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CNS Drugs
Published in: CNS Drugs 2/2015

01-02-2015 | Leading Article

mTOR Inhibition in Epilepsy: Rationale and Clinical Perspectives

Authors: Adam P. Ostendorf, Michael Wong

Published in: CNS Drugs | Issue 2/2015

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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.
Literature
1.
Hauser WA. Epidemiology of epilepsy in children. Neurosurg Clin N Am. 1995;6:419–29.PubMed
2.
Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010;51:676–85.CrossRefPubMed
3.
Kwan P, Brodie MJ. Refractory epilepsy: mechanisms and solutions. Expert Rev Neurother. 2006;6:397–406.CrossRefPubMed
4.
Weber JD, Gutmann DH. Deconvoluting mTOR biology. Cell Cycle Georget Tex. 2012;11:236–48.CrossRef
5.
6.
Bekinschtein P, Katche C, Slipczuk LN, Igaz LM, Cammarota M, Izquierdo I, et al. mTOR signaling in the hippocampus is necessary for memory formation. Neurobiol Learn Mem. 2007;87:303–7.CrossRefPubMed
7.
Tang SJ, Reis G, Kang H, Gingras A-C, Sonenberg N, Schuman EM. A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc Natl Acad Sci. 2002;99:467–72.CrossRefPubMedCentralPubMed
8.
Jaworski J, Spangler S, Seeburg DP, Hoogenraad CC, Sheng M. Control of dendritic arborization by the phosphoinositide-3′-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci Off J Soc Neurosci. 2005;25:11300–12.CrossRef
9.
Kumar V, Zhang M-X, Swank MW, Kunz J, Wu G-Y. Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci Off J Soc Neurosci. 2005;25:11288–99.CrossRef
10.
Sherman DL, Krols M, Wu L-MN, Grove M, Nave K-A, Gangloff Y-G, et al. Arrest of myelination and reduced axon growth when Schwann cells lack mTOR. J Neurosci Off J Soc Neurosci. 2012;32:1817–25.CrossRef
11.
Wong M. A critical review of mTOR inhibitors and epilepsy: from basic science to clinical trials. Expert Rev Neurother. 2013;13:657–69.CrossRefPubMed
12.
Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011;332:1317–22.CrossRefPubMedCentralPubMed
13.
Lasarge CL, Danzer SC. Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation. Front Mol Neurosci. 2014;7:18.CrossRefPubMedCentralPubMed
14.
Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355:1345–56.CrossRefPubMed
15.
16.
Orlova KA, Parker WE, Heuer GG, Tsai V, Yoon J, Baybis M, et al. STRADalpha deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice. J Clin Invest. 2010;120:1591–602.CrossRefPubMedCentralPubMed
17.
Scheffer IE, Heron SE, Regan BM, Mandelstam S, Crompton DE, Hodgson BL, et al. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol. 2014;75:782–7.CrossRefPubMed
18.
Ostendorf AP, Gutmann DH, Weisenberg JLZ. Epilepsy in individuals with neurofibromatosis type 1. Epilepsia. 2013;54:1810–4.CrossRefPubMed
19.
Sharma A, Hoeffer CA, Takayasu Y, Miyawaki T, McBride SM, Klann E, et al. Dysregulation of mTOR signaling in fragile X syndrome. J. Neurosci. 2010;30:694–702.CrossRefPubMedCentralPubMed
20.
Mirzaa GM, Poduri A. Megalencephaly and hemimegalencephaly: breakthroughs in molecular etiology. Am J Med Genet. 2014;166:156–72.CrossRef
21.
22.
Crino PB. mTOR: a pathogenic signaling pathway in developmental brain malformations. Trends Mol Med. 2011;17:734–42.CrossRefPubMed
23.
Huang X, Zhang H, Yang J, Wu J, McMahon J, Lin Y, et al. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis. 2010;40:193–9.CrossRefPubMedCentralPubMed
24.
Zeng L-H, Rensing NR, Wong M. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci. 2009;29:6964–72.CrossRefPubMedCentralPubMed
25.
