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Br J Pharmacol. 2009 Mar;156(6):994-1008. doi: 10.1111/j.1476-5381.2008.00110.x.

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

Author information

1
Reading School of Pharmacy, University of Reading, Whiteknights, Reading, UK. 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 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.

PMID:
19226287
PMCID:
PMC2697724
DOI:
10.1111/j.1476-5381.2008.00110.x
[Indexed for MEDLINE]
Free PMC Article

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