Anticonvulsant Action of GluN2A-Preferring Antagonist PEAQX in Developing Rats

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.

The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats

“…Incidence and latency of both seizure types (mS and GTCS) and other behavioral phenomena (e.g., isolated myoclonic jerks) and abnormalities were also recorded. To assess the severity of the epileptic phenomena, animals were assigned a score for the most severe behavioral characteristics as follows [ 18 ].…”

“…In our previous study, PEAQX, a GluN2A-preferring antagonist of NMDA receptors, exhibited anti-seizure activity in infantile rats [ 18 ]. Selectivity of PEAQX to GluN1/GluN2A receptors vs. GluN1/GluN2B receptors is relatively low and PEAQX in high doses effectively suppressed seizures also in juvenile P25 animals.…”