Study for drug-induced seizure prediction using cultured neurons and microelectrode array - rat primary neurons vs rat in vivo model/clinicalclinical

<p>Drug-induced convulsion is a serious adverse event in clinical. Most of the seizure risks of drug candidates are first detected in animal toxicity studies. Establishment of in vitro seizure risk assay which can predict in vivo convulsions is required for the drug development. </p><p>In the present study, we are discussing seizure risk assessment potency of an in vitro assay using rat primary cortical neurons and microelectrode arrays (MEA) in comparison with cerebrospinal fluid (CSF) concentrations induced seizures in the in vivo seizure study. The drug concentrations in CSF in rats with convulsion induced by 5 seizure-positive reference compounds (Paroxetine, Fluvoxamine, 4-Aminopiridine, Pentylenetetrazole, and Strychnine) were confirmed, showing clear convulsion-thresholds. Changes in a parameter, network burst frequency, in the MEA assay was remarkable at seizure-induced CSF concentrations of the reference compounds, except for fluvoxamine. It is suggested that the in vitro MEA assay could be a seizure liability assay to predict in vivo convulsions.</p><p>Convulsions were induced in patients treated with some of combinations of fluoroquinolones and nonsteroidal anti-inflammatory drugs (NSAIDs). We succeeded to see seizure phenotypes in the MEA assay by treatment of seizure-induced combinations of fluoroquinolones and NSAID in clinical. Mechanism of action (MOA) analysis was carried out by principal component analysis using multiple parameters from MEA data, classified to GABAA receptor inhibition.</p><p>MEA technology has the potential to predict the seizure liability of drugs with MOA.</p>