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Pre-treatment with the NMDA receptor glycine-binding site antagonist L-701,324 improves pharmacosensitivity in a mouse kindling model.
- 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.)
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Animals
Behavior, Animal drug effects
Brain drug effects
Brain metabolism
Disease Models, Animal
Drug Interactions
Male
Mice
Seizures metabolism
Anticonvulsants therapeutic use
Excitatory Amino Acid Antagonists pharmacology
Kindling, Neurologic drug effects
Phenobarbital therapeutic use
Quinolones pharmacology
Seizures drug therapy
Subjects
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