Abstract
Seizure is one of a severe toxicity for drug developments. Recently, many reports suggested a usefulness of in vitro microelectrode array (MEA) systems to detect seizure risks using the well-known seizure-inducible compounds with mechanism of action. On the other hands, there are few information about the usage of the in vitro MEA systems to detect the seizure risks with compounds whose pharmacological action is not directly associated with inducing seizure. In fact, these compounds, which do not have a theoretical risk for seizure based on their pharmacological actions, sometimes induce tonic/chronic convulsions in in vivo toxicity studies. Thus, we are now trying to assess the seizure risks of in-house compounds whose pharmacological action is not directly associated with seizure, and to confirm a usefulness of the in vitro MEA systems in more realistic cases. Neuronal activity of iPSC-derived neuron and human primary astrocyte (Neucyte) with these compounds was recorded by in vitro MEA systems (Axion Inc.) and some parameters were calculated. Using these parameters, PCA or cluster analysis were conducted to classify the test compounds into seizure-inducible or non-seizure-inducible compounds. In vitro MEA systems categorized some in-house compounds into seizure-inducible compound. These seizurogenic responses in neural activity were observed only in higher concentrations but not in lower concentrations. Further, the compounds categorized into the seizure-inducible compound induced the convulsions in in vivo toxicity studies which had been conducted previously, indicating that the results of the in vitro MEA were consistent with that of the in vivo studies. This study provided that in vitro MEA systems are useful to detect seizure risks even the case of the compounds whose pharmacological action is not directly suggested with seizure risks.
