Age-related decrease in the antiseizure effect of ifenprodil against pentylenetetrazole in mice

doi:10.1016/S0165-3806(97)00140-5

Developmental Brain Research

Volume 104, Issues 1–2, 19 December 1997, Pages 201-204

https://doi.org/10.1016/S0165-3806(97)00140-5 Get rights and content

Abstract

The developmental change in the antiseizure effect of ifenprodil against pentylenetetrazole (PTZ) was examined in mice. Ifenprodil (i.p.) significantly increased the latency to seizure induced by PTZ in 7- and 10-day-old mice, but not in 14- or 21-day-old mice. Intracerebroventricular administration of ifenprodil also failed to modify the latency to PTZ-induced seizure in 21-day-old mice. Dizocilpine produced an increase in the latency to PTZ-induced seizure in 7- and 21-day-old mice. In an NMDA receptor binding assay using [³H]dizocilpine, ifenprodil was clearly more potent in inhibiting [³H]dizocilpine binding in a forebrain membrane preparation from 7- rather than 21-day-old mice. These results suggest that the remarkable antiseizure effect of ifenprodil against PTZ in 7-day-old mice may be related to the high proportion of ifenprodil-sensitive NMDA receptors in the brain.

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Acknowledgements

This work was supported in part by a Grant-in-Aid from The Tokyo Biochemical Research Foundation and a Research Grant from the Ministry of Health and Welfare to T. Suzuki. We wish to thank Ms. Sachiko Komiya and Ms. Miho Soma for their expert technical assistance.

