title: Staged anticonvulsant screening for chronic epilepsy.
abstract: Current anticonvulsant screening programs are based on seizures evoked in normal animals. One-third of epileptic patients do not respond to the anticonvulsants discovered with these models. We evaluated a tiered program based on chronic epilepsy and spontaneous seizures, with compounds advancing from high-throughput in vitro models to low-throughput in vivo models.
  
  
  
  Epileptogenesis in organotypic hippocampal slice cultures was quantified by lactate production and lactate dehydrogenase release into culture media as rapid assays for seizure-like activity and cell death, respectively. Compounds that reduced these biochemical measures were retested with in vitro electrophysiological confirmation (i.e., second stage). The third stage involved crossover testing in the kainate model of chronic epilepsy, with blinded analysis of spontaneous seizures after continuous electrographic recordings.
  
  
  
  We screened 407 compound-concentration combinations. The cyclooxygenase inhibitor, celecoxib, had no effect on seizures evoked in normal brain tissue but demonstrated robust antiseizure activity in all tested models of chronic epilepsy.
  
  
  
  The use of organotypic hippocampal cultures, where epileptogenesis occurs on a compressed time scale, and where seizure-like activity and seizure-induced cell death can be easily quantified with biomarker assays, allowed us to circumvent the throughput limitations of in vivo chronic epilepsy models. Ability to rapidly screen compounds in a chronic model of epilepsy allowed us to find an anticonvulsant that would be missed by screening in acute models.
authors.affiliation: Department of Electrical and Computer Engineering and Bioengineering Program Lehigh University Bethlehem Pennsylvania 18015.
authors.forename: Yevgeny
authors.initials: Y
authors.lastname: Berdichevsky
authors.affiliation: Department of Neurology Massachusetts General Hospital Boston Massachusetts 02129; Harvard Medical School Boston Massachusetts 02129.
authors.forename: Yero
authors.initials: Y
authors.lastname: Saponjian
authors.affiliation: Department of Neurology Seoul National University Hospital Healthcare System Gangnam Center Seoul South Korea 06236.
authors.forename: Kyung-Il
authors.initials: KI
authors.lastname: Park
authors.affiliation: Department of Neurosurgery University of Utah School of Medicine Salt Lake City Utah 84108.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Roach
authors.affiliation: Department of Neurosurgery University of Utah School of Medicine Salt Lake City Utah 84108.
authors.forename: Wendy
authors.initials: W
authors.lastname: Pouliot
authors.affiliation: Boston University School of Medicine Boston Massachusetts 02119.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Lu
authors.affiliation: Department of Neurology Massachusetts General Hospital Boston Massachusetts 02129; Harvard Medical School Boston Massachusetts 02129.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Swiercz
authors.affiliation: Department of Neurosurgery University of Utah School of Medicine Salt Lake City Utah 84108.
authors.forename: F Edward
authors.initials: FE
authors.lastname: Dudek
authors.affiliation: Department of Neurology Massachusetts General Hospital Boston Massachusetts 02129; Harvard Medical School Boston Massachusetts 02129.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Staley