Inhibition of glutamate release by BIA 2-093 and BIA 2-024, two novel derivatives of carbamazepine, due to blockade of sodium but not calcium channels.
We investigated the mechanism(s) of action of two new putative antiepileptic drugs (AEDs), (S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (BIA 2-093) and 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide (BIA 2-024), by comparing their effects on the release of endogenous glutamate in hippocampal synaptosomes, with those of carbamazepine (CBZ) and oxcarbazepine (OXC). The AEDs inhibited the release of glutamate evoked by 4-aminopyridine (4-AP) or veratridine in a concentration-dependent manner, being CBZ more potent than the other AEDs. Using conditions of stimulation (30 mM KCl), where Na(+) channels are inactivated, the AEDs did not inhibit either the Ca(2+)-dependent or -independent release of glutamate. The results indicate that BIA 2-093 and BIA 2-024 have sodium channel-blocking properties, but CBZ and OXC are more potent than the new AEDs. Moreover, the present data also indicate that Ca(2+) channels coupled to the exocytotic release of glutamate and the activity of the glutamate transporter were not affected by the AEDs.
Ambrósio
A F
AF
Department of Cell Biology, Center for Neuroscience of Coimbra, University of Coimbra, 3004-517, Coimbra, Portugal.
Silva
A P
AP
Malva
J O
JO
Soares-da-Silva
P
P
Carvalho
A P
AP
Carvalho
C M
CM
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D003984:Dibenzazepines / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000378:metabolism
D000927:Anticonvulsants; D015220:Calcium Channels; D003984:Dibenzazepines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C416836:BIA 2-024; D018698:Glutamic Acid; C416835:eslicarbazepine acetate