Abstracts

BIA 2-093 [(S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide] is a novel antiepileptic drug endowed with an anticonvulsant potency similar to that of carbamazepine, and shares with carbamazepine and oxcarbazepine the capability to inhibit voltage-gated sodium channels. BIA 2-093 is efficacious against maximal electroshock seizure induced seizures, protects against picrotoxin-induced seizures in mice and rats, and prevents development of kindling in rats. We have tested the effect of BIA 2-093 on latrunculin A-induced seizures, and its effect on the increase in extracellular glutamate levels induced by latrunculin A. Rat hippocampus was continuously perfused with a latrunculin A solution (4[mu]M) through CMA/12 microdialysis probes at a flow rate of 2 [mu]l/min during 8 hours with continuous EEG and videotape recording for 3 consecutive days. The same protocol was repeated after oral administration of BIA 2-093 (10 and 30 mg/kg).Samples from the microdialysate were collected and analyzed by HPLC using pre-column derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) and fluorescence detection. Continuous microperfusion of latrunculin A alone induced a variable number of seizures (4.3[plusmn] 2.7) in the 90% of the animals studied and a significant increase in basal glutamate concentrations (from 27.6[plusmn] 8.2 mM to 62.1[plusmn] 14.9 mM four h after perfusion; p[lt]0.01). BIA 2-093, at both doses of 30 and 10 mg/kg, completely supressed seizures and significantly reduced extracellular glutamate concentrations (26.8[plusmn]6.6 mM and 18.1[plusmn]5.3 for doses of 10 and 30 mg/kg respectively; p[lt]0.01 when compared with latrunculin A treatment). BIA 2-093, at oral doses of 10 and 30 mg/kg, shows an excellent antiepileptic effect against seizures induced by latrunculin A microperfusion in the rat hippocampus. The molecular mechaninsms of latrunculin A seizures are still unknown, however, the increase in extracellular glutamate concentrations observed during latrunculin A microperfusion are completely reversed by BIA 2-093. (Supported by BIAL (Portugal).)