The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia

Silva, Anderson Brito da; Pennifold, Jane; Henley, Ben; Chatterjee, Koustav; Bateman, David; Whittaker, Roger W.; Joshi, Abhijit; Kumar, Hrishikesh; Nicholson, Claire; Baker, Mark R.; Greenhill, Stuart; Walsh, Richard; Seri, Stefano; Jones, Roland S.G.; Woodhall, Gavin L.; Cunningham, Mark

doi:10.1002/epi4.12549

Cited by 5 publications

(4 citation statements)

References 24 publications

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“…Applying the modelling framework presented, the parameters optimised for each subject could serve as an in silico 'twin' on which pharmacological, as well as nonpharmacological, interventions could be trialled virtually to aid clinical decision-making. As an example, the findings at the group level from this cohort suggest that utilising antiseizure medication that specifically modulates excitatory synapses, such as perampanel (a known AMPA receptor antagonist [41,35]), could be beneficial for seizure control in children with focal lesional epilepsies. Further work will include assessing the use of the model on prospective data to see if it can predict the effects of interventions with known mechanisms.…”

Section: Digital Twinning To Facilitate Personalised Antiseizure Mana...mentioning

confidence: 94%

“…We focused on perturbing the conductance parameters because these parameters represent a key mechanistic target of antiseizure medications (for example, see [33]). This includes benzodiazepines, which have been shown to increase the conductance of GABA A (inhibitory) channels [34] and perampanel, which is known to block AMPA (excitatory) mediated synaptic conductances [35]. Hence, to simulate the effects of treatment, we decreased the excitatory and leak conductances and increased the inhibitory and KNa conductances in models derived from patient data.…”

Section: In Silico Prediction For Interventionmentioning

confidence: 99%

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Neural mass modelling reveals that hyperexcitability underpins slow-wave sleep changes in children with epilepsy

Dunstan,

Chan,

Goodfellow

2024

Preprint

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ObjectiveThe relationship between sleep and epilepsy is important but imperfectly understood. We sought to understand why children with epilepsy have altered sleep homeostasis.MethodsWe used neural mass models to replicate sleep EEG recorded from 15 children with focal lesional epilepsies and 16 healthy age-matched controls.ResultsThe models revealed that sleep EEG differences are driven by enhanced firing rates in the neuronal populations of patients, which arise predominantly due to enhanced excitatory synaptic currents. These differences were more marked in patients who had seizures within 72 hours after the sleep recording. Furthermore, models inferred from patients resided closer in parameter space to models of a typical seizure rhythm.SignificanceThese results demonstrate that brain mechanisms relating to epilepsy manifest in the interictal EEG in slow-wave sleep, and that EEG recorded from patients can be mapped to synaptic deficits that may explain their predisposition to seizures. Neural mass models inferred from sleep EEG data have the potential to generate new biomarkers to predict seizure occurrence or inform treatment decisions.1.Key PointsThe mechanisms that differentiate children with epilepsy from controls during slow-wave sleep can be understood using a mathematical model.The observed spectral power shifts in patients are predominately explained by greater excitatory synaptic currents.These differences in currents place patients’ models closer to seizure rhythms.Ultimately, this framework could help foster the development of biomarkers to guide intervention in epilepsy.

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Section: Digital Twinning To Facilitate Personalised Antiseizure Mana...mentioning

confidence: 94%

Section: In Silico Prediction For Interventionmentioning

confidence: 99%

Neural mass modelling reveals that hyperexcitability underpins slow-wave sleep changes in children with epilepsy

