An antagonist of calcium permeable AMPA receptors, IEM1460: Anticonvulsant action in immature rats?

Szczurowska, Ewa; Mareš, Pavel

doi:10.1016/j.eplepsyres.2014.10.020

Cited by 25 publications

(24 citation statements)

References 61 publications

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“…Our findings showing therapeutic potential of IEM-1460 on seizure threshold, social interaction, and working memory deficits align with our previous work showing that the general AMPAR antagonist NBQX attenuates deficits in social preference following seizureinduced elevation of GluA2-lacking AMPARs in rats (Lippman-Bell et al, 2013). Additionally, prior reports show that IEM-1460 has age-specific therapeutic effects against seizures coinciding with peak levels of GluA2-lacking AMPARs during development (Szczurowska and Mares, 2015), and prevents seizure-induced phosphorylation of CaMKII and MeCP2 in immature rodents (Rosenberg et al, 2018). Finally, we previously showed a significant increase in synaptic GluA2-lacking AMPARs 48 h posthypoxic seizures in rats that resulted in enhanced epileptogenesis later in life (Sanchez et al, 2001;Rakhade et al, 2008;Lippman-Bell et al, 2013), suggesting that increased hippocampal GluA2lacking AMPARs in R59X mice may be a targetable contributor to hyperexcitable circuit formation and behavioral alterations, even in the absence of visible seizures, and that blocking GluA2lacking AMPARs with IEM-1460 may mitigate this process.…”

Section: Discussionsupporting

confidence: 91%

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AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder

2019

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Pathogenic mutations in cyclin-dependent kinase-like 5 (CDKL5) result in CDKL5 deficiency disorder (CDD), a rare disease marked by early-life seizures, autistic behaviors, and intellectual disability. Although mouse models of CDD exhibit dendritic instability and alterations in synaptic scaffolding proteins, studies of glutamate receptor levels and function are limited. Here we used a novel mouse model of CDD, the Cdkl5 R59X knock-in mouse (R59X), to investigate changes in synaptic glutamate receptor subunits and functional consequences. Male mice were used for all experiments to avoid the confounding effects of X-inactivation that would be present in female heterozygous mice. We showed that adult male R59X mice recapitulated the behavioral outcomes observed in other mouse models of CDD, including social deficits and memory and learning impairments, and exhibited decreased latency to seizure upon pentylenetetrazol administration. Furthermore, we observed a specific increase in GluA2-lacking ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors (AMPARs) in the adult R59X hippocampus, which is accompanied electrophysiologically by increased rectification ratio of AMPAR EPSCs and elevated early-phase long term potentiation (LTP). Finally, we showed that acute treatment with the GluA2-lacking AMPAR blocker IEM-1460 decreased AMPAR currents, and rescued social deficits, working memory impairments, and seizure behavior latency in R59X mice.

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Section: Discussionsupporting

confidence: 91%

“…Mutant mice and WT littermates were treated with IEM-1460 (10 mg/kg, i.p.) 1 h before behavioral tests (Magazanik et al, 1997;Szczurowska and Mares, 2015). In the social choice assay, drug treatment rescued R59X duration of time sniffing to salinetreated WT levels ( Fig.…”

Section: Iem-1460 Rescues Core Features Of Cdd In R59x Micementioning

confidence: 92%

AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder

2019

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“…This suggests it is unlikely any lack of effect of AP5 was caused by poor penetration into the brain. Furthermore, we [55] and others [70][71][72] have previously found CNS effects after peripheral administration of the AMPAR antagonist IEM-1460. We note that it is possible our results may be partially explained by IEM-1460 penetrating the brain more efficiently than AP5.…”

Section: Discussionsupporting

confidence: 52%

A new mouse line with reduced GluA2 Q/R site RNA editing exhibits loss of dendritic spines, hippocampal CA1-neuron loss, learning and memory impairments and NMDA receptor-independent seizure vulnerability

