Abstracts

Rationale: Theiler’s Murine Encephalomyelitis Virus (TMEV) infection in C57Bl/6J mice produces handling-induced seizures in the period following infection (3-7 days).  We have previously demonstrated in this model of temporal lobe epilepsy that some, but not all, prototype anti-seizure drugs (ASDs) can block or attenuate seizures during the acute infection period. Further, TMEV infection has been associated with various inflammatory signaling pathways including tumor necrosis factor alpha and interleukin-6 and therefore, drugs with anti-inflammatory mechanisms of action can also be evaluated in this model as potential therapies for infection-induced seizures. We previously demonstrated that minocycline (50 mg/kg/day) reduced seizures during the acute infection period whereas prednisone (5-10 mg/kg/day) had no significant effect. Therefore, we evaluated anti-inflammatory compounds in this model in order to determine if reducing inflammation using currently available therapies can reduce seizures in this infection-induced model.  Methods: Male C57Bl/6J mice received intracortical injections (Day 0, 20 µl, 3 x 105 plaque-forming units) of the Daniels strain of TMEV.  Animals received daily treatment (Day 3 – Day 7) with anti-inflammatory compounds.  The compounds evaluated included the non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac (5 or 10 mg/kg, twice daily) and ibuprofen (10 or 50 mg/kg, twice daily), or the steroids dexamethasone (20 mg/kg, once daily) and prednisone (20 mg/kg, once daily). One hour following each treatment, mice were handled briefly to observe for the presence of handling-induced seizures.  Seizure burden was calculated for each animal using either all seizures observed (i.e., during handling sessions and during drug injections) and using only post-treatment seizure observations (i.e., only those observed during post-treatment handling sessions).  Results: Of the NSAIDs evaluated, diclofenac did not reduce seizure burden at the doses tested whereas ibuprofen (50 mg/kg) significantly reduced seizure burden (40% and 46% reduction, post-treatment and all seizures analysis, respectively).  Similarly, the steroids dexamethasone (62% and 64% reduction; post-treatment and all seizures analysis, respectively) and prednisone (32% and 33% reduction; post-treatment and all seizures analysis, respectively) significantly reduced seizure burden.  Conclusions: The data acquired in this series of experiments suggests that both NSAIDs and steroids may provide potential benefit against infection-induced seizures, where inflammation is known to contribute to seizure occurrence.  Funding: NINDS: HHSN271201600048C