Abstracts

Rationale: Tetramethylenedisulfotetramine (TETS), one of the most hazardous and highly lethal rodenticides, is believed to act as a noncompetitive antagonist of GABA_A receptors through an interaction at the same site as the cage convulsant t-butylbicycloorthobenzoate. TETS intoxication has been reported to produce refractory status epilepticus in exposed humans. Lack of specific antidotes and poor outcome of current medical countermeasures for acute TETS intoxication provides an impetus for the investigation of treatment approaches. Methods: TETS was administered to mice by intraperitoneal (i.p.) injection and intravenously (i.v.). Perampanel was administered i.p. 10 min prior to TETS.Results: We found that intraperitoneal administration of TETS (74% pure; doses uncorrected) in mice elicited seizures in a dose-dependent fashion. The CD₅₀ (dose producing tonic seizures in 50% of animals) was 0.12 mg/kg for a nearly anhydrous batch of TETS and 0.25 mg/kg for a hydrated batch. The LD₅₀ value (dose in mg/kg that is estimated to produce mortality in 50% of animals) was 0.28 mg/kg (hydrated). At low doses, the onset of the convulsant action was delayed but the speed of seizure onset increased in a dose-dependent fashion (mean latency ~14 min for 0.2 mg/kg to ~2 min for 0.6 mg/kg). Intravenous infusion of TETS (0.02 mg/ml; hydrated) induced a similar sequence of seizure signs as did pentylenetetrazol (PTZ), a GABA_A receptor antagonist frequently administered intravenously to assess seizure threshold. Since the latency to onset of seizures with TETS is more prolonged than with PTZ, slower infusion rates were used (0.1 ml/min compared with 0.5 ml/min for PTZ). At this infusion rate, a 0.12 mg/kg cumulative dose of TETS was sufficient to elicit a myoclonic jerk response and a 0.15 mg/kg cumulative dose produced clonic seizures. We next determined the ability of perampanel, a high potency selective noncompetitive AMPA receptor antagonist currently being investigated as a treatment for epilepsy, to protect against TETS-induced seizures. Perampanel administered i.p. 10 min prior to TETS produced a dose-dependent protection against TETS evoked tonic seizures and mortality with ED₅₀ values of 2.2 mg/kg and 1.5 mg/kg, respectively.Conclusions: Our results demonstrate that AMPA receptor blockade may provide a treatment for TETS-induced seizures and lethality. This work was supported by NINDS R21 NS072094 (PJL and MAR), and a UC Davis Academic Federation Innovative Development Award (DZ). Perampanel was a gift of Eisai.