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

Abstract

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 (3NT). 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 3NT 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.

Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation

“…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). Therefore, both inflammation and oxidative stress occur in various animal models of epilepsy.…”

Cannabidiol reduces seizures following CNS infection with Theiler's murine encephalomyelitis virus

“…Excessive inflammation, oxidative stress, and parenchymal damage may contribute to the development of acute seizures. [6][7][8]27 Mice deficient in TNFR1, TNFα, or IL-6 are much less susceptible to developing TMEV-induced acute seizures compared to wild-type mice. 5,27 Indeed, protein levels of several cytokines, chemokines, and oxidative stress markers are significantly increased in the hippocampus of TMEV-infected mice during the acute seizure period.…”

“…6 Hz psychomotor seizure test was conducted as described before 16 to determine the TPE of CBD. Since CBD does not dissolve in aqueous solvents, it was formulated as an oil-in-water emulsion using a mixture of 100% Ethanol, Kolliphor®, and 0.9% saline (1:1:18).…”

Rapamycin provides anti‑epileptogenic effect in a rat model of post‑traumatic epilepsy via deactivation of mTOR signaling pathway

“…Multiple potential mechanisms may contribute to the antiepileptogenic effects of rapamycin. First, hyperactivation of mTOR/P70S6K signaling promotes oligodendrocyte proliferation and myelination ( 25 ), which is essential to the axonal sprouting susceptible to the development of epilepsy ( 2 ). Therefore, antiepileptogenic effect was obtained via blocking the mTOR signaling and decreasing the expression of downstream p-P70S6K.…”

“…Post-traumatic epilepsy (PTE) is a common type of acquired epilepsies secondary to traumatic brain injury (TBI), accounting for approximately 10–25% of patients with moderate to severe injuries ( 1 ). After TBI, the brain carries out a series of pathological processes, including neuronal loss, gliosis, axonal sprouting, neurogenesis, inflammatory response, neurotransmitter release, and mitochondrial dysfunction, all of which have been connected to the epileptogenesis ( 2 , 3 ). Evidence indicate that the risk of PTE increases obviously 10 years after TBI and it usually develops refractory to medical management ( 4 ).…”