title: Stereoselective effects of the novel anticonvulsant lacosamide against 4-AP induced epileptiform activity in rat visual cortex in vitro.
abstract: We examined effects of the novel anticonvulsant lacosamide and its inactive isomer (SPM 6953) in an in vitro model of epileptiform activity. Focal field potential recordings (34+/-0.2 degrees C) were obtained from 17 to 22 day old rat brain slices. Physiological synaptic transmission (fEPSP amplitude and duration) in CA1 of rat hippocampus was not significantly altered (P > 0.05, n = 4) by lacosamide (1 microM-1 mM). Recording from visual cortex during application of 4-aminopyridine (4-AP; 100 microM) revealed both spontaneous and evoked 'ictal like' discharges. Spontaneous ictal like discharges in the visual cortex were blocked by 100 microM carbamazepine (CBZ), 100 microM pentobarbital and 200 microM phenobarbital (PHB) but were insensitive to the anti-absence drug ethosuximide (750 microM; n = 4, P > 0.05). Lacosamide reduced tonic duration and maximal firing frequency with EC(50)s of 41 and 71 microM, respectively. In contrast, the S stereoisomer (100-320 microM) produced no significant effect on spontaneous ictal activity (n = 3-4, P > 0.05). Seizures induced by high frequency (100 Hz, 1s) stimulation were selectively reduced in amplitude by PHB (200 microM) and frequency by CBZ (100 microM; n = 6) and lacosamide (100 microM; n = 4). GABAergic negative going potentials were attenuated by CBZ (irreversible with washing) and lacosamide (reversible) but not by PHB. We conclude that lacosamide blocks 4-AP induced epileptiform activity in the visual cortex. This novel anticonvulsant drug appears to inhibit epileptogenesis (seizure spread) by interacting with a stereoselective, but as yet unidentified, target site in rodent neocortex in the mid-micromolar range.
authors.affiliation: Department of Pharmacology and Toxicology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand. george.lees@stonebow.otago.ac.nz
authors.forename: George
authors.initials: G
authors.lastname: Lees
authors.forename: Thomas
authors.initials: T
authors.lastname: Stöhr
authors.forename: Adam C
authors.initials: AC
authors.lastname: Errington
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D015761:4-Aminopyridine / Q000494:pharmacology*; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D004594:Electrophysiology; D004827:Epilepsy / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D000078334:Lacosamide; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D018408:Patch-Clamp Techniques; D010634:Phenobarbital / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D000091402:Prohibitins; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects; D014793:Visual Cortex / Q000187:drug effects* / Q000503:physiopathology*
chemical_list: D015763:2-Amino-5-phosphonovalerate; D015761:4-Aminopyridine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000081:Acetamides; D000927:Anticonvulsants; D002220:Carbamazepine; D003292:Convulsants; D018691:Excitatory Amino Acid Antagonists; D000078334:Lacosamide; D010634:Phenobarbital; D010852:Picrotoxin; D026902:Potassium Channel Blockers; D000091402:Prohibitins; C000717332:Phb protein, rat