Kainate/AMPA receptor antagonists are anticonvulsant against the tonic hindlimb component of pentylenetetrazol-induced seizures in developing rats

doi:10.1016/0091-3057(94)00329-H

Pharmacology Biochemistry and Behavior

Volume 51, Issue 1, May 1995, Pages 153-158

https://doi.org/10.1016/0091-3057(94)00329-H Get rights and content

Abstract

Non-NMDA receptor antagonists CNQX, DNQX, and NBQX (10–40 mg/kg IP) were tested against pentylenetetrazol-induced (100 mg/kg SC) seizures in 7 to 90-day-old rats. All three drugs significantly decreased the incidence of tonic hindlimb component of tonic-clonic pentylenetetrazol seizures, often in favor of increased incidence of forelimb tonus throughout development. In addition, in 7 to 25-day-old rats, DNQX and NBQX decreased the severity of seizures due to a decrease in total incidence of the tonic component of tonic-clonic seizures compared to age-matched controls. However, neither drug was able to consistently suppress the incidence or increase latency to onset of clonic and tonic-clonic pentylenetetrazol seizures. The data suggest that, during development, non-NMDA receptor transmission may play a role in the generation of the tonic component, but not in the generation of other components of pentylenetetrazol-induced seizures.

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Perampanel exhibits anticonvulsant action against pentylentetrazol-induced seizures in immature rats
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They also measured serum and brain concentrations of perampanel 30 min after an intraperitoneal injection and found serum/brain ratio around 0.4 in immature (14-day-old) animals but less than 0.2 in adult animals. We can compare the anticonvulsant action of perampanel with that of quinoxalindiones - „classical “AMPA receptor antagonists CNQX, DNQX and the most potent NBQX (Velíšek et al., 1995). These three drugs demonstrated an action against the tonic phase of generalized seizures affecting minimally the clonic phase and leaving untouched minimal clonic (i.e.minimal metrazol) seizures.
Perampanel is a new antiepileptic drug with unique mechanism of action – antagonism of AMPA receptors. Its action in immature animals is not yet sufficiently known therefore we started to study anticonvulsant action of perampanel pretreatment (1–20 mg/kg i.p.) against seizures elicited by pentylenetetrazol. Three age groups of rats were examined – 12, 18 and 25 days old. Perampanel selectively suppressed the tonic phase of generalized seizures in the two younger groups and whole tonic-clonic seizures in the 25-day-old group. It exhibited also an anticonvulsant action against minimal clonic seizures present in control 18- and 25-day-old rats.
Perampanel is an effective anticonvulsant drug even at very early stages of brain development.
The glutamate receptor antagonists CNQX and MPEP decrease fast ripple events in rats treated with kainic acid
2017, Neuroscience Letters
Citation Excerpt :
In addition, the lack of the GluA2 subunit has been associated with Ca++ permeability and lower desensitization time, which promotes abnormal discharges, particularly in CA3 neurons [29]. Additionally, in several models of epilepsy, AMPA receptor antagonists have been associated with various degrees of epileptiform activity reduction [30–32]. Kainate receptors, which are tetramers of protein subunits GluK1-5, are densely present in the hippocampus, particularly in the CA3 region in interneurons and other principal neurons [33–35].
Fast ripples (FR) are high frequency oscillations (250–600 Hz) that have been associated with epilepsy. FR are assumed to be generated in small areas of the hippocampus (1 mm³) that contain pathologically interconnected glutamate pyramidal cell clusters. Additionally, a relation between glutamate neurotransmission and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainite (AMPA/KA) and metabotropic mGluR5 receptors is well established. Therefore, we hypothesized that antagonism of these glutamate receptors would decrease FR activity. For this propose, we induced status epilepticus with a kainic acid injection in the posterior right hippocampus and performed intracranial EEG recordings to detect and evaluate the presence of FR 15 days after the injection. The glutamate AMPA/KA receptor antagonist CNQX (10 mg/kg) and the mGluR5 antagonist MPEP (20 mg/kg) were administered intraperitoneally, and the effects of the drugs were evaluated for a period of three hours after their administration. The results show a decrease in the number of FR in the first hour after drug administration in both cases (CNQX, p = 0.0125; MPEP, p = 0.0132) and a return to basal values in the third hour of the experiment, but not significant differences in the number of oscillations per event of FR, and the frequency and duration of each event of FR. We therefore conclude that blockade of AMPA/KA and mGluR5 receptors transiently decreases the generation of FR; however, the mechanisms by which this effect is achieved are to be further analyzed in future experiments.
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.
