Challenge to develop an in vitro MEA test to predict in vivo seizure risk

Abstract

Drug-induced convulsions/seizures are serious adverse events in clinic. There is a strong demand to establish in vitro assay systems which can predict the risk of drug-induced convulsions in in vivo with high probability in nonclinical studies. We’ll introduce a new in vitro seizure prediction method established using primary rat cerebral cortical neurons and microelectrode arrays (MEA) system with reference to cerebrospinal fluid (CSF) drug concentrations immediately after convulsions induced in rats for 14 known convulsion-inducing drugs with different mechanism of action (MOA). Rats were intraperitoneally or intravenously given one of the 14 convulsants at either convulsant or non-convulsant dose level (n = 5-6/dose level). Concentrations of the convulsants in CSF, which was obtained immediately after convulsion onset, were measured by LC-MS/MS. The primary rat cerebral cortical neurons were cultured on 48-well MEA plates and the changes of the parameters including network burst frequency (NBF) by the drugs were compared with the in vivo study results. The data exclusion criteria were also applied for the assay. The CSF concentrations revealed a convulsion-induced threshold for each drug. Changes in NBF of 9 out of 14 convulsants were well correlated with the results in rat convulsion studies. In conclusion, changes of NBF in in vitro MEA system assay using primary rat cerebral cortical neurons could be reliable parameter to predict in vivo convulsions regarding to specific types of MOA of the drugs.