Sliwa A, Plucinska G, Bednarczyk J, Lukasiuk K. Post-treatment with rapamycin does not prevent epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy. Neurosci Lett. 2012;509:105–9.CrossRefPubMed
26.
Buckmaster PS, Lew FH. Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy. J Neurosci. 2011;31:2337–47.CrossRefPubMedCentralPubMed
27.
Van Vliet EA, Forte G, Holtman L, den Burger JCG, Sinjewel A, de Vries HE, et al. Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation. Epilepsia. 2012;53:1254–63.CrossRefPubMed
28.
Guo D, Zeng L, Brody DL, Wong M. Rapamycin attenuates the development of posttraumatic epilepsy in a mouse model of traumatic brain injury. PloS One. 2013;8:e64078.CrossRefPubMedCentralPubMed
29.
Talos DM, Sun H, Zhou X, Fitzgerald EC, Jackson MC, Klein PM, et al. The interaction between early life epilepsy and autistic-like behavioral consequences: a role for the mammalian target of rapamycin (mTOR) pathway. PloS One. 2012;7:e35885.CrossRefPubMedCentralPubMed
30.
Raffo E, Coppola A, Ono T, Briggs SW, Galanopoulou AS. A pulse rapamycin therapy for infantile spasms and associated cognitive decline. Neurobiol Dis. 2011;43:322–9.CrossRefPubMedCentralPubMed
31.
Liu J, Reeves C, Michalak Z, Coppola A, Diehl B, Sisodiya SM, et al. Evidence for mTOR pathway activation in a spectrum of epilepsy-associated pathologies. Acta Neuropathol Commun. 2014;2:71.CrossRefPubMedCentralPubMed
32.
Sosunov AA, Wu X, McGovern RA, Coughlin DG, Mikell CB, Goodman RR, et al. The mTOR pathway is activated in glial cells in mesial temporal sclerosis. Epilepsia. 2012;53(Suppl 1):78–86.CrossRefPubMed
33.
Prabowo AS, Iyer AM, Veersema TJ, Anink JJ, Schouten-van Meeteren AYN, Spliet WGM, et al. BRAF V600E mutation is associated with mTOR signaling activation in glioneuronal tumors. Brain Pathol (Zurich Switz). 2014;24:52–66.CrossRef
34.
Sha L-Z, Xing X-L, Zhang D, Yao Y, Dou W-C, Jin L-R, et al. Mapping the spatio-temporal pattern of the mammalian target of rapamycin (mTOR) activation in temporal lobe epilepsy. PloS One. 2012;7:e39152.CrossRefPubMedCentralPubMed
35.
Baybis M, Yu J, Lee A, Golden JA, Weiner H, McKhann G, et al. mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann Neurol. 2004;56:478–87.CrossRefPubMed
36.
Boer K, Troost D, Timmermans W, van Rijen PC, Spliet WGM, Aronica E. PI3K-mTOR signaling and AMOG expression in epilepsy-associated glioneuronal tumors. Brain Pathol (Zurich Switz). 2010;20:234–44.CrossRef
37.
38.
Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, Sahin M, et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci. 2008;28:5422–32.CrossRefPubMedCentralPubMed
39.
Goto J, Talos DM, Klein P, Qin W, Chekaluk YI, Anderl S, et al. Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. Proc Natl Acad Sci. 2011;108:E1070–9.CrossRefPubMedCentralPubMed
40.
Zeng L-H, Rensing NR, Zhang B, Gutmann DH, Gambello MJ, Wong M. Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. Hum Mol Genet. 2011;20:445–54.CrossRefPubMedCentralPubMed
41.
Carson RP, Van Nielen DL, Winzenburger PA, Ess KC. Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin. Neurobiol Dis. 2012;45:369–80.CrossRefPubMedCentralPubMed
42.
Way SW, Rozas NS, Wu HC, McKenna J, Reith RM, Hashmi SS, et al. The differential effects of prenatal and/or postnatal rapamycin on neurodevelopmental defects and cognition in a neuroglial mouse model of tuberous sclerosis complex. Hum Mol Genet. 2012;21:3226–36.CrossRefPubMedCentralPubMed
43.
