Antiseizure drug efficacy and tolerability in established and novel drug discovery seizure models in outbred vs inbred mice

OBJECTIVE. Initial identification of new investigational drugs for the treatment of epilepsy is commonly conducted in well-established mouse acute and chronic seizure models: e.g. maximal electroshock (MES), 6 Hz, and corneal kindling. Comparison of the median effective dose (ED50) of approved antiseizure drugs (ASDs) versus investigational agents in these models provides evidence of their potential for clinical efficacy. Inbred and outbred mouse strains exhibit differential seizure susceptibility (Frankel et al, Genomics 2001). However, few comparisons exist of the ED50 or median behaviorally impairing dose (TD50) of prototype ASDs in these models in inbred C57Bl/6 versus outbred CF-1 mice, both of which are often used for ASD discovery. METHODS. We defined the strain-related ED50s and TD50s of several mechanistically distinct ASDs across established acute seizure models (MES, 6 Hz, and corneal kindled mouse). We further quantified the strain-related effect of the MES ED50 of each ASD on gross behavior in a locomotor activity assay. Lastly, we describe a novel pharmacoresistant corneal kindling protocol that is suitable for moderate-throughput ASD screening and demonstrates highly differentiated ASD sensitivity. RESULTS. We report significant strain-related differences in the MES ED50 of valproic acid (CF-1 ED50 - 190 mg/kg [95% confidence interval (CI): 165-214] versus C57Bl/6 - 276 mg/kg [226-366]), as well as significant differences in the ED50 of levetiracetam in the pharmacoresistant 6 Hz test (CF-1 - 22.5 mg/kg [14.7-30.2] versus C57Bl/6 - >500 mg/kg [CI not defined]). There were no differences in the calculated TD50 of these ASDs between strains. Further, the MES ED50 of phenobarbital significantly enhanced locomotor activity of outbred CF-1, but not C57Bl/6, mice. SIGNIFICANCE. Altogether, this study provides strain-related information to differentiate investigational agents from ASD standards-of-care in commonly employed preclinical discovery models and describes a novel kindled seizure model to further explore the mechanisms of drug-resistant epilepsy.