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

Authors


Dr BJ Whalley, Reading School of Pharmacy, University of Reading, Whiteknights, PO Box 226, Reading RG6 6AP, UK. E-mail: b.j.whalley@reading.ac.uk

Abstract

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 GABAA 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.

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