Pharmacological validation of a semi-automated in vitro hippocampal brain slice assay for assessment of seizure liability

摘要: Abstract Introduction Drug-induced seizures are a serious, life-threatening adverse drug reaction (ADR) that can result in the failure of drugs to be licensed for clinical use or withdrawn from market. Seizure liability potential is traditionally assessed using animal models run during later phases discovery process. Given low throughput, high usage and compound requirement associated with these assays, it would advantageous identify higher vitro could used give an earlier assessment seizure liability. The hippocampal brain slice one possibility but conventionally allows recording only at time. aim this study was validate semi-automated system (Slicemaster, Scientifica UK Ltd) which concurrent electrophysiological multiple slices. Methods Conventional techniques were record electrically evoked synaptic activity rat Population spikes (PS) 30 s intervals by electrical stimulation Schaffer collateral pathway recorded extracellular electrodes positioned CA1 cell body layer. Responses quantified as PS areas (the area above below 0 mV line). effects eight validation compounds known cause vivo and/or clinic assessed. Results Seven out concentration-dependent increase population spike statistically significant concentrations ( P Discussion All effect on slice. Although similar have been described previously, first time pharmacologically diverse set standardised assay. relatively throughput assay, assay may facilitate testing convulsant than currently possible models.