Chlormethiazole inhibits epileptiform activity by potentiating GABA(A) receptor function.
Chlormethiazole has sedative, hypnotic, anticonvulsant and neuroprotective properties. Using in vitro grease-gap recordings, we show that it inhibits epileptiform activity in neocortical slices superfused with Mg(2+)-free medium (IC(50) approximately 200 microM). At an antiepileptic concentration (300 microM), chlormethiazole potentiated the action of exogenously applied GABA (1 mM) but did not affect responses to the glutamate receptor agonists N-methyl-D-aspartate (10 microM) or L-quisqualic acid (3 microM). The GABA(A) receptor antagonist N-methyl-bicuculline (50 microM) reduced chlormethiazole's potency to inhibit the epileptiform activity. These results indicate that chlormethiazole's anticonvulsant action is likely mediated by potentiating GABA(A)ergic inhibition rather than by antagonising glutamatergic excitation.
Empson
R M
RM
Vernalis Research Ltd, Oakdene Court, 613 Reading Road, Winnersh, RG41 5UA, Wokingham, UK.
Gee
V J
VJ
Sheardown
M J
MJ
Newberry
N R
NR
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002719:Chlormethiazole / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
D018696:Neuroprotective Agents; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D002719:Chlormethiazole; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; C056639:2-amino-5-phosphopentanoic acid; D016318:Quisqualic Acid; D014633:Valine; D001640:Bicuculline