Evidence for anticonvulsant and neuroprotectant action of felbamate mediated by strychnine-insensitive glycine receptors.
Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a novel agent effective against maximal electroshock, pentylenetetrazol and other chemically induced seizures in mice and rats. Felbamate has been proposed as a novel anticonvulsant for the treatment of generalized tonic-clonic and complex partial seizures. In addition, felbamate has been shown to have neuroprotectant effects (in vitro and in vivo) in neonate models of cerebral ischemia. However, few existing studies have contributed to the elucidation of the mechanism of anticonvulsant and neuroprotectant action of felbamate. Because glycinergic mechanisms have been demonstrated to be involved with seizure disorders and neuroprotection, we investigated the binding interaction of felbamate with strychnine-insensitive glycine receptors and compared these findings with brain and plasma levels of felbamate after drug treatment. Inhibition of [3H]5,7-dichlorokynurenic acid (a high-affinity glycine receptor antagonist) binding by felbamate (IC50 = 374 microM) corresponded well with peak felbamate concentrations found in brain (683 and 759 microM) and plasma (679 and 807 microM) 8 hr after 300 (i.p.) or 500 mg/kg (p.o.) doses, respectively. Chemically diverse anticonvulsants tested and MK 801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine maleate] did not modulate [3H]5,7-dichlorokynurenic acid binding. Additional studies have shown that felbamate does not interact with other sites associated with the N-methyl-D-aspartate receptor complex. Thus, the data presented in this report strongly indicate a mechanism of action for felbamate through strychnine-insensitive glycine receptor interaction.
McCabe
R T
RT
Laboratory for Neuroscience, Pharmaceutical Discovery Corporation, Elmsford, New York.
Wasterlain
C G
CG
Kucharczyk
N
N
Sofia
R D
RD
Vogel
J R
JR
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D000078328:Felbamate; D005260:Female; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects*; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000502:physiology; D013331:Strychnine / Q000494:pharmacology*
D000927:Anticonvulsants; D048448:Phenylcarbamates; D011409:Propylene Glycols; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter; D016291:Dizocilpine Maleate; D007736:Kynurenic Acid; D013331:Strychnine; C066192:5,7-dichlorokynurenic acid; D000078328:Felbamate