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Over the last decade, sigma-1 receptor (Sig1R) has been recognized as a valid target for the treatment of seizure disorders and seizure-related comorbidities. Clinical trials with Sig1R ligands are underway testing therapies for the treatment of drug-resistant seizures, developmental and epileptic encephalopathies, and photosensitive epilepsy. However, the direct molecular mechanism by which Sig1R modulates seizures and the balance between excitatory and inhibitory pathways has not been fully elucidated. This review article aims to summarize existing knowledge of Sig1R and its involvement in seizures by focusing on the evidence obtained from Sig1R knockout animals and the anti-seizure effects of Sig1R ligands. In addition, this review article includes a discussion of the advantages and disadvantages of the use of existing compounds and describes the challenges and future perspectives on the use of Sig1R as a target for the treatment of seizure disorders.
Epileptiform GluN2B–driven excitation in hippocampus as a therapeutic target against temporal lobe epilepsy
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Ictogenic processes are one of the prime targets in medication aiming at suppression of seizure initiation (Blauwblomme et al., 2014; Lillis and Staley, 2018). While the role of NMDARGluN2B in the pathophysiology of seizure initiation has been well examined in models of acute convulsions (De Sarro et al., 1997, 1995; Doyle and Shaw, 1996; Pontecorvo et al., 1991; Tsuda et al., 1997), it has not been sufficiently studied in recurrent seizures in TLE. Ifenprodil, a selective antagonist of NMDARGluN2B, has been demonstrated to decrease neuronal excitability in lateral temporal lobe and neocortex resections from epileptic patients with cortical dysplasia (Möddel et al., 2005; Wang et al., 2017).
GluN2B is an NMDAR subunit that displays restricted expression in the mature hippocampus - a structure playing a major role in temporal lobe epilepsy. However, the contribution of GluN2B to the pathophysiology of the condition has not been fully explored. Here we combined status epilepticus models of temporal lobe epilepsy, protein expression studies, and patch-clamp experiments to demonstrate the profound change in the nature of glutamatergic transmission mediated in the epileptiform hippocampus by a subpopulation of GluN2B-containing NMDAR receptors. Satisfactory control of chronic seizures in temporal lobe epilepsy is still impossible for about 40% of patients. Therefore, new therapeutic approaches against the condition are desired. Using video-EEG recordings in animals and ex vivo extracellular recordings in brain sections, we present here the potential of ifenprodil (GluN2B selective NMDAR antagonist) for altering the course of epileptogenesis and ictogenesis in temporal lobe epilepsy. In sum, we identify GluN2B as one of the factors in the pathogenesis of recurrent seizures and provide a rationale for clinical studies on ifenprodil as a new candidate therapeutic against temporal lobe epilepsy.
Does status epilepticus modify the effect of ifenprodil on cortical epileptic afterdischarges in immature rats?
2018, Pharmacological Reports
Citation Excerpt :
The same age-dependent effects were demonstrated with another NR2B antagonist Ro 25-6981 [20]. All our data are in agreement with results in mice, where ifenprodil injected either intraperitoneally or intracerebroventricularly exhibited anticonvulsant action against pentetrazol-induced seizures only during the first two postnatal weeks [21]. Interpretation of our data is complicated by effects of lithiuim-paraldehyde treatment.
Ifenprodil as a specific antagonist of NMDA receptors containing a dominant NR2B subunit exhibits age-dependent anticonvulsant action. Possible changes of this action due to status epilepticus (SE) elicited at early stage of development were studied using cortical epileptic afterdischarges (ADs) as a model.
Lithium-pilocarpine SE was induced at postnatal day 12 and effects of ifenprodil were studied 3, 6, 9, and 13 days after SE in rat pups with implanted epidural electrodes. Controls (LiPAR) received saline instead of pilocarpine. ADs were elicited by low frequency stimulation of sensorimotor cortex. Intensity of stimulation current increased in 18 steps from 0.2 to 15 mA. Ifenprodil (20 mg/kg) was administered intraperitoneally (ip) after the stimulation with 3.5-mA current. Threshold for four different phenomena as well as duration of ADs were evaluated.
The threshold for the transition into the limbic type of ADs was higher in 15-day-old SE rats than in LiPAR controls. Opposite difference was found in 18-day-old animals, older rats did not exhibit any difference. Isolated significant changes in total duration of ADs were found after high stimulation intensities. These changes appeared in 18-day-old rats where ADs were shorter in SE than in control LiPAR rats.
Changes in ifenprodil action were found only in the first week after SE but not in the second week. Interpretation of the results is complicated by failure of significant differences between SE and LiPAR rats probably due to a high dose of paraldehyde.
The NMDA receptor complex as a therapeutic target in epilepsy: A review
2011, Epilepsy and Behavior
Citation Excerpt :
