2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and 5-7-dichlorokynurenic-acid

The anticonvulsant effects of felbamate (10-300 mg/kg, intraperitoneally, IP), and those of two representative antagonists of the excitatory amino acid receptors, 5-7 dichlorokynurenic acid (5-7DCKA; 0.6-30 nmol/mouse, intracerebroventricularly, ICV), and 2, 3-dihydroxy-6 nitro-7-sulfamoylbenzo (F) quinoxoline (NBQX; 1.1-33.6 mg/kg, IP) were studied in the DBA/2 mice. All drugs protected the animals from sound-induced seizures. The drugs were also effective against seizures induced by stimulation of the excitatory amino acid receptor complex using the agonists N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA). In separate studies, felbamate protected mice from seizures induced by ICV administration of the activator of dihydropyridine-sensitive calcium channels, methyl-1, 4-dihydro-2, 6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate (Bay k 8644), with ED50 values of 26 and 46.9 mg/kg for tonus and clonus, respectively. Using Bay k 8644, NBQX (1-40 mg/kg IP) was uneffective, while 5,7DCKA (5-90 nmol/mouse, ICV) protected mice against tonus. Moreover, felbamate prevented seizures induced by blocking voltage-dependent K+ channels using alpha-dendrotoxin, with ED50 values of 22.6 mg/kg for tonus and of 34.8 mg/kg for clonus. Conversely, 5,7DCKA or NBQX did not significantly antagonize seizures induced by alpha-dendrotoxin. The present data indicate that felbamate is an effective anticonvulsant drug in DBA/2 mice with a broader anticonvulsant spectrum than 5,7DCKA and NBQX.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Behavior, Animal; Convulsants; Electroshock; Excitatory Amino Acid Antagonists; Felbamate; Female; Injections, Intraventricular; Ion Channel Gating; Kynurenic Acid; Male; Mice; Mice, Inbred DBA; Motor Activity; Phenylcarbamates; Potassium Channels; Propylene Glycols; Quinoxalines

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.

Topics: Acoustic Stimulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Binding, Competitive; Disease Models, Animal; Dose-Response Relationship, Drug; Felbamate; Female; Glycine; Injections, Intraperitoneal; Injections, Intraventricular; Kynurenic Acid; Male; Mice; Mice, Inbred DBA; N-Methylaspartate; Phenylcarbamates; Propylene Glycols; Quinoxalines; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Seizures; Serine; Stereoisomerism; Synaptic Transmission