The anticonvulsant effect of the non-NMDA antagonists, NBQX and GYKI 52466, in mice

doi:10.1016/0920-1211(91)90018-B

Epilepsy Research

Volume 9, Issue 2, July 1991, Pages 92-96

https://doi.org/10.1016/0920-1211(91)90018-B Get rights and content

Abstract

The excitatory amino acid antagonists, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline) and GYKI 52466 (l-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzodiazepine) that act on non-NMDA receptors, provide potent anticonvulsant protection against AMPA ((RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-induced seizures in Swiss mice and against sound-induced seizures in seizure-susceptible DBA/2 mice. Maximal anticonvulsant protection is observed 5–30 min after the i.p. administration of NBQX and 5–15 min after the i.p. administration of GYKI 52466 in DBA/2 mice. The ED₅₀ values for the protection against AMPA-induced seizures by NBQX (30 min i.p.) and GYKI 52466 (15 min i.p.) are 23.6 (11.6–48.0) and 18.5 (11.5–29.5) μmol/kg, respectively. The ED₅₀ values at 15 min for the protection against sound-induced seizures in DBA/2 mice are 31.3 (24.9–39.4) μmol/kg (NBQX i.p.), 37.8 (21.2–67.4) μmol/kg (NBQX i.v.) and 13.7 (11.5–16.5) μmol/kg (GYKI 52466, i.p.). In DBA/2 mice the therapeutic index (ratio of ED₅₀ values for impaired rotarod performance and anticonvulsant action) is 6.6 for NBQX (15 and 30 min, i.p.) and 2.0 for GYKI 52466 (15 min i.p.).

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Cited by (194)

