Abstracts

Rationale: The 6 Hz model of psychomotor seizures is a well-established and commonly used pre-clinical model in mice. Despite its widespread use both in the identification and differentiation of novel antiseizure drugs in mice, a corresponding assay in rats has not been developed. We established a method for 6 Hz seizure induction in rats, with similar seizure behaviors as those observed in mice including head nod, jaw clonus, and forelimb clonus. Methods: A convulsive current that elicits these seizure behaviors in 97% of rats (CC97) was determined using a Probit analysis wherein various stimulus intensities were applied to different groups of rats and seizures occurred in a stimulus intensity-dependent manner. Following, several prototype antiseizure drugs were evaluated in this model using stimulus intensities of 1.5x and 2x the CC97, which is similar to the approach used in the mouse 6 Hz seizure model with evaluation at 32 and 44 mA stimulus intensities. Compounds evaluated included those that act on sodium channels (carbamazepine, eslicarbazepine, lacosamide, lamotrigine, phenytoin, and rufinamide), GABA receptors and uptake (clobazam, clonazepam, phenobarbital, and tiagabine), potassium channels (ezogabine), calcium channels (ethosuximide, gabapentin), synaptic vesicle 2A (levetiracetam), and mixed mechanism of action (topiramate, valproic acid). Efficacy in selected compounds (median effective dose, ED50) was compared to median toxic dose, TD50, values for motor impairment in rats: protective index, PI = TD50/ED50. Results: Compounds that were effective at the 1.5xCC97 stimulus intensity at PI values > 1 were clobazam, ethosuximide, ezogabine, levetiracetam, phenobarbital, and valproic acid. Compounds that were effective at the 2xCC97 stimulus intensity at PI values > 1 were ezogabine, phenobarbital, and valproic acid. Conclusions: The limited number of established antiseizure drugs with demonstrable efficacy at the higher stimulus intensity suggests that, like the mouse 6 Hz 44 mA model, the rat 6 Hz seizure model may be a useful screening tool for pharmacoresistant seizures. Funding: NINDS, HHSN271291199929C, "Identification and Characterization of Novel Therapeutics for the Treatment and Prevention of Epilepsy and Neurprotectants as Counter Measures (CM) to Chemical Threats."