Abstracts

Rationale: Theiler's Murine Encephalomyelitis Virus (TMEV) can induce seizures following infection in mice and has been proposed as a model of temporal lobe epilepsy (TLE) during which an acute insult (viral infection) is followed by a latent period and chronic spontaneous recurrent seizures. Viral infection can produce neuronal loss in the hippocampus, increased cytokine levels, oxidative stress, astrogliosis, microgliosis, increased hippocampal CA3 excitability, reduced seizure threshold, behavioral/cognitive comorbidities. The present studies were designed to evaluate the effect of prototype antiseizure drugs (ASDs) in this novel model of TLE. Methods: To evaluate the effect of various compounds on the initial post-infection period (day 3-7 post-infection), where handling-induced seizures can be observed, C57Bl/6 mice infected with TMEV were treated with various antiseizure drugs (ASDs) twice daily (BID; intraperitoneal injection), beginning on the third day after infection, for a period of 5 days (through day 7 post-infection). Doses selected for each ASD were derived from mouse 6 Hz (44 mA) median effective dose values (in CF-1 mice). Mice were observed for handling-induced seizure behaviors during daily drug treatments, and during behavioral monitoring sessions (twice daily 1-2h following each injection). Following each 5-day treatment and testing period, cumulative seizure burden (i.e., summed Racine score for all seizures observed) for each treatment group were compared to mean cumulative seizure burdens for vehicle (VEH)-treated mice. Analysis was conducted for only seizures observed during the daily behavioral monitoring sessions (post-treatment), or for all seizures observed (all seizures; post-treatment monitoring as well as seizures observed during injections). Results: Of the compounds evaluated, clonazepam (0.2 mg/kg BID) and ethosuximide (300 mg/kg BID) were without effect in this model. Gabapentin (350 mg/kg BID), lacosamide (13 mg/kg BID), and lamotrigine (20 mg/kg BID) reduced cumulative seizure burden for both the post-treatment observation (9.8, 18.3, and 12.2% of VEH cumulative seizure burden, respectively) and when all seizures were included in the analysis (28.5, 46.7, and 27.8 % of VEH cumulative seizure burden). Tiagabine (1.3 mg/kg BID), topiramate (300 mg/kg BID), and valproic acid (239 mg/kg BID) reduced cumulative seizure burden during the post-treatment observation period only (19.2, 42.7, 0.6 % of VEH cumulative seizure burden). The anti-inflammatory compound minocycline (50 mg/kg, once daily) reduced cumulative seizure burden for all seizures (40.9% of VEH cumulative seizure burden). Conclusions: Results from these studies suggest that novel compounds can be evaluated in this assay for anti-inflammatory, anti-seizure, or mixed mechanisms of action. Funding: HHSN271201100029C