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

Background 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 µmol·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 µmol·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 µmol·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 µmol·L⁻¹) mimicked carisbamate, implying similar modes of action. Carisbamate (300–600 µmol·L⁻¹) had no effect on spontaneous GABA_A miniature inhibitory postsynaptic currents and at lower concentrations (50–200 µmol·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.