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mTOR Inhibition in Epilepsy: Rationale and Clinical Perspectives

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Abstract

Despite a large number of available medical options, many individuals with epilepsy are refractory to existing therapies that mainly target neurotransmitter or ion channel activity. A growing body of preclinical data has uncovered a molecular pathway that appears crucial in many genetic and acquired epilepsy syndromes. The mammalian target of rapamycin (mTOR) pathway regulates a number of cellular processes required in the growth, metabolism, structure, and cell-cell interactions of neurons and glia. Rapamycin and similar compounds inhibit mTOR complex 1 and decrease seizures, delay seizure development, or prevent epileptogenesis in many animal models of mTOR hyperactivation. However, the exact mechanisms by which mTOR inhibition drives decreased seizure activity have not been completely determined. Nonetheless, these preclinical data have led to limited use in humans with epilepsy due to tuberous sclerosis complex and polyhydramnios, megalencephaly, and symptomatic epilepsy with promising results. Currently, larger controlled studies are underway using mTOR inhibitors in individuals with tuberous sclerosis complex and intractable epilepsy.

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Acknowledgments

M. Wong is supported by National Institutes of Health Grant Nos. R01 NS079321, R01 NS056872 and P20NS080199. M. Wong is a site-PI for the Novartis EXIST-3 clinical trial of everolimus. A. Ostendorf has no potential conflicts of interest to report. No funding was received for the publication of this review.

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  1. Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO, 63110, USA

    Adam P. Ostendorf & Michael Wong

  2. The Hope Center for Neurological Disorders, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO, 63110, USA

    Michael Wong

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Correspondence to Michael Wong.

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Ostendorf, A.P., Wong, M. mTOR Inhibition in Epilepsy: Rationale and Clinical Perspectives. CNS Drugs 29, 91–99 (2015). https://doi.org/10.1007/s40263-014-0223-x

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