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Stereoselective effects of the novel anticonvulsant lacosamide against 4-AP induced epileptiform activity in rat visual cortex in vitro

Lees, George, Stöhr, Thomas and Errington, Adam C. 2006. Stereoselective effects of the novel anticonvulsant lacosamide against 4-AP induced epileptiform activity in rat visual cortex in vitro. Neuropharmacology 50 (1) , pp. 98-110. 10.1016/j.neuropharm.2005.08.016

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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 °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 μM–1 mM). Recording from visual cortex during application of 4-aminopyridine (4-AP; 100 μM) revealed both spontaneous and evoked ‘ictal like’ discharges. Spontaneous ictal like discharges in the visual cortex were blocked by 100 μM carbamazepine (CBZ), 100 μM pentobarbital and 200 μM phenobarbital (PHB) but were insensitive to the anti-absence drug ethosuximide (750 μM; n = 4, P > 0.05). Lacosamide reduced tonic duration and maximal firing frequency with EC50s of 41 and 71 μM, respectively. In contrast, the S stereoisomer (100–320 μM) produced no significant effect on spontaneous ictal activity (n = 3–4, P > 0.05). Seizures induced by high frequency (100 Hz, 1 s) stimulation were selectively reduced in amplitude by PHB (200 μM) and frequency by CBZ (100 μM; n = 6) and lacosamide (100 μM; 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Elsevier
ISSN: 0028-3908
Date of Acceptance: 25 August 2005
Last Modified: 11 Sep 2019 10:30
URI: http://orca.cf.ac.uk/id/eprint/123729

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