Mechanism of action of the anticonvulsant felbamate: Opposing effects on N‐methyl‐D‐aspartate and γ‐aminobutyric acidA receptors

@article{Rho1994MechanismOA,
  title={Mechanism of action of the anticonvulsant felbamate: Opposing effects on N‐methyl‐D‐aspartate and $\gamma$‐aminobutyric acidA receptors},
  author={Jong M. Rho and Sean D. Donevan and Michael A. Rogawski},
  journal={Annals of Neurology},
  year={1994},
  volume={35}
}
Felbamate is a promising new antiepileptic drug whose mechanism of action is unknown. In whole‐cell voltage clamp recordings from cultured rat hippocampal neurons, clinically relevant concentrations of felbamate (0.1–3 mM) inhibited N‐methyl‐D‐aspartate (NMDA) responses and potentiated γ‐aminobutyric acid (GABA) responses. Single‐channel recordings indicated that the effect on NMDA responses occurred via a channel blocking mechanism. Felbamate is the first anticonvulsant drug with dual actions… 
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TLDR
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Mechanisms of action of antiseizure drugs.
Mechanisms of action of antiepileptic drugs
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This chapter considers each of the targets and discusses how AEDs affect the activity of these targets, most notably voltagegated sodium and potassium channels and GABAA receptors.
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References

SHOWING 1-10 OF 20 REFERENCES
Effect of Anticonvulsant Felbamate on GABAA Receptor System
TLDR
Felbamate (FBM, 2‐phenyl‐1,3‐propanediol dicarbamate), a potential antiepileptic drug (AED), has an unknown mechanism of action and results suggest that the anticonvulsant effect of FBM does not involve GABAAergic transmission.
Evidence for anticonvulsant and neuroprotectant action of felbamate mediated by strychnine-insensitive glycine receptors.
TLDR
The data presented in this report strongly indicate a mechanism of action for felbamate through strychnine-insensitive glycine receptor interaction as a novel anticonvulsant for the treatment of generalized tonic-clonic and complex partial seizures.
Comparative Anticonvulsant Activity and Neurotoxicity of Felbamate and Four Prototype Antiepileptic Drugs in Mice and Rats
TLDR
Felbamate is a relatively nontoxic agent with a unique profile of anticonvulsant action and is effective after nontoxic oral doses in both mice and rats by the MES and s.c. PTZ tests.
Felbamate for partial seizures
TLDR
The results of a double-blind, randomized, placebo-controlled clinical trial in patients with partial seizures indicates that felbamate is safe and effective in the treatment of comedicated patients with severely refractory epilepsy.
Arcaine blocks N-methyl-D-aspartate receptor responses by an open channel mechanism: whole-cell and single-channel recording studies in cultured hippocampal neurons.
TLDR
Results indicate that arcaine inhibits NMDA-induced [3H]dizocilpine binding by blocking the open NMDA receptor channel, an action that is independent of the polyamine site.
CGS 9896 and ZK 91296, but not CGS 8216 and RO 15-1788, are pure benzodiazepine receptor antagonists on mouse neurons in culture.
TLDR
CGS 8216 and methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) reversibly and dose-dependently reduced GABA responses on spinal cord neurons and antagonized the reduction of GABA responses by DMCM.
Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds.
TLDR
Antiepileptic drug pheny toin potentiates GABA in the rat cuneate nucleus and its metabolite as potent inhibitors of microsomal metabolism of phenytoin and carbamazepine.
Do NMDA antagonists prevent neuronal injury? Yes.
TLDR
The observed neuroprotective effects of NMDA antagonists do not represent isolated findings, but rather they are predictions of a strong hypothesis implicating excitotoxicity—the lethal overstimulation of neuronal glutamate receptors in the pathogenesis of hypoxicischemic central neuronal degeneration.
Felbamate: A Clinical Trial for Complex Partial Seizures
TLDR
A randomized, double‐blind, three‐period cross‐over study of felbamate (FBM, 2‐phenyl‐l,3‐propanediol dicarbamate: Carter‐Wallace 554) in patients with complex partial seizures suggested a strong antiseizure effect of FBM.
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