Buckmaster PS, Ingram EA, Wen X. Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J Neurosci. 2009;29:8259–69.CrossRefPubMedCentralPubMed
44.
Pun RYK, Rolle IJ, Lasarge CL, Hosford BE, Rosen JM, Uhl JD, et al. Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron. 2012;75:1022–34.CrossRefPubMedCentralPubMed
45.
Berdichevsky Y, Dryer AM, Saponjian Y, Mahoney MM, Pimentel CA, Lucini CA, et al. PI3K-Akt signaling activates mTOR-mediated epileptogenesis in organotypic hippocampal culture model of post-traumatic epilepsy. J Neurosci. 2013;33:9056–67.CrossRefPubMedCentralPubMed
46.
Heng K, Haney MM, Buckmaster PS. High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy. Epilepsia. 2013;54:1535–41.CrossRefPubMedCentralPubMed
47.
Parker WE, Orlova KA, Parker WH, Birnbaum JF, Krymskaya VP, Goncharov DA, et al. Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder. Sci Transl Med. 2013;5:182ra53.CrossRefPubMedCentralPubMed
48.
Tavazoie SF, Alvarez VA, Ridenour DA, Kwiatkowski DJ, Sabatini BL. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci. 2005;8:1727–34.CrossRefPubMed
49.
Abs E, Goorden SMI, Schreiber J, Overwater IE, Hoogeveen-Westerveld M, Bruinsma CF, et al. TORC1-dependent epilepsy caused by acute biallelic Tsc1 deletion in adult mice. Ann Neurol. 2013;74:569–79.CrossRefPubMed
50.
51.
Rüegg S, Baybis M, Juul H, Dichter M, Crino PB. Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons. Epilepsy Res. 2007;77:85–92.CrossRefPubMedCentralPubMed
52.
Daoud D, Scheld HH, Speckmann E-J, Gorji A. Rapamycin: brain excitability studied in vitro. Epilepsia. 2007;48:834–6.CrossRefPubMed
53.
Casadio A, Martin KC, Giustetto M, Zhu H, Chen M, Bartsch D, et al. A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell. 1999;99:221–37.CrossRefPubMed
54.
Raab-Graham KF, Haddick PCG, Jan YN, Jan LY. Activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites. Science. 2006;314:144–8.CrossRefPubMed
55.
Huang X, McMahon J, Yang J, Shin D, Huang Y. Rapamycin down-regulates KCC2 expression and increases seizure susceptibility to convulsants in immature rats. Neuroscience. 2012;219:33–47.CrossRefPubMedCentralPubMed
56.
Mori K, Mori T, Toda Y, Fujii E, Miyazaki M, Harada M, et al. Decreased benzodiazepine receptor and increased GABA level in cortical tubers in tuberous sclerosis complex. Brain Dev. 2012;34:478–86.CrossRefPubMed
57.
Wong M, Ess KC, Uhlmann EJ, Jansen LA, Li W, Crino PB, et al. Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model. Ann Neurol. 2003;54:251–6.CrossRefPubMed
58.
Lozovaya N, Gataullina S, Tsintsadze T, Tsintsadze V, Pallesi-Pocachard E, Minlebaev M, et al. Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model. Nat Commun. 2014;5:4563.CrossRefPubMedCentralPubMed
59.
McMahon J, Huang X, Yang J, Komatsu M, Yue Z, Qian J, et al. Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis. J Neurosci Off J Soc Neurosci. 2012;32:15704–14.CrossRef
60.
Komatsu M, Wang QJ, Holstein GR, Friedrich VL, Iwata J, Kominami E, et al. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc Natl Acad Sci. 2007;104:14489–94.CrossRefPubMedCentralPubMed
61.
Coupé B, Ishii Y, Dietrich MO, Komatsu M, Horvath TL, Bouret SG. Loss of autophagy in pro-opiomelanocortin neurons perturbs axon growth and causes metabolic dysregulation. Cell Metab. 2012;15:247–55.CrossRefPubMedCentralPubMed
62.
Yasin SA, Ali AM, Tata M, Picker SR, Anderson GW, Latimer-Bowman E, et al. mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: evidence from focal cortical dysplasia and tuberous sclerosis. Acta Neuropathol (Berl.). 2013;126:207–18.CrossRef
63.
