Anticonvulsant Action of GluN2A-Preferring Antagonist PEAQX in Developing Rats.

Pavel Mares,Hana Kubova,Grygoriy Tsenov

doi:10.3390/pharmaceutics13030415

Abstract

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.

Highlights

Epilepsy is a common disorder leading to staggering costs, both with regard to human suffering and to economics
Because epilepsy frequently begins during childhood and has a higher incidence during the first decade of life than at any other time [1], issues of safety and efficacy of antiepileptic drugs (AEDs) represent a major concern in pediatrics
The effects of PEAQX on incidence of generalized tonic-clonic seizures (GTCS) depended on age

Summary

Introduction

Epilepsy is a common disorder leading to staggering costs, both with regard to human suffering and to economics. There is no causal cure for epilepsy, and the management of epileptic seizures in patients with epilepsy relies mostly on long-term administration of antiepileptic drugs (AEDs). Because epilepsy frequently begins during childhood and has a higher incidence during the first decade of life than at any other time [1], issues of safety and efficacy of AEDs represent a major concern in pediatrics. Some antiepileptic drugs affecting glutamate ionotropic receptors are used in human medicine—e.g., felbamate (among other mechanisms of action antagonist of N-methyl-D-aspartate (NMDA) receptors [2]) and perampanel—α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist [3].

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