et al. 2020

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Calcium (Ca 2+ )-permeable AMPA receptors may, in certain circumstances, contribute to normal synaptic plasticity or to neurodegeneration. AMPA receptors are Ca 2+ -permeable if they lack the GluA2 subunit or if GluA2 is unedited at a single nucleic acid, known as the Q/R site. In this study, we examined mice engineered with a point mutation in the intronic editing complementary sequence (ECS) of the GluA2 gene, Gria2. Mice heterozygous for the ECS mutation (named GluA2 +/ECS(G) ) had a~20% reduction in GluA2 RNA editing at the Q/R site. We conducted an initial phenotypic analysis of these mice, finding altered current-voltage relations (confirming expression of Ca 2+permeable AMPA receptors at the synapse). Anatomically, we observed a loss of hippocampal CA1 neurons, altered dendritic morphology and reductions in CA1 pyramidal cell spine density. Behaviourally, GluA2 +/ECS(G) mice exhibited reduced motor coordination, and learning and memory impairments. Notably, the mice also exhibited both NMDA receptor-independent long-term potentiation (LTP) and vulnerability to NMDA receptor-independent seizures. These NMDA receptor-independent seizures were rescued by the Ca 2+ -permeable AMPA receptor antagonist IEM-1460. In summary, unedited GluA2(Q) may have the potential to drive NMDA receptor-independent processes in brain function and disease. Our study provides an initial characterisation of a new mouse model for studying the role of unedited GluA2(Q) in synaptic and dendritic spine plasticity in disorders where unedited GluA2(Q), synapse loss, neurodegeneration, behavioural impairments and/or seizures are observed, such as ischemia, seizures and epilepsy, Huntington's disease, amyotrophic lateral sclerosis, astrocytoma, cocaine seeking behaviour and Alzheimer's disease.

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“…This drug crosses the blood-brain barrier, rapidly blocks calcium-permeable AMPA receptors, and has been tested against seizures. 41 However, administration of higher doses of IEM-1460 caused respiratory depression in animals in SE and in naive animals. Thus, detailed toxicology and safety studies are needed to further develop this compound for the treatment of SE.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies demonstrated that SE‐induced modification of AMPA receptors renders them calcium permeable; IEM‐1460 is available to block these receptors. This drug crosses the blood–brain barrier, rapidly blocks calcium‐permeable AMPA receptors, and has been tested against seizures . However, administration of higher doses of IEM‐1460 caused respiratory depression in animals in SE and in naive animals.…”

Section: Discussionmentioning

confidence: 99%

α‐Amino‐3‐Hydroxy‐5‐Methyl‐4‐Isoxazolepropionic Acid Receptor Plasticity Sustains Severe, Fatal Status Epilepticus

Adotevi

Lewczuk

Sun

et al. 2019

Annals of Neurology

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Objective Generalized convulsive status epilepticus is associated with high mortality. We tested whether α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor plasticity plays a role in sustaining seizures, seizure generalization, and mortality observed during focal onset status epilepticus. We also determined whether modified AMPA receptors generated during status epilepticus could be targeted with a drug. Methods Electrically induced status epilepticus was characterized by electroencephalogram and behavior in GluA1 knockout mice and in transgenic mice with selective knockdown of the GluA1 subunit in hippocampal principal neurons. Excitatory and inhibitory synaptic transmission in CA1 neurons was studied using patch clamp electrophysiology. The dose response of N,N,H,‐trimethyl‐5‐([tricyclo(3.3.1.13,7)dec‐1‐ylmethyl]amino)‐1‐pentanaminiumbromide hydrobromide (IEM‐1460), a calcium‐permeable AMPA receptor antagonist, was determined. Results Global removal of the GluA1 subunit did not affect seizure susceptibility; however, it reduced susceptibility to status epilepticus. GluA1 subunit knockout also reduced mortality, severity, and duration of status epilepticus. Absence of the GluA1 subunit prevented enhancement of glutamatergic synaptic transmission associated with status epilepticus; however, γ‐aminobutyric acidergic synaptic inhibition was compromised. Selective removal of the GluA1 subunit from hippocampal principal neurons also reduced mortality, severity, and duration of status epilepticus. IEM‐1460 rapidly terminated status epilepticus in a dose‐dependent manner. Interpretation AMPA receptor plasticity mediated by the GluA1 subunit plays a critical role in sustaining and amplifying seizure activity and contributes to mortality. Calcium‐permeable AMPA receptors modified during status epilepticus can be inhibited to terminate status epilepticus. ANN NEUROL 2020;87:84–96

show abstract

An antagonist of calcium permeable AMPA receptors, IEM1460: Anticonvulsant action in immature rats?

Cited by 25 publications

References 61 publications

AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder

AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder

A new mouse line with reduced GluA2 Q/R site RNA editing exhibits loss of dendritic spines, hippocampal CA1-neuron loss, learning and memory impairments and NMDA receptor-independent seizure vulnerability

α‐Amino‐3‐Hydroxy‐5‐Methyl‐4‐Isoxazolepropionic Acid Receptor Plasticity Sustains Severe, Fatal Status Epilepticus

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