Abstracts

Rationale: Valnoctamide (VCD) and sec-butylpropylacetamide (SPD) are amide derivatives of valproic acid (VPA) with anticonvulsant activity in a variety of seizure and status epilepticus (SE) models. VCD is a chiral constitutional isomer of valpromide (VPD), the corresponding amide of VPA. Unlike VPD that in humans acts as a prodrug to VPA, VCD acts as a drug on its own with minimal biotransformation to its corresponding acid, valnoctic acid. SPD is a one-carbon homologue of VCD; both compounds possess 2 stereocenters and exist in 4 stereoisomeric forms. Here we assessed the activity of racemic VCD and SPD in a model of SE in which seizures were induced by tetramethylenedisulfotetramine (TETS), a highly lethal neurotoxic rodenticide that acts as a noncompetitive GABAA receptor antagonist. For comparison, we evaluated VPA in the same model. Methods: Severe TETS intoxication in humans is often associated with refractory convulsive SE. To create a model mimicking these seizures, mice were pretreated with a single dose of riluzole (10 mg/kg, IP) and 10 min later received a lethal dose of TETS (0.2 mg/kg, IP). Riluzole does not inhibit TETS-induced SE but does protect against the rapidly lethal effects of TETS in mice, providing a model of persistent seizure activity. Behavioral seizure activity was assessed by visual observation and the latency to cessation of SE was recorded. Animals were monitored for 7 days after seizure termination. Latency to cessation of SE was defined as the interval between the first behavioral myoclonic twitch and termination of seizure activity. Clear solutions of SPD and VCD were prepared in a mixture containing propylene glycol (PG), ethanol (EtOH) and distilled water (DiH2O) at different ratios. SPD (27 and 25 mg/ml) was dissolved in PG, EtOH and DiH2O at ratio 5:1:4. VCD (50 mg/ml) was prepared in PG, EtOH and DiH2O at ratio 4:1:5. VPA was dissolved in sterile saline. Results: SPD, VCD and VPA were administered IP at 40 min after the first myoclonic twitch. SPD injected IP at doses of 54 and 100 mg/kg terminated SE within, respectively, ~4 and ~2 min and protected 65 and 100% of animals from mortality for >7 days. VCD (IP) administered at doses 50 and 100 mg/kg terminated SE within, respectively, ~7 and ~2 min and protected 62.5 and 90% of animals from mortality. Both SPD and VCD produced sedation in treated animals, which was especially pronounced at the dose of 100 mg/kg. VPA administered IP at a dose of 100 mg/kg terminated TETS SE transiently in 80% of animals and only 20% animals survived. VPA at 200 mg/kg terminated SE within ~8.8 min and protected 80% of animals from mortality. Vehicle treatment failed to terminate TETS SE, resulting in delayed mortality in more than 80% animals within 24 h with the exception of vehicle to SPD 100 mg/kg where 42% of animals survived for 7 days. Higher survival in the vehicle group for SPD 100 mg/kg is most likely a result of increased volume of a solution (~2 x volume of vehicle to 54 mg/kg group) that contains ethanol, which may have antiseizure properties. Conclusions: Our results demonstrate that both SPD and VCD effectively terminate TETS-induced behavioral SE and protect animals from mortality; these agents are more potent and more rapidly acting than VPA. Funding: NINDS grant #1U54NS079202, DZ, MAR