmacological removal of reactive oxygen species (ROS) prevents 1) oxidative stress, 2) deficits in mitochondrial oxygen consumption rates, 3) hippocampal neuronal loss and 4) cognitive dysfunction without altering the intensity of the initial status epilepticus (SE) or epilepsy development in a rat model of SE-induced TLE. Moreover, the effects of the catalytic antioxidant on cognition persisted beyond the treatment period suggestive of disease-modification. The data implicate oxidative stress as a novel mechanism by which cognitive dysfunction can arise during epileptogenesis and suggest a potential disease-modifying therapeutic approach to target it.

Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation

“…The increases in pro-inflammatory cytokines follows a similar pattern as the production of ROS, mitochondrial complex I inactivation, post-translational modifications and occurrence of mitochondrial respiration deficits in chemoconvulsant models of TLE (Jarrett et al, 2008; Pearson et al, 2015; Rowley et al, 2015; Ryan et al, 2012). It is also somewhat reminiscent of the time course of alterations in tissue redox status following kainic acid or pilocarpine-induced SE (Ryan et al, 2014; Waldbaum et al, 2010) suggesting a relationship between ROS production, redox state and inflammation.…”

“…, hydrogen peroxide, peroxynitrite and lipid peroxides. We have previously shown that 5mg/kg, s.c. injection of MnIIITDE-2-ImP5+ 60 min after pilocarpine SE did not interfere with SE (Pearson et al, 2015). Using this dosing paradigm, we first confirmed the ability of this compound to inhibit SE-induced oxidative stress by measuring the levels of the most abundant non-protein thiol glutathione (GSH) and its oxidized form GSSG.…”

“…Treatment with this compound after the onset of SE ameliorated inflammatory cytokine production as well as microgliosis in pilocarpine injected rats. Recent publication from our laboratory has demonstrated that Mn III TDE-2-ImP 5+ penetrates the BBB and attains effective concentrations in the brain, without interfering with pilocarpine-induced SE (Pearson et al, 2015). It is important to emphasize that MnIIITDE-2-ImP5 + does not directly interfere with SE when administered 60 after pilocarpine injection (Pearson et al, 2015), suggesting that its effects on inflammatory cytokine production was not due to its effect on ongoing SE.…”

“…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). Additionally, pharmacological scavenging of seizure-induced ROS inhibits neuronal death, improves mitochondrial function and cognitive function in chemoconvulsant models of TLE (Pearson et al, 2015; Rowley et al, 2015). Finally, we have recently demonstrated the occurrence of oxidative and nitrative stress in a mouse model of virus-induced TLE by Theiler’s murine encephalomyelitis virus (TMEV) infection, where seizures arise because of inflammation (Bhuyan et al, 2015).…”

Evaluation of antiepileptic effect of S-adenosyl methionine and its role in memory impairment in pentylenetetrazole-induced kindling model in rats

“…Recently, a French pharmacovigilance database study concluded that even newer antiepileptic drugs (AED) like topiramate, pregabalin, and levetiracetam have a negative impact on memory [6]. Oxidative stress is considered to play an important role in epileptogenesis and cognitive deficits [7].…”