Assessing seizure liability using multi-electrode arrays (MEA). (March 2019)

• Record Type: Journal Article
• Authors: Fan, Jingsong; Thalody, George; Kwagh, Jae; Burnett, Elisabeth; Shi, Hong; Lewen, Geoff; Chen, Shen-Jue; Levesque, Paul
• Is Part Of: Toxicology in vitro. Volume 55(2019)
• Page Start: 93
• Page End: 100
• Publication Date: 2019-03
• Subjects: 4-AP 4-Aminopyridine -- APAP Acetaminophen -- Bic Bicuculline -- FP Field Potential -- Gab Gabazine -- MEA Multi-electrode array -- Pic Picrotoxin -- PTZ Pentylenetetrazol; Brain slices -- Drug safety -- Extracellular recording -- Hippocampus, MEA -- Neuron -- Seizure liability; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2018.12.001
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: The purpose of these studies was to develop ex vivo tissue-based and in vitro cell-based assays using multi-electrode array (MEA) technology to predict seizure liability at the early stage of preclinical studies. Embryonic rat hippocampal neurons and adult rat hippocampal slices were used in these studies. Spontaneous activity in cultured neurons and evoked field potentials in hippocampal brain slices were recorded using MEA technology. Six seizurogenic compounds bicuculline, pentylenetetrazole, picrotoxin, gabazine, 4-Aminopyridine and BMS-A increased field potential area and peak number in brain slices and spontaneous spike activity in hippocampal neurons. Physostigmine, another seizurogenic compound, had no effect on brain slices at lower concentrations (0.1, 1, and 10 μM), and mildly increased field potential area at 100 μM. However, physostigmine induced multiple peaks in evoked field potential starting at 10 μM. Physostigmine showed greater potency in the cultured neuron assay, and increased spike rates in the nanomolar range. Two seizurogenic compounds, BMS-B and BMS-C increased the spontaneous activity in hippocampal neurons, but did not increase area and peak number of field potentials in brain slices. These findings suggest that MEA technology and rat hippocampal brain slices or rat embryonic hippocampal neurons, may be useful as early, predictive in vitro assays for seizure liability. Highlights: MEA hippocampal slice assay can replace traditional extracellular recording of hippocampal slice in drug safety assessment MEA embryonic hippocampal neuron assay may be more sensitive to some seizurogenic substances than MEA hippocampal slice assay Both assays may predict drug induced seizure liability