Inhibitory effect of anti-seizure medications on ionotropic glutamate receptors: special focus on AMPA receptor subunits
2020, Epilepsy Research
Citation Excerpt :
In addition to perampanel, NBQX and GYKI 52466, which are competitive and non-competitive antagonists, respectively, were found to directly inhibit AMPA receptors, which is consistent with previous findings (Donevan and Rogawski, 1993; Sheardown et al., 1990). Studies have also shown that NBQX and GYKI 52466 block seizures in animal models (Chapman et al., 1991; Chen et al., 2016; Namba et al., 1994). However, these compounds have not been approved as ASMs due to issues including poor blood-brain barrier penetration, poor solubility at a neutral pH range, and short half-life (Hanada, 2014b).
The purpose of the current analysis was to investigate the direct inhibitory effects of perampanel and other anti-seizure medications (ASMs) on the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartic acid (NMDA), and kainate glutamate receptor subtypes using electrophysiological assessments.
AMPA receptor subunit-expressing cell lines (hGluA1–4, including two kinds of Q/R RNA-editing variants of hGluA2), NMDA receptor-expressing cells (hNR1/hNR2B), and kainate receptor-expressing cells (hGluK2) were developed in house. The effects of perampanel, and other ASMs including topiramate, phenobarbital, lamotrigine, gabapentin, carbamazepine, valproate, levetiracetam, and lacosamide, on AMPA, NMDA, and kainate receptors were evaluated by automated patch-clamp technique. In the same way, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) and GYKI 52466 were evaluated as reference compounds of AMPA receptor antagonists. For the AMPA receptor functional assay, AMPA currents were elicited by AMPA in the presence of cyclothiazide. NMDA with glycine was used as a stimulant for the NMDA receptor assays, while glutamate was used for the kainate receptor assays. The mean 50 % inhibitory concentration (IC₅₀) values were determined based on sigmoidal-curve fitting using GraphPad Prism software.
Perampanel inhibited functions of hGluA1–4, but did not inhibit hNR1/hNR2B and hGluK2 up to 25 μM, the maximum soluble concentration. The IC₅₀ values were 660 nM for hGluA1, 780 nM for hGluA2(R), 1200 nM for hGluA2(Q), 1200 nM for hGluA3, and 1800 nM for hGluA4. NBQX and GYKI 52466 also inhibited the function of all AMPA receptor subunits, but did not inhibit hNR1/hNR2B and hGluK2. The IC₅₀ values for NBQX were 880 nM for hGluA1, 290 nM for hGluA2(R), 310 nM for hGluA2(Q), 330 nM for hGluA3, and 630 nM for hGluA4. For GYKI 52466, IC₅₀ values were 25,000 nM for hGluA1, 30,000 nM for hGluA2(R), 42,000 nM for hGluA2(Q), 28,000 nM for hGluA3, and 53,000 nM for hGluA4. Phenobarbital inhibited hGluA2(R) at an IC₅₀ value of 730,000 nM. The majority of other ASMs evaluated in this study did not show a direct inhibitory effect on almost any of the glutamate receptor functions examined up to 1 M. However, lamotrigine and carbamazepine inhibited hNR1/hNR2B function at IC₅₀ values of 930,000 and 1,000,000 nM, respectively.
Only a few ASMs evaluated in this study showed direct interaction with ionotropic glutamate receptors. Perampanel is the only ASM that had a potent inhibitory effect on all AMPA receptor subtypes, but did not inhibit NMDA or kainate receptor subunits; while phenobarbital inhibited GluA2(R), and carbamazepine and lamotrigine inhibited the NMDA receptor at high concentration ranges.
NBQX, a highly selective competitive antagonist of AMPA and KA ionotropic glutamate receptors, increases seizures and mortality following picornavirus infection
2016, Experimental Neurology
Seizures occur due to an imbalance between excitation and inhibition, with the balance tipping towards excitation, and glutamate is the predominant excitatory neurotransmitter in the central nervous system of mammals. Since upregulation of expression and/or function of glutamate receptors can contribute to seizures we determined the effects of three antagonists, NBQX, GYKI-52466 and MK 801, of the various ionotropic glutamate receptors, AMPA, NMDA and KA, on acute seizure development in the Theiler's murine encephalomyelitis virus (TMEV)-induced seizure model. We found that only NBQX had an effect on acute seizure development, resulting in a significantly higher number of mice experiencing seizures, an increase in the number of seizures per mouse, a greater cumulative seizure score per mouse and a significantly higher mortality rate among the mice. Although NBQX has previously been shown to be a potent anticonvulsant in animal seizure models, seizures induced by electrical stimulation, drug administration or as a result of genetic predisposition may differ greatly in terms of mechanism of seizure development from our virus-induced seizure model, which could explain the opposite, proconvulsant effect of NBQX observed in the TMEV-induced seizure model.
AMPA Receptors as Therapeutic Targets for Neurological Disorders
2016, Advances in Protein Chemistry and Structural Biology
