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

Authors :
Zellinger C
Salvamoser JD
Soerensen J
van Vliet EA
Aronica E
Gorter J
Potschka H
Source :
Epilepsy research [Epilepsy Res] 2014 May; Vol. 108 (4), pp. 634-43. Date of Electronic Publication: 2014 Mar 02.
Publication Year :
2014

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.<br /> (Copyright © 2014 Elsevier B.V. All rights reserved.)

Details

Language :
English
ISSN :
1872-6844
Volume :
108
Issue :
4
Database :
MEDLINE
Journal :
Epilepsy research
Publication Type :
Academic Journal
Accession number :
24656981
Full Text :
https://doi.org/10.1016/j.eplepsyres.2014.02.012