Excitatory amino acid neurotransmission through both NMDA and non-NMDA receptors is involved in the anticonvulsant activity of felbamate in DBA/2 mice.
The anticonvulsant activity of felbamate against sound-induced seizures was studied in the DBA/2 mouse model. Felbamate (10-300 mg/kg, i.p.) produced dose-dependent effects with ED50 values for the suppression of tonic, clonic and wild running phases of 23.1, 48.8 and 114.6 mg/kg, respectively. Felbamate also protected DBA/2 mice from N-methyl-D-aspartate (NMDA)-induced seizures with ED50 values of 12.1 and 29 mg/kg for tonus and clonus, respectively. Pretreatment with glycine, an agonist to the glycine/NMDA receptors, shifted the dose-response effect of felbamate to the right (ED50 = 56.8 against tonus and 94.8 mg/kg versus clonus). Similarly, D-serine, an agonist at the glycine site, shifted the ED50 of felbamate against the tonic component of audiogenic seizures from 23.1 to 78.1, and that against clonus from 48.8 to 90.3 mg/kg. Felbamate was also potent to prevent seizures induced by administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), an AMPA/kainate receptor agonist (ED50 = 11.8 and 20.9 mg/kg, against tonus and clonus, respectively). The data indicate that felbamate is an effective anticonvulsant drug in the genetic model of seizure-prone DBA/2 mice. Our findings suggest that the anticonvulsant properties of felbamate depend upon its interaction with neurotransmission mediated by both the glycine/NMDA and the AMPA/kainate receptor complex.
De Sarro
G
G
Department of Experimental and Clinical Medicine, School of Medicine, University of Reggio Calabria, Catanzaro, Italy.
Ongini
E
E
Bertorelli
R
R
Aguglia
U
U
De Sarro
A
A
D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001667:Binding, Competitive; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000078328:Felbamate; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016202:N-Methylaspartate / Q000633:toxicity; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D012694:Serine / Q000008:administration & dosage / Q000494:pharmacology; D013237:Stereoisomerism; D009435:Synaptic Transmission / Q000187:drug effects; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D000927:Anticonvulsants; D048448:Phenylcarbamates; D011409:Propylene Glycols; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D012694:Serine; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007736:Kynurenic Acid; C066192:5,7-dichlorokynurenic acid; D005998:Glycine; D000078328:Felbamate