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Investigation of the effects of the novel anticonvulsant compound carisbamate (RWJ-333369) on rat piriform cortical neurones in vitro.

AbstractBACKGROUND AND PURPOSE:
Carisbamate is being developed for adjuvant treatment of partial onset epilepsy. Carisbamate produces anticonvulsant effects in primary generalized, complex partial and absence-type seizure models, and exhibits neuroprotective and antiepileptogenic properties in rodent epilepsy models. Phase IIb clinical trials of carisbamate demonstrated efficacy against partial onset seizures; however, its mechanisms of action remain unknown. Here, we report the effects of carisbamate on membrane properties, evoked and spontaneous synaptic transmission and induced epileptiform discharges in layer II-III neurones in piriform cortical brain slices.
EXPERIMENTAL APPROACH:
Effects of carisbamate were investigated in rat piriform cortical neurones by using intracellular electrophysiological recordings.
KEY RESULTS:
Carisbamate (50-400 micromol x L(-1)) reversibly decreased amplitude, duration and rise-time of evoked action potentials and inhibited repetitive firing, consistent with use-dependent Na+ channel block; 150-400 micromol x L(-1) carisbamate reduced neuronal input resistance, without altering membrane potential. After microelectrode intracellular Cl(-) loading, carisbamate depolarized cells, an effect reversed by picrotoxin. Carisbamate (100-400 micromol x L(-1)) also selectively depressed lateral olfactory tract-afferent evoked excitatory synaptic transmission (opposed by picrotoxin), consistent with activation of a presynaptic Cl(-) conductance. Lidocaine (40-320 micromol x L(-1)) mimicked carisbamate, implying similar modes of action. Carisbamate (300-600 micromol x L(-1)) had no effect on spontaneous GABA(A) miniature inhibitory postsynaptic currents and at lower concentrations (50-200 micromol x L(-1)) inhibited Mg2+-free or 4-aminopyridine-induced seizure-like discharges.
CONCLUSIONS AND IMPLICATIONS:
Carisbamate blocked evoked action potentials use-dependently, consistent with a primary action on Na+ channels and increased Cl(-) conductances presynaptically and, under certain conditions, postsynaptically to selectively depress excitatory neurotransmission in piriform cortical layer Ia-afferent terminals.
AuthorsB J Whalley, G J Stephens, A Constanti
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 156 Issue 6 Pg. 994-1008 (Mar 2009) ISSN: 1476-5381 [Electronic] England
PMID19226287 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anticonvulsants
  • Carbamates
  • Chloride Channels
  • Convulsants
  • Culture Media
  • Pyrimidines
  • S-2-O-carbamoyl-1-o-chlorophenyl-ethanol
  • Sodium Channels
  • 4-aminopyrimidine
  • Lidocaine
  • Calcium
Topics
  • Action Potentials (drug effects)
  • Animals
  • Anticonvulsants (pharmacology)
  • Calcium (physiology)
  • Carbamates (pharmacology)
  • Cell Membrane (drug effects, physiology)
  • Chloride Channels (physiology)
  • Convulsants (pharmacology)
  • Culture Media
  • Excitatory Postsynaptic Potentials (drug effects)
  • Female
  • In Vitro Techniques
  • Lidocaine (pharmacology)
  • Male
  • Neurons (drug effects, physiology)
  • Olfactory Pathways (cytology)
  • Patch-Clamp Techniques
  • Pyrimidines (pharmacology)
  • Rats
  • Rats, Wistar
  • Sodium Channels (physiology)

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