Oxidative stress in murine Theiler's virus-induced temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most common form of acquired epilepsy that can be caused by several inciting events including viral infections. However, one-third of TLE patients are pharmacoresistant to current antiepileptic drugs and therefore, there is an urgent need to develop antiepileptogenic therapies that prevent the development of the disease. Oxidative stress and redox alterations have recently been recognized as important etiological factors contributing to seizure-induced neuronal damage. The goal of this study was to determine if oxidative stress occurs in the TMEV (Theiler's murine encephalomyelitis virus) model of temporal lobe epilepsy (TLE). C57Bl/6 mice were injected with TMEV or with PBS intracortically and observed for acute seizures. At various time points after TMEV injection, hippocampi were analyzed for levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and 3-nitrotyrosine (3 NT). Mice infected with TMEV displayed behavioral seizures between days 3 and 7 days post-infection (dpi). The intensity of seizures increased over time with most of the seizures being a stage 4 or 5 on the Racine scale at 6 days p.i. Mice exhibiting at least one seizure during the observation period were utilized for the biochemical analyses. The levels of GSH were significantly depleted in TMEV infected mice at 3, 4 and 14 days p.i. with a concomitant increase in GSSH levels as well as an impairment of the redox status. Additionally, there was a substantial increase in 3 NT levels in TMEV infected mice at these time points. These redox changes correlated with the occurrence of acute seizures in this model. Interestingly, we did not see changes in any of the indices in the cerebellum of TMEV-infected mice at 3 dpi indicating that these alterations are localized to the hippocampus and perhaps other limbic regions. This is the first study to demonstrate the occurrence of oxidative stress in the TMEV model of infection-induced TLE. The redox alterations were observed at time points coinciding with the appearance of acute behavioral seizures suggesting that these changes might be a consequence of seizure activity. Our results support the hypothesis that redox changes correlate with seizure activity in acquired epilepsies, regardless of the inciting insults, and suggest oxidative stress as a potential therapeutic target for their treatment.