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.
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Authors | B J Whalley, G J Stephens, A Constanti |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 156
Issue 6
Pg. 994-1008
(Mar 2009)
ISSN: 1476-5381 [Electronic] England |
PMID | 19226287
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anticonvulsants
- Carbamates
- Chloride Channels
- Convulsants
- Culture Media
- Pyrimidines
- S-2-O-carbamoyl-1-o-chlorophenyl-ethanol
- Sodium Channels
- 4-aminopyrimidine
- Lidocaine
- Calcium
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Topics |
- Action Potentials
(drug effects)
- Animals
- Anticonvulsants
(pharmacology)
- Calcium
(physiology)
- Carbamates
(pharmacology)
- Cell Membrane
(drug effects, physiology)
- Chloride Channels
(physiology)
- Convulsants
(pharmacology)
- Culture Media
- Excitatory Postsynaptic Potentials
(drug effects)
- Female
- In Vitro Techniques
- Lidocaine
(pharmacology)
- Male
- Neurons
(drug effects, physiology)
- Olfactory Pathways
(cytology)
- Patch-Clamp Techniques
- Pyrimidines
(pharmacology)
- Rats
- Rats, Wistar
- Sodium Channels
(physiology)
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