Excitatory amino acid neurotransmission through both NMDA and non-NMDA receptors is involved in the anticonvulsant activity of felbamate in DBA/2 mice

Eur J Pharmacol. 1994 Sep 1;262(1-2):11-9. doi: 10.1016/0014-2999(94)90022-1.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation
  • Animals
  • Anticonvulsants / administration & dosage
  • Anticonvulsants / pharmacology*
  • Anticonvulsants / therapeutic use
  • Binding, Competitive
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Felbamate
  • Female
  • Glycine / administration & dosage
  • Glycine / antagonists & inhibitors
  • Glycine / pharmacology
  • Injections, Intraperitoneal
  • Injections, Intraventricular
  • Kynurenic Acid / analogs & derivatives
  • Kynurenic Acid / pharmacology
  • Male
  • Mice
  • Mice, Inbred DBA
  • N-Methylaspartate / toxicity
  • Phenylcarbamates
  • Propylene Glycols / administration & dosage
  • Propylene Glycols / pharmacology*
  • Propylene Glycols / therapeutic use
  • Quinoxalines / pharmacology
  • Receptors, AMPA / agonists
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / physiology*
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Seizures / chemically induced
  • Seizures / etiology
  • Seizures / prevention & control*
  • Serine / administration & dosage
  • Serine / pharmacology
  • Stereoisomerism
  • Synaptic Transmission / drug effects
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / toxicity

Substances

  • Anticonvulsants
  • Phenylcarbamates
  • Propylene Glycols
  • Quinoxalines
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
  • Serine
  • N-Methylaspartate
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Kynurenic Acid
  • 5,7-dichlorokynurenic acid
  • Glycine
  • Felbamate