Pre-treatment with the NMDA receptor glycine-binding site antagonist L-701,324 improves pharmacosensitivity in a mouse kindling model.

Abstract

The glycine co-agonist binding site of the N-methyl-D-aspartat (NMDA) receptor is discussed as an interesting target for different central nervous system diseases. Antagonism at this co-agonist site has been suggested as an alternative to the use of non-competitive or competitive NMDA receptor antagonists, which are associated with a pronounced adverse effect profile in chronic epilepsy models and epilepsy patients. In the present study, we addressed the hypothesis that sub-chronic administration of the glycine-binding site antagonist L-701,324 might exert disease-modifying effects in fully kindled mice during a period with frequent seizure elicitation (massive kindling). Moreover, we analyzed whether L-701,324 exposure during this phase affects the subsequent response to an antiepileptic drug. L-701,324 treatment during the massive kindling phase did not affect ictogenesis. Mean seizure severity and cumulative seizure duration proved to be comparable between vehicle- and L-701,324-treated mice. Following withdrawal of L-701,324 seizure thresholds did not differ in a significant manner from those in animals that received vehicle injections. A low dosage of phenobarbital caused a significant increase of the generalized seizure threshold in the L-701,324 pre-treated group, whereas it did not exert a comparable effect in animals that received vehicle during the massive kindling phase. Analysis of P-glycoprotein in the hilus of the hippocampus revealed lower expression rates in L-701,324 pre-treated kindled mice. In conclusion, the data indicate that targeting of the NMDA receptor glycine-binding site does not result in anticonvulsant or disease-modifying effects. However, it might improve antiepileptic drug responses. The findings might be linked to an impact on P-glycoprotein expression. However, future studies are necessary to further evaluate the mechanisms and assess the potential of respective add-on approaches.

• Authors: Christina Zellinger, Josephine D Salvamoser, Jonna Soerensen, Erwin A van Vliet, Eleonora Aronica, Jan Gorter, Heidrun Potschka
• Journal: Epilepsy research (Epilepsy Res) Vol. 108 Issue 4 Pg. 634-43 (May 2014) ISSN: 1872-6844 [Electronic] Netherlands
• PMID: 24656981 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Anticonvulsants
• Excitatory Amino Acid Antagonists
• Quinolones
• L 701324
• Phenobarbital

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Animals
• Anticonvulsants (therapeutic use)
• Behavior, Animal (drug effects)
• Brain (drug effects, metabolism)
• Disease Models, Animal
• Drug Interactions
• Excitatory Amino Acid Antagonists (pharmacology)
• Kindling, Neurologic (drug effects)
• Male
• Mice
• Phenobarbital (therapeutic use)
• Quinolones (pharmacology)
• Seizures (drug therapy, metabolism)