Cellular antiseizure mechanisms of everolimus in pediatric tuberous sclerosis complex, cortical dysplasia, and non–mTOR‐mediated etiologies

Cepeda, Carlos; Levinson, S. Rock; Yazon, Vannah Wila; Barry, Joshua; Mathern, Gary W.; Fallah, Aria; Vinters, Harry V.; Levine, Michael S.; Wu, Joyce

doi:10.1002/epi4.12253

Cited by 16 publications

(14 citation statements)

References 48 publications

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“…A recent study comparing ex vivo brain slices from TSC, HME and non‐mTOR pathology demonstrated robust anti‐seizure effects of everolimus (through reduction in glutamate receptor‐mediated excitatory activity after sustained exposure over time) in mTOR pathway‐related malformations (TSC and HME; Cepeda et al. ).…”

Section: What We Have Learned So Farmentioning

confidence: 99%

New insights into a spectrum of developmental malformations related tomTORdysregulations: challenges and perspectives

et al. 2019

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In recent years the role of the mammalian target of rapamycin (mTOR) pathway has emerged as crucial for normal cortical development. Therefore, it is not surprising that aberrant activation of mTOR is associated with developmental malformations and epileptogenesis. A broad spectrum of malformations of cortical development, such as focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC), have been linked to either germline or somatic mutations in mTOR pathway-related genes, commonly summarised under the umbrella term 'mTORopathies'. However, there are still a number of unanswered questions regarding the involvement of mTOR in the pathophysiology of these abnormalities. Therefore, a monogenetic disease, such as TSC, can be more easily applied as a model to study the mechanisms of epileptogenesis and identify potential new targets of therapy. Developmental neuropathology and genetics demonstrate that FCD IIb and hemimegalencephaly are the same diseases. Constitutive activation of mTOR signalling represents a shared pathogenic mechanism in a group of developmental malformations that have histopathological and clinical features in common, such as epilepsy, autism and other comorbidities. We seek to understand the effect of mTOR dysregulation in a developing cortex with the propensity to generate seizures as well as the aftermath of the surrounding environment, including the white matter.

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Section: What We Have Learned So Farmentioning

confidence: 99%

New insights into a spectrum of developmental malformations related tomTORdysregulations: challenges and perspectives

et al. 2019

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“…4-aminopyridine (4-AP) is a convulsant drug that blocks A-type K+ current, thereby facilitating neurotransmitter release at both excitatory and inhibitory synapses and has been shown to block fAHPs and increase AP halfwidth to dictate neuron firing rate and firing adaptation (Lorenzon et al, 1992, Faber et al, 2002, Guerrini et al, 2015) 10,42,29 . 4-AP has also been used in concert with a mg2+ free aCSF, high extracellular K+, GABA, glutamate, and inhibitory neurotransmitter blockers to promote and induce interictal and ictal activity in human epilepsy brain slice studies (Avoli et al,1991, Avoli et al, 1998, Cepeda et al, 2018, Chang et al, 2019, Guerrini et al, 2015 Levinson et al, 2020) 10,17,46,33,54,55 . However, to our knowledge, no substantial work has gone into how 4-AP influences L2/3 pyramidal neurons from epileptic acute slices.…”

Section: Resultsmentioning

confidence: 99%

Characterizing the diversity of L2/3 human neocortical neurons in epilepsy

Kushner

Hoffman

Brzezinski

et al. 2022

Preprint

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In the current study, we performed whole-cell current clamp recordings from human cortical neurons in layer 2/3 of the human neocortex in order to characterize the diversity of L2/3 human neocortical neurons in epileptic foci with various etiologies in order to begin to elucidate the underlying mechanisms of hyperexcitability which are still mostly unknown. We differentiated neuronal subtypes based on their firing patterns and AHP kinetics or epilepsy subtype (malformation of cortical development (MCD) vs. other (non-MCD)). We found that L2/3 pyramidal neurons have diverse firing properties and action potential kinetics, with some neurons looking remarkably similar to LTS interneurons. We also saw that L2/3 pyramidal neurons could be split into those with fast AHPs and those without, medium AHPs (mAHPs). Based on these parameters, we were unable to significantly differentiate neurons based on firing properties indicating that AHP component kinetics alone do not dictate L2/3 pyramidal neuron firing in human epileptic cortical slices. We also report significant differences in intrinsic properties between MCD and non-MCD and control L2/3 pyramidal neurons and are the first to characterize that wash on of the proconvulsant drug, 4-aminopyridine (4-AP), leads to increased AP duration, less firing rate (FR) accommodation, and slowed down AHPs. Overall, the present study is the first to characterize the large variability of L2/3 human neocortical pyramidal neurons, to compare between L2/3 pyramidal neurons within the epileptic foci between MCD and non-MCD cases, to use control tissue from tumor patients without incidence of seizure, and to determine the influence of 4-AP on L2/3 pyramidal neuron intrinsic properties.

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“…Consequently, inactivation of TSC1 or - 2 leads to hyperactivation of the mTORC1 pathway, which upregulates normal cortical development and cellular proliferation and induces the development of tubers and SEGAs [ 10 ]. Additionally, abnormal functioning of mTOR pathway plays a crucial role in TSC-related epilepsy [ 11 , 12 ]. Therefore, mTOR inhibitors can be effective against both tumour growth and control of seizures [ 13 ].…”

Section: Reviewmentioning

confidence: 99%

Targeted Therapies in Rare Brain Tumours

Bruno

Pellerino

Bertero³

et al. 2021

IJMS

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Rare central nervous system (CNS) tumours represent a unique challenge. Given the difficulty of conducting dedicated clinical trials, there is a lack of therapies for these tumours supported by high quality evidence, and knowledge regarding the impact of standard treatments (i.e., surgery, radiotherapy or chemotherapy) is commonly based on retrospective studies. Recently, new molecular techniques have led to the discovery of actionable molecular alterations. The aim of this article is to review recent progress in the molecular understanding of and therapeutic options for rare brain tumours, both in children and adults. We will discuss options such as targeting the mechanistic target of rapamycin (mTOR) pathway in subependymal giant cells astrocytomas (SEGAs) of tuberous sclerosis and BRAF V600E mutation in rare glial (pleomorphic xanthoastrocytomas) or glioneuronal (gangliogliomas) tumours, which are a model of how specific molecular treatments can also favourably impact neurological symptoms (such as seizures) and quality of life. Moreover, we will discuss initial experiences in targeting new molecular alterations in gliomas, such as isocitrate dehydrogenase (IDH) mutations and neurotrophic tyrosine receptor kinase (NTRK) fusions, and in medulloblastomas such as the sonic hedgehog (SHH) pathway.

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Cellular antiseizure mechanisms of everolimus in pediatric tuberous sclerosis complex, cortical dysplasia, and non–mTOR‐mediated etiologies

Cited by 16 publications

References 48 publications

New insights into a spectrum of developmental malformations related tomTORdysregulations: challenges and perspectives

New insights into a spectrum of developmental malformations related tomTORdysregulations: challenges and perspectives

Characterizing the diversity of L2/3 human neocortical neurons in epilepsy

Targeted Therapies in Rare Brain Tumours

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