In vitro 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.
Ashton
D
D
Department of Neuropsychopharmacology, Janssen Research Foundation, Beerse, Belgium.
Willems
R
R
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002118:Calcium / Q000172:deficiency / Q000502:physiology; D004558:Electric Stimulation; D004827:Epilepsy / Q000503:physiopathology; D005045:Etomidate / Q000494:pharmacology; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects*; D066298:In Vitro Techniques; D008275:Magnesium Deficiency / Q000503:physiopathology; D010424:Pentobarbital / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000927:Anticonvulsants; D014230:Triazoles; D005680:gamma-Aminobutyric Acid; C066440:loreclezole; D010424:Pentobarbital; D002118:Calcium; D010634:Phenobarbital; D005045:Etomidate