Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 156, Issue 6, Pages 994-1008Publisher
WILEY
DOI: 10.1111/j.1476-5381.2008.00110.x
Keywords
RWJ-333369; carisbamate; lidocaine; piriform cortical brain slices; intracellular recording
Categories
Funding
- Johnson & Johnson Pharmaceutical Research & Development, L.L.C, Titusville, NJ, USA
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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. Effects of carisbamate were investigated in rat piriform cortical neurones by using intracellular electrophysiological recordings. Carisbamate (50-400 mu mol.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 mu mol.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 mu mol.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 mu mol.L-1) mimicked carisbamate, implying similar modes of action. Carisbamate (300-600 mu mol.L-1) had no effect on spontaneous GABA(A) miniature inhibitory postsynaptic currents and at lower concentrations (50-200 mu mol.L-1) inhibited Mg2+-free or 4-aminopyridine-induced seizure-like discharges. 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.
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