Harris H, Rubinsztein DC. Control of autophagy as a therapy for neurodegenerative disease. Nat Rev Neurol. 2012;8:108–17.CrossRef
64.
Russo E, Citraro R, Donato G, Camastra C, Iuliano R, Cuzzocrea S, et al. mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy. Neuropharmacology. 2013;69:25–36.CrossRefPubMed
65.
Talos DM, Chang M, Kosaras B, Fitzgerald E, Murphy A, Folkerth RD, et al. Antiepileptic effects of levetiracetam in a rodent neonatal seizure model. Pediatr Res. 2013;73:24–30.CrossRefPubMed
66.
67.
Ljungberg MC, Sunnen CN, Lugo JN, Anderson AE, D’Arcangelo G. Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia. Dis Model Mech. 2009;2:389–98.CrossRefPubMedCentralPubMed
68.
McDaniel SS, Rensing NR, Thio LL, Yamada KA, Wong M. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia. 2011;52:e7–11.CrossRefPubMedCentralPubMed
69.
Zhang B, McDaniel SS, Rensing NR, Wong M. Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex. PloS One. 2013;8:e57445.CrossRefPubMedCentralPubMed
70.
Franz DN, Leonard J, Tudor C, Chuck G, Care M, Sethuraman G, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol. 2006;59:490–8.CrossRefPubMed
71.
Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363:1801–11.CrossRefPubMed
72.
Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008;358:140–51.CrossRefPubMedCentralPubMed
73.
Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013;381:125–32.CrossRefPubMed
74.
Kotulska K, Borkowska J, Jozwiak S. Possible prevention of tuberous sclerosis complex lesions. Pediatrics. 2013;132:e239–42.CrossRefPubMed
75.
Perek-Polnik M, Jóźwiak S, Jurkiewicz E, Perek D, Kotulska K. Effective everolimus treatment of inoperable, life-threatening subependymal giant cell astrocytoma and intractable epilepsy in a patient with tuberous sclerosis complex. Eur J Paediatr Neurol. 2012;16:83–5.CrossRefPubMed
76.
Cardamone M, Flanagan D, Mowat D, Kennedy SE, Chopra M, Lawson JA. Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex. J Pediatr. 2014;164:1195–200.CrossRefPubMed
77.
Krueger DA, Wilfong AA, Holland-Bouley K, Anderson AE, Agricola K, Tudor C, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol. 2013;74:679–87.CrossRefPubMed
78.
79.
Wiegand G, May TW, Ostertag P, Boor R, Stephani U, Franz DN. Everolimus in tuberous sclerosis patients with intractable epilepsy: a treatment option? Eur J Paediatr Neurol. 2013;17:631–8.CrossRefPubMed
80.
81.
Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia. 2010;51:1236–41.CrossRefPubMedCentralPubMed
82.
83.
Sunnen CN, Brewster AL, Lugo JN, Vanegas F, Turcios E, Mukhi S, et al. Inhibition of the mammalian target of rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice. Epilepsia. 2011;52:2065–75.CrossRefPubMedCentralPubMed
84.
Zhou J, Blundell J, Ogawa S, Kwon C-H, Zhang W, Sinton C, et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J Neurosci Off J Soc Neurosci. 2009;29:1773–83.CrossRef
85.
Chachua T, Poon K-L, Yum M-S, Nesheiwat L, DeSantis K, Velíšková J, et al. Rapamycin has age-, treatment paradigm-, and model-specific anticonvulsant effects and modulates neuropeptide Y expression in rats. Epilepsia. 2012;53:2015–25.CrossRefPubMedCentralPubMed
Metadata
Title
mTOR Inhibition in Epilepsy: Rationale and Clinical Perspectives
Authors
Adam P. Ostendorf
Michael Wong
Publication date
01-02-2015
Publisher
Springer International Publishing
Published in
CNS Drugs / Issue 2/2015
Print ISSN: 1172-7047
Electronic ISSN: 1179-1934
DOI
https://doi.org/10.1007/s40263-014-0223-x

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