FELBAMATE INHIBITS DIHYDROPYRIDINE-SENSITIVE CALCIUM CHANNELS IN CENTRAL NEURONS

The effect of the antiepileptic drug felbamate (FBM) on high-voltage-a ctivated Ca++ currents was studied in cortical and neostriatal neurons acutely isolated from adult rats. Patch-clamp recordings in the whole -cell configuration were performed. Ba++ ions as the charge carrier fo r Ca++ channels were used. In pyramidal cortical cells, FBM dose-depen dently reduced high-voltage-activated Ca++ currents in all the tested neurons. At concentrations of 30 to 100 nM, FBM already produced a sig nificant inhibition of high-voltage-activated Ca++ currents (-6/-15%). At saturating concentrations (1-3 mu M), FBM-mediated inhibition aver aged 44%. The responses were fully reversible. The dose-response curve s revealed IC50 of 504 nM. In striatal neurons, FBM decreased the same conductances by about 28%; the threshold dose was 1 to 2 mu M, with a n IC50 of 18.7 mu M. In both structures, the observed inhibitions were unaffected by omega-conotoxin GVIA and omega-agatoxin IVA, suggesting that N-like channels and P-Like channels were not involved in the PPM -mediated responses. In addition, when omega-conotoxin GVIA and omega- agatoxin IVA (100 nM) were coapplied, the FBM-mediated inhibition on t he remaining Ca++ currents averaged 87%. The FBM responses were occlud ed by micromolar concentrations of nifedipine, supporting a direct int erference with dihydropyridine-sensitive channels. It is concluded tha t the described effect of FBM might represent an efficacious mechanism for either controlling spike discharge from epileptic foci or protect ing neurons from excessive Ca++ loading. In both cases, FBM would act as a broad spectrum neuroprotective agent.