INVITRO STUDIES ON THE BROAD-SPECTRUM ANTICONVULSANT LORECLEZOLE IN THE HIPPOCAMPUS

In hippocampal slices from guinea-pig a paired-pulse stimulation protocol was used to examine the effects of loreclezole, R-(+)-etomidate, phenobarbital and pentobarbital on orthodromic and antidromic GABAergic neuronal inhibition in the CA1 region. All four compounds increased orthodromic GABAergic inhibition, with R-(+)-etomidate and pentobarbital inducing a quantitatively larger effect than loreclezole and phenobarbital. Only R-(+)-etomidate and pentobarbital increased antidromic GABAergic inhibition. We propose that all four compounds are anticonvulsant by increasing feed-forward dendritic GABAergic inhibition, whilst only the sedative/hypnotic compounds (R-(+)-etomidate, pentobarbital) increase feedback recurrent GABAergic inhibition. Loreclezole was also shown to inhibit 'low Ca2+, and 'low Mg2+, epileptogenesis at similar concentrations to those active on inhibition. Thus loreclezole may possess other pharmacodynamic properties, beyond its ability to increase feed-forward GABAergic neuronal inhibition, which contribute to its antiepileptic action.