Suppression of neuronal network excitability and seizure-like events by 2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine in juvenile rat hippocampus

Involvement of a metabotropic glutamate receptor

Bálint Lasztóczi, Zsuzsa Emri, Éva Szárics, László Héja, Ágnes Simon, Lajos Nyikos, Julianna Kardos

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

We present data on the antiepileptic potency of 2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine (Q5) in juvenile (P9-13) rat hippocampal slices and in particular Q5's action mechanism and target. Q5 (200-500 μM), but not α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/Kainate receptor antagonists blocked low-[Mg2+]-induced seizure-like events (SLE) in the CA3 region. Q5 (100 μM) decreased Glu-induced [35S]guanosine 5′-O-(3-thiotriphosphate) binding enhancement in brain homogenates, without interaction with ionotropic Glu receptor sites and Glu transport. In voltage-clamped CA3 pyramidal cells, Q5 (500 μM) depressed activities of spontaneous excitatory and inhibitory postsynaptic currents without affecting miniature inhibitory currents. Metabotropic Glu receptor (mGluR) subtype antagonists affected network excitability dissimilarly. Intracellular Ca2+ ion transients induced by the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) were suppressed by Q5. Agreeing predictions obtained by modelling Q5 binding to different experimental conformations of mGlu1, Q5 was bound partially to an mGluR binding site in the presence of 1 mM ACPD. Findings suggest the apparent involvement of a novel phenotype of action or a new mGluR subtype in the specific suppression of epileptiform activity by Q5 through the depression of network excitability.

Original languageEnglish
Pages (from-to)41-54
Number of pages14
JournalNeurochemistry International
Volume49
Issue number1
DOIs
Publication statusPublished - Jul 2006

Fingerprint

Quinazolines
Metabotropic Glutamate Receptors
Hippocampus
Seizures
Guanosine 5'-O-(3-Thiotriphosphate)
Kainic Acid Receptors
Inhibitory Postsynaptic Potentials
Pyramidal Cells
Excitatory Postsynaptic Potentials
Anticonvulsants
Binding Sites
Ions
Phenotype
Brain
1-amino-1,3-dicarboxycyclopentane
piperidine
propionic acid
bucide

Keywords

  • 2-Methyl-4-oxo-3H-quinazoline-3-acetyl piperidine
  • Cytosolic Ca ion transients
  • Glutamate binding targets
  • Metabotropic glutamate receptors
  • Network excitability
  • Seizure-like events

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

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title = "Suppression of neuronal network excitability and seizure-like events by 2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine in juvenile rat hippocampus: Involvement of a metabotropic glutamate receptor",
abstract = "We present data on the antiepileptic potency of 2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine (Q5) in juvenile (P9-13) rat hippocampal slices and in particular Q5's action mechanism and target. Q5 (200-500 μM), but not α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/Kainate receptor antagonists blocked low-[Mg2+]-induced seizure-like events (SLE) in the CA3 region. Q5 (100 μM) decreased Glu-induced [35S]guanosine 5′-O-(3-thiotriphosphate) binding enhancement in brain homogenates, without interaction with ionotropic Glu receptor sites and Glu transport. In voltage-clamped CA3 pyramidal cells, Q5 (500 μM) depressed activities of spontaneous excitatory and inhibitory postsynaptic currents without affecting miniature inhibitory currents. Metabotropic Glu receptor (mGluR) subtype antagonists affected network excitability dissimilarly. Intracellular Ca2+ ion transients induced by the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) were suppressed by Q5. Agreeing predictions obtained by modelling Q5 binding to different experimental conformations of mGlu1, Q5 was bound partially to an mGluR binding site in the presence of 1 mM ACPD. Findings suggest the apparent involvement of a novel phenotype of action or a new mGluR subtype in the specific suppression of epileptiform activity by Q5 through the depression of network excitability.",
keywords = "2-Methyl-4-oxo-3H-quinazoline-3-acetyl piperidine, Cytosolic Ca ion transients, Glutamate binding targets, Metabotropic glutamate receptors, Network excitability, Seizure-like events",
author = "B{\'a}lint Laszt{\'o}czi and Zsuzsa Emri and {\'E}va Sz{\'a}rics and L{\'a}szl{\'o} H{\'e}ja and {\'A}gnes Simon and Lajos Nyikos and Julianna Kardos",
year = "2006",
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T1 - Suppression of neuronal network excitability and seizure-like events by 2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine in juvenile rat hippocampus

T2 - Involvement of a metabotropic glutamate receptor

AU - Lasztóczi, Bálint

AU - Emri, Zsuzsa

AU - Szárics, Éva

AU - Héja, László

AU - Simon, Ágnes

AU - Nyikos, Lajos

AU - Kardos, Julianna

PY - 2006/7

Y1 - 2006/7

N2 - We present data on the antiepileptic potency of 2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine (Q5) in juvenile (P9-13) rat hippocampal slices and in particular Q5's action mechanism and target. Q5 (200-500 μM), but not α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/Kainate receptor antagonists blocked low-[Mg2+]-induced seizure-like events (SLE) in the CA3 region. Q5 (100 μM) decreased Glu-induced [35S]guanosine 5′-O-(3-thiotriphosphate) binding enhancement in brain homogenates, without interaction with ionotropic Glu receptor sites and Glu transport. In voltage-clamped CA3 pyramidal cells, Q5 (500 μM) depressed activities of spontaneous excitatory and inhibitory postsynaptic currents without affecting miniature inhibitory currents. Metabotropic Glu receptor (mGluR) subtype antagonists affected network excitability dissimilarly. Intracellular Ca2+ ion transients induced by the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) were suppressed by Q5. Agreeing predictions obtained by modelling Q5 binding to different experimental conformations of mGlu1, Q5 was bound partially to an mGluR binding site in the presence of 1 mM ACPD. Findings suggest the apparent involvement of a novel phenotype of action or a new mGluR subtype in the specific suppression of epileptiform activity by Q5 through the depression of network excitability.

AB - We present data on the antiepileptic potency of 2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine (Q5) in juvenile (P9-13) rat hippocampal slices and in particular Q5's action mechanism and target. Q5 (200-500 μM), but not α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/Kainate receptor antagonists blocked low-[Mg2+]-induced seizure-like events (SLE) in the CA3 region. Q5 (100 μM) decreased Glu-induced [35S]guanosine 5′-O-(3-thiotriphosphate) binding enhancement in brain homogenates, without interaction with ionotropic Glu receptor sites and Glu transport. In voltage-clamped CA3 pyramidal cells, Q5 (500 μM) depressed activities of spontaneous excitatory and inhibitory postsynaptic currents without affecting miniature inhibitory currents. Metabotropic Glu receptor (mGluR) subtype antagonists affected network excitability dissimilarly. Intracellular Ca2+ ion transients induced by the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) were suppressed by Q5. Agreeing predictions obtained by modelling Q5 binding to different experimental conformations of mGlu1, Q5 was bound partially to an mGluR binding site in the presence of 1 mM ACPD. Findings suggest the apparent involvement of a novel phenotype of action or a new mGluR subtype in the specific suppression of epileptiform activity by Q5 through the depression of network excitability.

KW - 2-Methyl-4-oxo-3H-quinazoline-3-acetyl piperidine

KW - Cytosolic Ca ion transients

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KW - Metabotropic glutamate receptors

KW - Network excitability

KW - Seizure-like events

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