Ifenprodil (4-[2-(4-benzylpiperidin-1-yl)-1-hydroxypropyl]phenol) selectively blocks the polyamine site at the NR2B subunit of the NMDAR. Several preclinical studies have shown that ifenprodil exerts anticonvulsant effects in a variety of animal models of epilepsy including seizures induced by NMDA, spermine, lindane, and PTZ in rodents [336–340]; spinal seizures in mice induced by handling following pretreatment with a sub-convulsive dose of strychnine [341]; the MES test [230,336,342]; audiogenic seizures in genetically epilepsy-prone rats [151,343]; motor and electrocortical seizures induced by unilateral local injection of putrescine into the rat deep prepiriform cortex [326]; ethanol withdrawal seizures in mice [344]; amygdala-kindling development [345]; proconvulsive effects of interleukin(IL)-1β on electrographic seizures induced by intrahippocampal injection of kainic acid in C57BL6 adult mice [346]; PTZ-induced seizures in spermidine/spermine N1-acetyltransferase transgenic mice [347]; cocaine-induced convulsions and lethality in mice [237]; prolonged status epilepticus induced by continuous hippocampal stimulation [348]; and activity evoked by intracortical stimulation in brain slices from freeze-lesioned rat neocortex [349]. However, it is noteworthy that ifenprodil had no effect in some animal models.
A substantial amount of research has shown that N-methyl-D-aspartate receptors (NMDARs) may play a key role in the pathophysiology of several neurological diseases, including epilepsy. Animal models of epilepsy and clinical studies demonstrate that NMDAR activity and expression can be altered in association with epilepsy and particularly in some specific seizure types. NMDAR antagonists have been shown to have antiepileptic effects in both clinical and preclinical studies. There is some evidence that conventional antiepileptic drugs may also affect NMDAR function. In this review, we describe the evidence for the involvement of NMDARs in the pathophysiology of epilepsy and provide an overview of NMDAR antagonists that have been investigated in clinical trials and animal models of epilepsy.
NMDA NR2B subtype-selective receptor antagonists fail to antagonize electrically-precipitated seizures and elicit popping in mice
2010, European Neuropsychopharmacology
NR2B-subtype-selective antagonists differ from MK-801, a nonselective NMDA receptor antagonist. MK-801 antagonizes electrical seizures at doses as low as 0.1 to 0.18 mg/kg and elicits popping at doses as low as 0.5 mg/kg, whereas ifenprodil and Ro 8-4304 were unable to do so at the doses tested. Ro 25-6981, however, was able to antagonize electrically-precipitated tonic hindlimb extension at 100 mg/kg, but was not able to elicit popping behavior at this dose.
Different effects of two N-methyl-d-aspartate receptor antagonists on seizures, spontaneous behavior, and motor performance in immature rats
2009, Epilepsy and Behavior
Citation Excerpt :
The anticonvulsant activity of ifenprodil is markedly different from that of memantine: ifenprodil was able to specifically suppress the tonic phase of generalized tonic–clonic seizures in 7-, 12-, and 18-day-old rats, but not in the oldest group studied. This developmental change is in agreement with the results of Tsuda et al. in mice [25], who reported an anticonvulsant effect of ifenprodil in 7- and 10-day-old mice but not in older mice. The difference in age when the change took place might be due to a difference in the doses used (only the 20-mg/kg dose in Tsuda and colleagues’ study) and to the lower sensitivity of mice and faster metabolism in this smaller rodent species.
Typical N-methyl-d-aspartate (NMDA) receptor antagonists exhibit anticonvulsant action and unwanted effects, even in developing rats. Therefore, we studied the actions of the low-affinity, noncompetitive antagonist memantine and the NR2B-specific antagonist ifenprodil. Seizures (minimal clonic and generalized tonic–clonic) were elicited with pentylenetetrazol (100 mg/kg subcutaneously) in rats 7, 12, 18, and 25 days old pretreated with memantine (2.5–40 mg/kg intraperitoneally) or ifenprodil (10–60 mg/kg intraperitoneally). The effects of both drugs were studied in open field and motor performance tests in 12-, 18-, and 25-day-old rats. Memantine suppressed generalized tonic–clonic seizures in all age groups; minimal seizures were potentiated. Ifenprodil abolished the tonic phase of generalized tonic–clonic seizures in 7-, 12-, and 18-day-old rats only; minimal seizures remained untouched. Memantine induced locomotor hyperactivity and compromised motor performance in all age groups. Ifenprodil exerted these effects only in 12-day-old rats; older animals were less active in open field tests. Memantine exhibits both anti- and pro-convulsant and behavioral effects typical of NMDA antagonists. Ifenprodil exerted the same effects in 12-day-old rats, but its anticonvulsant action in 18-day-old rats was accompanied by a decrease in locomotion.

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Short communicationAge-related decrease in the antiseizure effect of ifenprodil against pentylenetetrazole in mice

Abstract

Section snippets

Acknowledgements

Neurosci. Lett.

Brain Res.

Neuropharmacology

Neuron

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Life Sci.

Pharmacol. Biochem. Behav.

Neuron

Activity-dependent decrease in NMDA receptor response during development of the visual cortex

Science

Excitatory amino acid receptors in the vertebrate central nervous system

Pharmacol. Rev.

Anticonvulsant action of excitatory amino acid antagonists

Science

Short communication
Age-related decrease in the antiseizure effect of ifenprodil against pentylenetetrazole in mice