Finding a better drug for epilepsy: The mTOR pathway as an antiepileptogenic target

Authors

  • Aristea S. Galanopoulou,

    1. Saul R. Korey Department of Neurology, Dominick P. Purpura Department of Neuroscience, Laboratory of Developmental Epilepsy, Montefiore/Einstein Epilepsy Management Center, Albert Einstein College of Medicine, Bronx, New York, U.S.A.
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  • Jan A. Gorter,

    1. Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam and Epilepsy Institute in The Netherlands Foundation (Stichting Epilepsie Instellingen Nederland, SEIN), Heemstede, The Netherlands
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  • Carlos Cepeda

    1. Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, U.S.A.
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Address correspondence to Aristea S. Galanopoulou, M.D., Ph.D., Albert Einstein College of Medicine, 1410 Pelham Parkway South, Kennedy Center Rm 306, Bronx, NY 10461, U.S.A. E-mail: aristea.galanopoulou@einstein.yu.edu; Jan A. Gorter, Ph.D., Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Rm C3.266, Science Park 904, 1098XH Amsterdam, The Netherlands. E-mail: j.a.gorter@uva.nl; or Carlos Cepeda, Ph.D., IDDRC, Semel Institute for Neuroscience, Room 58-258, UCLA School of Medicine, 760 Westwood Plaza, Los Angeles, CA 90024, U.S.A. E-mail: ccepeda@mednet.ucla.edu

Summary

The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth, differentiation, proliferation, and metabolism. Loss-of-function mutations in upstream regulators of mTOR have been highly associated with dysplasias, epilepsy, and neurodevelopmental disorders. These include tuberous sclerosis, which is due to mutations in TSC1 or TSC2 genes; mutations in phosphatase and tensin homolog (PTEN) as in Cowden syndrome, polyhydramnios, megalencephaly, symptomatic epilepsy syndrome (PMSE) due to mutations in the STE20-related kinase adaptor alpha (STRADalpha); and neurofibromatosis type 1 attributed to neurofibromin 1 mutations. Inhibition of the mTOR pathway with rapamycin may prevent epilepsy and improve the underlying pathology in mouse models with disrupted mTOR signaling, due to PTEN or TSC mutations. However the timing and duration of its administration appear critical in defining the seizure and pathology-related outcomes. Rapamycin application in human cortical slices from patients with cortical dysplasias reduces the 4-aminopyridine–induced oscillations. In the multiple-hit model of infantile spasms, pulse high-dose rapamycin administration can reduce the cortical overactivation of the mTOR pathway, suppresses spasms, and has disease-modifying effects by partially improving cognitive deficits. In post–status epilepticus models of temporal lobe epilepsy, rapamycin may ameliorate the development of epilepsy-related pathology and reduce the expression of spontaneous seizures, but its effects depend on the timing and duration of administration, and possibly the model used. The observed recurrence of seizures and epilepsy-related pathology after rapamycin discontinuation suggests the need for continuous administration to maintain the benefit. However, the use of pulse administration protocols may be useful in certain age-specific epilepsy syndromes, like infantile spasms, whereas repetitive-pulse rapamycin protocols may suffice to sustain a long-term benefit in genetic disorders of the mTOR pathway. In summary, mTOR dysregulation has been implicated in several genetic and acquired forms of epileptogenesis. The use of mTOR inhibitors can reverse some of these epileptogenic processes, although their effects depend upon the timing and dose of administration as well as the model used.

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