Neuroservice proconvulsive (NS-PC) set: A new platform of electrophysiology-based assays to determine the proconvulsive potential of lead compounds
| Autor: | Fabien Maddalena, Esther Steidl, Bruno Buisson, Dominique Debanne, Melanie Gleyzes |
|---|---|
| Přispěvatelé: | Neuroservice, Laboratoire privé, Unité de Neurobiologie des canaux Ioniques et de la Synapse (UNIS - Inserm U1072), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Proconvulsive
Multielectrode arrays [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology Population Hippocampal slices 030204 cardiovascular system & hematology Toxicology Inhibitory postsynaptic potential 030226 pharmacology & pharmacy 03 medical and health sciences 0302 clinical medicine Methods Medicine education Extracellular recording Pharmacology education.field_of_study business.industry Safety pharmacology Carbamazepine Bicuculline Clonazepam Electrophysiology Excitatory postsynaptic potential Seizure liability business Neuroscience medicine.drug |
| Zdroj: | Journal of Pharmacological and Toxicological Methods Journal of Pharmacological and Toxicological Methods, Elsevier, 2019, ⟨10.1016/j.vascn.2019.106587⟩ Journal of Pharmacological and Toxicological Methods, 2019, ⟨10.1016/j.vascn.2019.106587⟩ |
| ISSN: | 1056-8719 |
| DOI: | 10.1016/j.vascn.2019.106587⟩ |
| Popis: | Introduction Failures in drug development often result from the emergence of unexpected adverse drug reactions. It is clear that adverse drug reactions, including seizure liability, should be assessed earlier. The goal of the present work was to develop a new platform of in vitro assays, NS-PC set (for Neuroservice proconvulsive set), to determine the proconvulsive potential of compounds earlier in preclinical development. Methods Assays were based on electrophysiological recordings in acute hippocampal slices performed with multielectrode arrays. 4 reference proconvulsive/seizurogenic compounds (4-aminopyridine, bicuculline, kainate and carbachol) and 4 anti-epileptic drugs (AEDs; phenobarbital, carbamazepine, clonazepam and valproic acid) were evaluated on electrophysiological endpoints involved in seizure risk (neuronal excitability, balance of excitatory/inhibitory synaptic transmission, occurrence of neuronal synchronization mechanisms materialized by epileptiform discharges). Results The reference compounds increased the number and area under the curve of population spikes, triggered epileptiform discharges and enhanced the firing rate of CA1 neurons. The effects of the 4 antiepileptic drugs were assessed on these 3 parameters. They were able to partially of completely reverse the effects of proconvulsive compounds. Discussion The use of reference proconvulsive compounds and AEDs validated the electrophysiological parameters to detect proconvulsive risk. Systematic evaluation of compounds with the 3 complementary endpoints increase the probability to detect seizure liability in vitro. Depending on the compound mechanism of action, only one or two of the identified parameters might be modified. |
| Databáze: | OpenAIRE |
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