Abstract:
PURPOSE:The antiepileptic effects of clobazam, a 1,5-benzodiazepine, have been well documented in animal experiments and clinical trials. However, the drug's mechanisms of antiepileptic actions are still undetermined. The purpose of this study was to learn how clobazam and its active metabolite modulate gamma-aminobutyric acid (GABA)-activated currents in rat cerebral neurons in culture. METHODS:Whole-cell voltage-clamp recordings were performed on cultured cerebral neurons of the rat. Clobazam or its metabolite N-desmethylclobazam was dissolved in the extracellular solution and applied for 2 s by pressure ejection from a micropipette. To maintain GABA-activated currents, 2 mM Mg adenosine triphosphate (ATP) was added to the intracellular solution. RESULTS:GABA elicited outward currents that were mediated by GABAA receptor-coupled Cl- channels. Applying clobazam with 10 microM GABA elicited enhanced outward currents. Flumazenil, an antagonist of the benzodiazepine receptor, inhibited the enhancing effect of clobazam. The enhancement ratio increased as much as 2.28-fold in a dose-dependent manner at a concentration of 3 microM clobazam. However, it started to decrease at a concentration of 10 microM clobazam. The metabolite N-desmethylclobazam was tested in the same manner, and exhibited an identical dose-dependent enhancement of GABA-activated currents. CONCLUSIONS:The antiepileptic effects of the 1,5-benzodiazepines are attributed to the enhancement of GABAergic inhibitory neurotransmission. The antiepileptic effects of clobazam are thought to depend mainly on its active metabolite N-desmethylclobazam, which is present in high concentrations in patients who receive long-term clobazam. Clobazam's enhancement of GABA-activated currents was most marked on weaker GABA currents. We therefore infer that clobazam acts more efficiently on tissues in which the release of GABA is diminished.
journal_name
Epilepsiajournal_title
Epilepsiaauthors
Nakamura F,Suzuki S,Nishimura S,Yagi K,Seino Mdoi
10.1111/j.1528-1157.1996.tb00643.xsubject
Has Abstractpub_date
1996-08-01 00:00:00pages
728-35issue
8eissn
0013-9580issn
1528-1167journal_volume
37pub_type
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