Dunstan,

Chan,

Goodfellow

2024

Preprint

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“…A third-generation ASD, perampanel (PER), recently gained attention as it was shown to significantly reduce the seizure frequency of previously drug-refractory GBM-related seizures (Vecht et al, 2017 ; Dunn-Pirio et al, 2018 ; Izumoto et al, 2018 ; Coppola et al, 2020 ; Maschio et al, 2020 ). Its anti-seizure effects are mediated by its actions as a non-competitive AMPARs antagonist (Hanada et al, 2011 ; Frampton, 2015 ; Augustin et al, 2018 ; Brito da Silva et al, 2021 ). PER exhibits significant anti-proliferative effects on multiple GBM cell lines at various concentrations, and appears to reduce the overall concentration of extracellular glutamate (Lange et al, 2019 ; Salmaggi et al, 2021 ).…”

Section: From Laboratory To Clinical Translationmentioning

confidence: 99%

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

Hills

Kostarelos

Wykes

2022

Front. Mol. Neurosci.

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Glioblastoma (GBM) is the most common and advanced form of primary malignant tumor occurring in the adult central nervous system, and it is frequently associated with epilepsy, a debilitating comorbidity. Seizures are observed both pre- and post-surgical resection, indicating that several pathophysiological mechanisms are shared but also prompting questions about how the process of epileptogenesis evolves throughout GBM progression. Molecular mutations commonly seen in primary GBM, i.e., in PTEN and p53, and their associated downstream effects are known to influence seizure likelihood. Similarly, various intratumoral mechanisms, such as GBM-induced blood-brain barrier breakdown and glioma-immune cell interactions within the tumor microenvironment are also cited as contributing to network hyperexcitability. Substantial alterations to peri-tumoral glutamate and chloride transporter expressions, as well as widespread dysregulation of GABAergic signaling are known to confer increased epileptogenicity and excitotoxicity. The abnormal characteristics of GBM alter neuronal network function to result in metabolically vulnerable and hyperexcitable peri-tumoral tissue, properties the tumor then exploits to favor its own growth even post-resection. It is evident that there is a complex, dynamic interplay between GBM and epilepsy that promotes the progression of both pathologies. This interaction is only more complicated by the concomitant presence of spreading depolarization (SD). The spontaneous, high-frequency nature of GBM-associated epileptiform activity and SD-associated direct current (DC) shifts require technologies capable of recording brain signals over a wide bandwidth, presenting major challenges for comprehensive electrophysiological investigations. This review will initially provide a detailed examination of the underlying mechanisms that promote network hyperexcitability in GBM. We will then discuss how an investigation of these pathologies from a network level, and utilization of novel electrophysiological tools, will yield a more-effective, clinically-relevant understanding of GBM-related epileptogenesis. Further to this, we will evaluate the clinical relevance of current preclinical research and consider how future therapeutic advancements may impact the bidirectional relationship between GBM, SDs, and seizures.

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“…In addition, human brain slices provides an ideal ex vivo electrophysiological platform to allow novel and established compounds to be tested on activity associated with refractoriness. This approach allows an assessment of target engagement and efficacy (Brito da Silva et al., 2021) prior to conducting complex and costly clinical trials.…”

Section: In Vitro Brain Slices – a Powerful Tool For Neurophysiologic...mentioning

confidence: 99%

Cross Talk proposal: Human‐derived brain tissue is a better epilepsy model than animal‐based approaches

Cunningham

2022

The Journal of Physiology

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Human cerebrospinal fluid increases the excitability of pyramidal neurons in the in vitro brain slice. Journal of Physiology, 593(1), 231-243' was inadvertently included in the Reference list. It has been deleted.] I will argue here that the use of human-derived brain tissue (primarily from neurosurgical samples) is a better model of epilepsy than animal-based approaches. Following CrossTalk guidelines, I have attempted to focus on data published over the last decade.

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The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 5 publications

References 24 publications

Neural mass modelling reveals that hyperexcitability underpins slow-wave sleep changes in children with epilepsy

Neural mass modelling reveals that hyperexcitability underpins slow-wave sleep changes in children with epilepsy

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

Cross Talk proposal: Human‐derived brain tissue is a better epilepsy model than animal‐based approaches

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