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Epilepsia Open. 2018 Sep 2;3(Suppl Suppl 2):180-190. doi: 10.1002/epi4.12253. eCollection 2018 Dec.

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

Author information

1
IDDRC Semel Institute for Neuroscience and Human Behavior UCLA School of Medicine University of California Los Angeles Los Angeles California, U.S.A.
2
Department of Neurosurgery David Geffen School of Medicine at University of California Los Angeles Los Angeles California, U.S.A.
3
Section of Neuropathology Department of Pathology and Laboratory Medicine and Department of Neurology David Geffen School of Medicine at University of California Los Angeles Los Angeles California, U.S.A.
4
Division of Pediatric Neurology Mattel Children's Hospital David Geffen School of Medicine at University of California Los Angeles Los Angeles California U.S.A.

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.

KEYWORDS:

Everolimus; Ex vivo; Mechanisms; Pediatric epilepsy surgery; mTOR pathway

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