| Description |
Central nervous system (CNS) infection can induce epilepsy that is often refractory to established antiseizure drugs. The Theiler’s murine encephalomyelitis virus (TMEV)-induced mouse model of limbic epilepsy is an important model in which to study the mechanisms underlying epileptogenesis and to identify novel therapeutics. Previous studies have demonstrated the importance of inflammation, especially mediated by tumor necrosis factor-α (TNFα), in the development of TMEV-induced acute seizures. TNFα is known to modulate glutamate receptor trafficking via TNF receptor 1 (TNFR1) to cause increased excitatory synaptic transmission. Therefore, we hypothesized that an increase in hippocampal TNFα following TMEV infection might contribute to hyperexcitability and seizures by increasing excitatory postsynaptic strength through TNFR1. Furthermore, inflammation is known to contribute to oxidative stress that in turn can precipitate seizures. Therefore, we also investigated the occurrence of oxidative stress in TMEV-infected mice. We found a significant increase in the levels of oxidative stress markers and TNFα in the hippocampus, a brain region known to be involved in seizure generation, following TMEV infection. In addition, a significant increase in the protein expression ratio of TNF receptors (TNFR1:TNFR2) in hippocampus suggests that TNFα signaling, predominantly through TNFR1, may contribute to limbic hyperexcitability. Consistent with increased TNFR1 signaling, increases in hippocampal cell surface glutamate receptor expression was also observed during the acute period. While pharmacological inhibition of TNFR1-mediated signaling had no effect on acute seizures, several lines of transgenic animals deficient in either TNFα or its receptors were found to have robust changes in seizure incidence and severity following TMEV infection. TNFR2-/- mice were highly susceptible to developing TMEV-induced acute seizures, suggesting that signaling through the TNFR2 pathway may provide beneficial effects during the acute seizure period. Moreover, cannabidiol (180 mg/kg), which exhibits antiinflammatory and antiseizure properties, dramatically inhibited TMEV-induced acute seizures. Taken together the present results suggest that oxidative stress and inflammation in the hippocampus contribute to hyperexcitability and increase the probability of seizures following TMEV infection and that the TNFα signaling pathway is involved in this process. Pharmacotherapies designed to suppress inflammation and oxidative stress may provide antiseizure and disease modifying effects following CNS infection. |
