Seizure liability assessments using the hippocampal tissue slice: Comparison of non-clinical species

Abstract

IntroductionTraditionally, rat hippocampal tissue slice models are used as an in vitro electrophysiology assay to assess seizurogenic potential in early drug development despite non-clinical species-specific differences noted during in vivo seizure studies. MethodsHippocampal tissue slices were acutely isolated from rats, minipigs, dogs and nonhuman primates (NHP). Population spikes (PS) were evoked through stimulation of the CA3 Schaffer collateral pathway and recorded using in vitro electrophysiological techniques via an extracellular electrode placed within the CA1 stratum pyramidale cell body layer. ResultsHippocampal slices, across all species, displayed a concentration-dependent increase in PS area and number with the pro-convulsant pentylenetetrazol (PTZ; 0.1–10mM). Beagle dogs exhibited higher sensitivities to PTZ-induced changes in PS area and number compared to both rats and NHPs which presented nuanced differences in their responsiveness to PTZ modulation. Minipigs were comparatively resistant to PTZ-induced changes in both PS area and number. Rat and NHP hippocampal tissues were further characterized with the pro-convulsant agents 4-aminopyradine (4-AP; 1–100μM) and cefazolin (0.001–10mM). Rats possessed higher sensitivities to 4-AP- and cefazolin-induced changes to both PS area and number whereas NHP displayed greater modulation in PS duration. The anti-convulsant agents, diazepam (10–500μM) and lidocaine (1–500μM), were also tested on either rat and/or NHP tissue with both drugs repressing PS activation at high concentrations. DiscussionHippocampal tissue slices, across all species, possessed distinct sensitivities to pro- and anti-convulsant agents which may benefit the design of non-clinical seizure liability studies and their associated data interpretation.