Abstracts

Rationale: The Epilepsy Therapy Screening Program Contract Site, formerly the Anticonvulsant Drug Development Program, has retained the continuous support of the NIH/NINDS since 1975. Throughout the 40-plus year history of this screening program at the University of Utah, acute models such as the maximal electroshock model in mice and rats, the 6 Hz stimulation model of focal seizures in mice and the subcutaneous pentylenetetrazol (PTZ) model in mice and rats have been used as identification-stage models to identify potential antiseizure compounds. Herein we show the reproducibility of these models throughout the history of the program using clinically available and validated antiseizure drugs (ASDs) as test compounds. Methods: Historical data for the maximal electroshock model, the 6 Hz model, the subcutaneous PTZ model, and the mouse rotarod behavioral assessment or rat minimal motor impairment (MMI) models were obtained from laboratory notebooks and the Epilepsy Therapy Screening Program Database at NINDS/NIH. Median effective doses (ED50) of prototype antiseizure drugs were compared throughout the history of the program. In addition, rotarod (mouse) and MMI (rat) test results were also used to compare median toxic doses (TD50) over time. For the purposes of this study, only results from male CF-1 mice and Sprague Dawley rats were compared. Compounds evaluated included carbamazepine, clonazepam, gabapentin, levetiracetam, phenytoin, topiramate, and valproic acid. Results: Despite numerous changes in principal investigator, laboratory buildings, housing facilities, lab spaces, technicians, animal suppliers, sub-strains, and other variables, the seizure models used to test clinically available and validated antiseizure drugs show reproducibility over time, with the ED50 values largely remaining within the confidence intervals of previous test results. TD50 values were also largely consistent over time. Conclusions: The 44 years of antiseizure drug data collected from screening models used by the ETSP allows for a unique assessment of the quality control and reproducibility of testing results over an extended time period. Despite numerous variables over time, there have been little changes in the effective doses of the compounds in these models, showing an encouraging reproducibility in these models. Much of this data will be accessible at the NINDS Epilepsy Therapy Screening Program website at https://panache.ninds.nih.gov/. Funding: Supported by NINDS research contract: HHSN271201600048C