Abstracts

Rationale: Tetramethylenedisulfotetramine (tetramine, TETS) is a highly lethal neurotoxic rodenticide that is believed to induce seizures as a result of blockade of GABAA receptors. In humans, severe TETS intoxication leads to refractory status epilepticus (SE). In this study we utilized a mouse TETS SE model to assess the efficacy of the potent AMPA receptor antagonist perampanel as a potential treatment for TETS-induced SE.Methods: Mice were implanted with right frontal and parietal cortical screw EEG recording electrodes. An EMG electrode was implanted in the neck. Recordings were conducted with respect to a screw reference electrode located in the left parietal cortex area. Animals were monitored using a video-EEG system. After a recovery period, mice were pretreated with riluzole (10 mg/kg, IP) and 10 min later received a lethal dose of TETS (0.2 mg/kg, IP). Animals treated according to this protocol experience persistent behavioral seizure activity and a dynamic pattern of epileptiform EEG discharges, starting in about 2-4 min with behavioral myoclonic twitch (associated with spike/sharp wave complexes) and progressing into clonic seizures that merge into continuous convulsive activity. This activity is punctuated by periods of periodic spike and sharp wave activity and spike/sharp wave clusters. During the course of each experiment, animals were scored on a minute-by-minute basis with respect to the behavioral and EEG activity. Latency to cessation of SE is defined as the interval between the first behavioral myoclonic jerk and termination of continuous seizure activity.Results: Vehicle treatment failed to terminate TETS-induced SE, resulting in delayed mortality in more than 80% animals within 24 h. Perampanel (IP) was administered at the doses of 0.3-3 mg/kg at either 10 min (early) or 40 min (late) after the first myoclonic twitch. Perampanel at 3 mg/kg terminated continuous convulsive activity but did not eliminate epileptiform discharges (periodic spike and sharp wave activity and spike/sharp wave clusters). Mortality was prevented in 100% of animals receiving perampanel at either 10 or 40 min. The latency to cessation of convulsive seizure activity was slightly shorter at 3 mg/kg when the treatment was administered early than late. At a dose of 1 mg/kg, perampanel prevented mortality in 86% and 100% of animals when injected early or late after the first myoclonic twitch, respectively. Perampanel at the dose of 0.3 mg/kg was ineffective in terminating SE in the majority of animals.Conclusions: Our results demonstrate that AMPA receptor blockade prevents TETS-induced mortality and terminates continuous convulsive activity without eliminating all epileptiform activity. This work was supported by NINDS (NS079202; DZ, CB, DAB, BH, PJL, MR). Perampanel was a gift of Eisai.