Almost every neurological disease directly or indirectly affects synapse function in the brain. However, these diseases alter synapses through different mechanisms, ultimately resulting in altered synaptic transmission and/or plasticity. Glutamate is the major neurotransmitter that mediates excitatory synaptic transmission in the brain through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. These receptors have therefore been identified as a target for the development of therapeutic treatments for neurological disorders including epilepsy, neurodegenerative diseases, autism, and drug addiction. The fact that AMPA receptors play a dominant role throughout the brain raises the significant challenge of selectively targeting only those regions affected by disease, and clinical trials have raised doubt regarding the feasibility of specifically targeting AMPA receptors for new therapeutic options. Benzamide compounds that act as positive allosteric AMPA receptor modulators, known as AMPAkines, can act on specific brain regions and were initially proposed to revolutionize the treatment of cognitive deficits associated with neurological disorders. Their therapeutic potential has since declined due to inconsistent results in clinical trials. However, recent advances in basic biomedical research are significantly increasing our knowledge of AMPA receptor structure, binding sites, and interactions with auxiliary proteins. In particular, the large complex of postsynaptic proteins that interact with AMPA receptor subunits have been shown to control AMPA receptor insertion, location, pharmacology, synaptic transmission, and plasticity. These proteins are now being considered as alternative therapeutic target sites for modulating AMPA receptors in neurological disorders.
An antagonist of calcium permeable AMPA receptors, IEM1460: Anticonvulsant action in immature rats?
2015, Epilepsy Research
AMPA receptors lacking GluA2 subunit are widely distributed in developing brain. IEM1460 as a specific antagonist of these receptors might be a potential age-specific anticonvulsant. Possible anticonvulsant action was assessed in two models of epileptic seizures: pentylenetetrazol (PTZ) – induced convulsions and cortical afterdischarges elicited in 12-, 18- and 25-day-old rats. IEM1460 was administered intraperitoneally in doses of 3, 10 and 20 mg/kg. Pretreatment with IEM1460 at the dose of 20 mg/kg resulted in delayed onset of PTZ-induced minimal clonic seizures in all age groups. PTZ-induced generalized tonic–clonic seizures were suppressed in 18- and 25-day-old rats by 10 and 20 mg/kg doses of IEM1460.
Duration of cortical afterdischarges progressively increased with repeated stimulations in control 12-day-old rats. The IEM1460 dose of 10 mg/kg fully blocked this prolongation and the 20-mg/kg dose partly suppressed it. Administration of IEM1460 had moderate proconvulsant effect on 18- and 25-day-old animals – afterdischarges were prolonged with repeated stimulations. The duration of cortical epileptic afterdischarges in adult (80-day-old) animals was not affected by IEM1460. Effects of IEM1460 are dependent on the model of seizures used, their ictogenic structures and developmental changes in subunit composition of AMPA receptors.
Synthesis and characterization of a diaziridinium ion. Conversion of 3,4-dihydroisoquinolines to 4,5-dihydro-3H-benzo[2,3]diazepines via a formal N-insertion process
2014, Tetrahedron
A diaziridinium ion has been synthesized in high yield and its structure unambiguously confirmed by X-ray crystal analysis. The predicted N-transfer reactivity with olefins of this species was not observed. Instead, upon heating, the diaziridinium ion underwent ring opening to produce a dihydrobenzodiazepene product in good yield, thus achieving a formal N-insertion of the starting dihydroisoquinoline substrate. This process has been demonstrated on 11 total substrates.
The diverse therapeutic actions of pregabalin: Is a single mechanism responsible for several pharmacological activities?
2013, Trends in Pharmacological Sciences
Citation Excerpt :
However, modulation of glutamate synapses must be limited and subtle to avoid compromising vital brain functions. In contrast to pregabalin and gabapentin, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists completely abolish glutamate synaptic action and to date are not clinically useful [22]. Mechanisms initiating partial seizures are similar to those of cortical spreading depression (CSD) [23].
Pregabalin is a specific ligand of the alpha₂-delta (α₂-δ) auxiliary subunit of voltage-gated calcium channels. A growing body of evidence from studies of anxiety and pain indicate that the observed responses with pregabalin may result from activity at the α₂-δ auxiliary protein expressed presynaptically, in several different circuits of the central nervous system (CNS). The disorders that appear to be effectively treated with pregabalin are thematically linked by neuronal dysregulation or hyperexcitation within the CNS. This review proposes how binding to the α₂-δ protein target in different regions of the CNS may contribute to the observed clinical activity of pregabalin, as well as to the adverse event profile of the compound. Whether this compound regulates synaptic function via α₂-δ in additional conditions is yet to be discovered. The potential of pregabalin to regulate neuronal hyperactivity involving other CNS circuits will require further exploration.

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Research reportThe anticonvulsant effect of the non-NMDA antagonists, NBQX and GYKI 52466, in mice

Abstract

Neurosci. Lett.

Brain Res.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Research report
The anticonvulsant effect of the non-NMDA antagonists, NBQX and GYKI 52466, in mice