BDNF is required for seizure-induced but not developmental up-regulation of KCC2 in the neonatal hippocampus
2015, Neuropharmacology
A robust increase in the functional expression of the neuronal K–Cl cotransporter KCC2 during CNS development is necessary for the emergence of hyperpolarizing ionotropic GABAergic transmission. BDNF-TrkB signaling has been implicated in the developmental up-regulation of KCC2 and, in mature animals, in fast activity-dependent down-regulation of KCC2 function following seizures and trauma. In contrast to the decrease in KCC2 expression observed in the adult hippocampus following trauma, seizures in the neonate trigger a TrkB-dependent up-regulation of neuronal Cl⁻ extrusion capacity associated with enhanced surface expression of KCC2. Here, we show that this effect is transient, and impaired in the hippocampus of Bdnf^−/− mice. Notably, however, a complete absence of BDNF does not compromise the increase in KCC2 protein or K-Cl transport functionality during neuronal development. Furthermore, we present data indicating that the functional up-regulation of KCC2 by neonatal seizures is temporally limited by calpain activity.
This article is part of the Special Issue entitled ‘GABAergic Signaling in Health and Disease’.
Restoration of Nigrostriatal Pathway in Parkinson's Animals by the Bridge Transplantation Technique
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Laboratory and clinical studies have indicated that fetal ventral mesencephalic tissue transplantation into the lesioned striatum improves the behavioral and biochemical symptoms of Parkinsonian animals and patients. Restoration of tyrosine hydroxylase immuno-reactivity and dopamine release is limited to the transplantation site. Unfortunately, clinical studies using this approach have demonstrated severe dyskinetic side effects. This may be because afferent fibers normally providing input to the nigra are not available at the heterotypic striatal site. In this review, we discuss a bridge transplantation technique that has been shown to be effective in restoring the nigrostriatal dopaminergic pathway of Parkinsonian animals, and that may have translational applications to humans.
Different effects of nonNMDA and NMDA receptor antagonists (NBQX and dizocilpine) on cortical epileptic afterdischarges in rats
2006, Brain Research
Citation Excerpt :
Their participation in epileptic activities is also different. As the two antagonists used in the present study, NBQX was found to be active (among others) against audiogenic seizures (Chapman et al., 1991) and maximal electroshock and pentylenetetrazol-induced seizures in mice (Yamaguchi et al., 1993; Löscher and Hönack, 1994), tonic phase of generalized seizures elicited by pentetrazol (Velíšek et al., 1995) and amygdala kindled seizures in rats (Namba et al., 1994; Löscher, 1998). A broad spectrum of anticonvulsant action of dizocilpine was repeatedly described (Dingledine et al., 1990; Chapman, 1991; Meldrum, 1992; Löscher, 1998).
Excitatory amino acids play an important role in generation of epileptic seizures. To study the participation of different types of their receptors in cortical epileptic afterdischarges, a noncompetitive NMDA receptor antagonist dizocilpine and a competitive AMPA receptor antagonist NBQX were used. Adult rats with implanted epidural stimulation and registration electrodes were pretreated either with NBQX (30 or 60 mg/kg i.p.) or with dizocilpine (0.1 or 0.5 mg/kg i.p.) and low-frequency stimulation of sensorimotor cortical area was repeatedly applied with stepwise increased current intensities. Lower dose of NBQX unexpectedly decreased thresholds for elicitation of spike-and-wave afterdischarges (ADs), clonic seizures accompanying this type of ADs and for transition into the second, limbic type of ADs. Lower dose of dizocilpine increased these three thresholds. Higher doses of either drug did not significantly change threshold intensities. Duration of ADs was also influenced by the two antagonists in opposite directions: higher dose of NBQX resulted in prolongation of ADs mainly due to an increased duration of the spike-and-wave part of ADs whereas dizocilpine shortened ADs in a dose-dependent manner affecting both types of ADs. In addition, NBQX did not influence interhemispheric responses meanwhile dizocilpine moderately suppressed these evoked potentials. According to our results, NMDA receptors are important for generation of cortical epileptic afterdischarges meanwhile the role of AMPA receptors is not clear and has to be analyzed.

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Brief communicationKainate/AMPA receptor antagonists are anticonvulsant against the tonic hindlimb component of pentylenetetrazol-induced seizures in developing rats

Abstract

Dev. Brain Res.

Neuroscience

Exp. Neurol.

Epilepsy Res.

Eur. J. Pharmacol.

Epilepsy Res.

Pharmacol. Biochem. Behav.

Dev. Brain Res.

Brain Res.

Epilepsy Res.

Epilepsy Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Epilepsy Res.

Eur. J. Pharmacol.

Brief communication
Kainate/AMPA receptor antagonists are anticonvulsant against the tonic hindlimb component of pentylenetetrazol-induced seizures in developing rats