title: 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.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Koeniginstr. 16, D-80539 Munich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Zellinger
authors.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Koeniginstr. 16, D-80539 Munich, Germany.
authors.forename: Josephine D
authors.initials: JD
authors.lastname: Salvamoser
authors.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Koeniginstr. 16, D-80539 Munich, Germany.
authors.forename: Jonna
authors.initials: J
authors.lastname: Soerensen
authors.affiliation: Epilepsy Institute in The Netherlands (SEIN), Achterweg 5, 2103 SW Heemstede, The Netherlands; Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, P.O. Box 94215, 1090 GE Amsterdam, The Netherlands.
authors.forename: Erwin A
authors.initials: EA
authors.lastname: van Vliet
authors.affiliation: Epilepsy Institute in The Netherlands (SEIN), Achterweg 5, 2103 SW Heemstede, The Netherlands; Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, P.O. Box 94215, 1090 GE Amsterdam, The Netherlands; Department of (Neuro) Pathology, Academic Medical Center, University of Amsterdam, Postbus 22660, 1100 DD Amsterdam, The Netherlands.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.affiliation: Epilepsy Institute in The Netherlands (SEIN), Achterweg 5, 2103 SW Heemstede, The Netherlands; Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, P.O. Box 94215, 1090 GE Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Gorter
authors.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Koeniginstr. 16, D-80539 Munich, Germany. Electronic address: potschka@pharmtox.vetmed.uni-muenchen.de.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Potschka
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D051379:Mice; D010634:Phenobarbital / Q000627:therapeutic use*; D015363:Quinolones / Q000494:pharmacology*; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D015363:Quinolones; C094635:L 701324; D010634:Phenobarbital
keywords: Blood–brain barrier; Drug resistance; Glycine-binding site; Multidrug transporter; NMDA receptor