title: Investigation of the effects of the novel anticonvulsant compound carisbamate (RWJ-333369) on rat piriform cortical neurones in vitro.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Effects of carisbamate were investigated in rat piriform cortical neurones by using intracellular electrophysiological recordings.
  
  
  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
  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.
authors.affiliation: Reading School of Pharmacy, University of Reading, Whiteknights, Reading, UK. b.j.whalley@reading.ac.uk
authors.forename: B J
authors.initials: BJ
authors.lastname: Whalley
authors.forename: G J
authors.initials: GJ
authors.lastname: Stephens
authors.forename: A
authors.initials: A
authors.lastname: Constanti
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D002219:Carbamates / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D018118:Chloride Channels / Q000502:physiology; D003292:Convulsants / Q000494:pharmacology; D003470:Culture Media; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009833:Olfactory Pathways / Q000166:cytology*; D018408:Patch-Clamp Techniques; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000502:physiology
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D018118:Chloride Channels; D003292:Convulsants; D003470:Culture Media; D011743:Pyrimidines; C518914:S-2-O-carbamoyl-1-o-chlorophenyl-ethanol; D015222:Sodium Channels; C034821:4-aminopyrimidine; D008012:Lidocaine; D002118:Calcium