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Anticonvulsant Action of GluN2A-Preferring Antagonist PEAQX in Developing Rats

The GluN2A subunit of N-methyl-D-aspartate (NMDA) receptors becomes dominant during postnatal development, overgrowing the originally dominant GluN2B subunit. The aim of our study was to show changes of anticonvulsant action of the GluN2A subunit-preferring antagonist during postnatal development of...

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Autores principales: Mares, Pavel, Tsenov, Grygoriy, Kubova, Hana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003757/
https://www.ncbi.nlm.nih.gov/pubmed/33808912
http://dx.doi.org/10.3390/pharmaceutics13030415
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author Mares, Pavel
Tsenov, Grygoriy
Kubova, Hana
author_facet Mares, Pavel
Tsenov, Grygoriy
Kubova, Hana
author_sort Mares, Pavel
collection PubMed
description The GluN2A subunit of N-methyl-D-aspartate (NMDA) receptors becomes dominant during postnatal development, overgrowing the originally dominant GluN2B subunit. The aim of our study was to show changes of anticonvulsant action of the GluN2A subunit-preferring antagonist during postnatal development of rats. Possible anticonvulsant action of GluN2A-preferring antagonist of NMDA receptors P = [[[(1S)-1-(4-bromophenyl)ethyl]amino](1,2,3,4-tetrahydro-2,3-dioxo-5-quinoxalinyl)methyl]phosphonic acid tetrasodium salt (PEAQX) (5, 10, 20 mg/kg s.c.) was tested in 12-, 18-, and 25-day-old rats in three models of convulsive seizures. Pentylenetetrazol-induced generalized seizures with a loss of righting reflexes generated in the brainstem were suppressed in all three age groups in a dose-dependent manner. Minimal clonic seizures with preserved righting ability exhibited only moderately prolonged latency after the highest dose of PEAQX. Anticonvulsant action of all three doses of PEAQX against cortical epileptic afterdischarges (generated in the forebrain) was found in the 25-day-old animals. The highest dose (20 mg/kg) was efficient also in the two younger groups, which might be due to lower specificity of PEAQX and its partial affinity to the GluN2B subunit. Our results are in agreement with the postero-anterior maturation gradient of subunit composition of NMDA receptors (i.e., an increase of GluN2A representation). In spite of the lower selectivity of PEAQX, our data demonstrate, for the first time, developmental differences in comparison with an antagonist of NMDA receptors with a dominant GluN2B subunit.
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spelling pubmed-80037572021-03-28 Anticonvulsant Action of GluN2A-Preferring Antagonist PEAQX in Developing Rats Mares, Pavel Tsenov, Grygoriy Kubova, Hana Pharmaceutics Article The GluN2A subunit of N-methyl-D-aspartate (NMDA) receptors becomes dominant during postnatal development, overgrowing the originally dominant GluN2B subunit. The aim of our study was to show changes of anticonvulsant action of the GluN2A subunit-preferring antagonist during postnatal development of rats. Possible anticonvulsant action of GluN2A-preferring antagonist of NMDA receptors P = [[[(1S)-1-(4-bromophenyl)ethyl]amino](1,2,3,4-tetrahydro-2,3-dioxo-5-quinoxalinyl)methyl]phosphonic acid tetrasodium salt (PEAQX) (5, 10, 20 mg/kg s.c.) was tested in 12-, 18-, and 25-day-old rats in three models of convulsive seizures. Pentylenetetrazol-induced generalized seizures with a loss of righting reflexes generated in the brainstem were suppressed in all three age groups in a dose-dependent manner. Minimal clonic seizures with preserved righting ability exhibited only moderately prolonged latency after the highest dose of PEAQX. Anticonvulsant action of all three doses of PEAQX against cortical epileptic afterdischarges (generated in the forebrain) was found in the 25-day-old animals. The highest dose (20 mg/kg) was efficient also in the two younger groups, which might be due to lower specificity of PEAQX and its partial affinity to the GluN2B subunit. Our results are in agreement with the postero-anterior maturation gradient of subunit composition of NMDA receptors (i.e., an increase of GluN2A representation). In spite of the lower selectivity of PEAQX, our data demonstrate, for the first time, developmental differences in comparison with an antagonist of NMDA receptors with a dominant GluN2B subunit. MDPI 2021-03-19 /pmc/articles/PMC8003757/ /pubmed/33808912 http://dx.doi.org/10.3390/pharmaceutics13030415 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Mares, Pavel
Tsenov, Grygoriy
Kubova, Hana
Anticonvulsant Action of GluN2A-Preferring Antagonist PEAQX in Developing Rats
title Anticonvulsant Action of GluN2A-Preferring Antagonist PEAQX in Developing Rats
title_full Anticonvulsant Action of GluN2A-Preferring Antagonist PEAQX in Developing Rats
title_fullStr Anticonvulsant Action of GluN2A-Preferring Antagonist PEAQX in Developing Rats
title_full_unstemmed Anticonvulsant Action of GluN2A-Preferring Antagonist PEAQX in Developing Rats
title_short Anticonvulsant Action of GluN2A-Preferring Antagonist PEAQX in Developing Rats
title_sort anticonvulsant action of glun2a-preferring antagonist peaqx in developing rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003757/
https://www.ncbi.nlm.nih.gov/pubmed/33808912
http://dx.doi.org/10.3390/pharmaceutics13030415
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