Seizure liability assessments using hippocampal brain slice: comparison of multiple preclinical species
Michael V. Accardi 1, Hai Huang 1, Eric Troncy 2, Roy Forster 1 and Simon Authier 1,2
- Citoxlab North America, Laval, QC, Canada
- Faculty of Veterinary Medicine, University of Montreal, St-Hyacinthe, QC, Canada
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Introduction: Hippocampal brain slices can be used as an in vitro assay to characterize seizure liabilities early in drug development. Traditionally, this assay has relied upon the rat hippocampal slice which sometime possesses limited translational value. Species differences are often noted during in vivo seizure liability assessments and drug safety testing may benefit from early ranking of the various animal models.
Methodology: Transverse hippocampal brain slices were isolated from animal models (e.g., rat, minipig, dog, nonhuman primate). Population spikes (PS) were evoked through Schaffer collateral pathway stimulation via a concentric bipolar stimulating electrode and recorded using conventional in vitro electrophysiological techniques via an extracellular electrode placed into the CA1 cell body layer.
Results: All preclinical animal hippocampal slices displayed a concentration-dependent increase in PS area and number in the presence of the pro-convulsant Pentylenetetrazol (PTZ; 0.1-10 mM) – in good agreement with previously published in vivo and in vitro PTZ data. However, nuanced and distinct differences were observed in certain species with respect to their sensitivity to PTZ. For instance, PS area reached significance at lower thresholds in nonhuman primates compared to rats (1 mM vs. 10 mM) whereas rats demonstrated greater evoked PS numbers when compared to monkeys (2.3 vs 1.8).
Discussion: Our results suggest the nuanced differences between hippocampal slices isolated from different preclinical animal models should influence the design of non-clinical seizure liability studies and their associated data interpretation. Hippocampal brain slices from multiple preclinical animal models can be a valuable approach to complement seizure risk assessment.
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