title: Heterogeneous effects of antiepileptic drugs in an in vitro epilepsy model--a functional multineuron calcium imaging study.
abstract: Epilepsy is a chronic brain disease characterised by recurrent seizures. Many studies of this disease have focused on local neuronal activity, such as local field potentials in the brain. In addition, several recent studies have elucidated the collective behavior of individual neurons in a neuronal network that emits epileptic activity. However, little is known about the effects of antiepileptic drugs on neuronal networks during seizure-like events (SLEs) at single-cell resolution. Using functional multineuron Ca(2+) imaging (fMCI), we monitored the activities of multiple neurons in the rat hippocampal CA1 region on treatment with the proconvulsant bicuculline under Mg(2+) -free conditions. Bicuculline induced recurrent synchronous Ca(2+) influx, and the events were correlated with SLEs. Other proconvulsants, such as 4-aminopyridine, pentetrazol, and pilocarpine, also induced synchronous Ca(2+) influx. We found that the antiepileptic drugs phenytoin, flupirtine, and ethosuximide, which have different mechanisms of action, exerted heterogeneous effects on bicuculline-induced synchronous Ca(2+) influx. Phenytoin and flupirtine significantly decreased the peak, the amount of Ca(2+) influx and the duration of synchronous events in parallel with the duration of SLEs, whereas they did not abolish the synchronous events themselves. Ethosuximide increased the duration of synchronous Ca(2+) influx and SLEs. Furthermore, the magnitude of the inhibitory effect of phenytoin on the peak synchronous Ca(2+) influx level differed according to the peak amplitude of the synchronous event in each individual cell. Evaluation of the collective behavior of individual neurons by fMCI seems to be a powerful tool for elucidating the profiles of antiepileptic drugs.
authors.affiliation: Pain & Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi Co. Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka, 561-0825, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Hongo
authors.affiliation: Pain & Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi Co. Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka, 561-0825, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Takasu
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan.|Center for Information and Neural Networks, Suita City, Osaka, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikegaya
authors.affiliation: Pain & Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi Co. Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka, 561-0825, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Pain & Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi Co. Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka, 561-0825, Japan.
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
authors.affiliation: Pain & Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi Co. Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka, 561-0825, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ogawa
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D001640:Bicuculline / Q000633:toxicity; D002118:Calcium / Q000378:metabolism*; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D026902:Potassium Channel Blockers; D015761:4-Aminopyridine; D002118:Calcium; D001640:Bicuculline
keywords: antiepileptic drugs; hippocampus; seizure-like events; synchronous Ca2+ influx