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

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

doi:10.1002/epi4.12253

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

Carlos Cepeda^*, Simon Levinson, Vannah Wila Yazon, Joshua Barry, Gary W. Mathern, Aria Fallah, Harry V. Vinters, Michael S. Levine, Joyce Y. Wu

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

The present study was designed to examine the potential cellular antiseizure mechanisms of everolimus, a mechanistic target of rapamycin (mTOR) pathway blocker, in pediatric epilepsy cases. Cortical tissue samples obtained from pediatric patients (n = 11, ages 0.67–6.75 years) undergoing surgical resections for the treatment of their pharmacoresistant epilepsy were examined electrophysiologically in ex vivo slices. The cohort included mTOR-mediated pathologies (tuberous sclerosis complex [TSC] and severe cortical dysplasia [CD]) as well as non–mTOR-mediated pathologies (tumor and perinatal infarct). Bath application of everolimus (2 μm) had practically no effect on spontaneous inhibitory postsynaptic activity. In contrast, long-term application of everolimus reduced spontaneous excitatory postsynaptic activity, burst discharges induced by blockade of γ-aminobutyric acid A (GABA_A) receptors, and epileptiform activity generated by 4-aminopyridine, a K⁺ channel blocker. The antiseizure effects were more pronounced in TSC and CD cases, whereas in non–mTOR-mediated pathologies, the effects were subtle at best. These results support further clinical trials of everolimus in mTOR pathway–mediated pathologies and emphasize that the effects require sustained exposure over time.

Original language	English (US)
Pages (from-to)	180-190
Number of pages	11
Journal	Epilepsia Open
Volume	3
Issue number	S2
DOIs	https://doi.org/10.1002/epi4.12253
State	Published - Dec 2018

Funding

This study was supported by an investigator-initiated study between JYW and Novartis Pharmaceutical Inc. (study number RAD001-MUS246T). GWM was supported by the Davies/Crandall Endowed Chair for epilepsy research at UCLA. We would like to thank the patients and their parents for allowing the use of resected specimens for experimentation. We also thank the UCLA Hospital Pediatric Neurology staff for their assistance. Ms. My N. Huynh did the biocytin processing.

Keywords

Everolimus
Ex vivo
Mechanisms
Pediatric epilepsy surgery
mTOR pathway

ASJC Scopus subject areas

Neurology
Clinical Neurology

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title = "Cellular antiseizure mechanisms of everolimus in pediatric tuberous sclerosis complex, cortical dysplasia, and non–mTOR-mediated etiologies",

abstract = "The present study was designed to examine the potential cellular antiseizure mechanisms of everolimus, a mechanistic target of rapamycin (mTOR) pathway blocker, in pediatric epilepsy cases. Cortical tissue samples obtained from pediatric patients (n = 11, ages 0.67–6.75 years) undergoing surgical resections for the treatment of their pharmacoresistant epilepsy were examined electrophysiologically in ex vivo slices. The cohort included mTOR-mediated pathologies (tuberous sclerosis complex [TSC] and severe cortical dysplasia [CD]) as well as non–mTOR-mediated pathologies (tumor and perinatal infarct). Bath application of everolimus (2 μm) had practically no effect on spontaneous inhibitory postsynaptic activity. In contrast, long-term application of everolimus reduced spontaneous excitatory postsynaptic activity, burst discharges induced by blockade of γ-aminobutyric acid A (GABAA) receptors, and epileptiform activity generated by 4-aminopyridine, a K+ channel blocker. The antiseizure effects were more pronounced in TSC and CD cases, whereas in non–mTOR-mediated pathologies, the effects were subtle at best. These results support further clinical trials of everolimus in mTOR pathway–mediated pathologies and emphasize that the effects require sustained exposure over time.",

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

Abstract

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Keywords

ASJC Scopus subject areas

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