Mechanisms of action of Antiseizure Drugs and the Ketogenic diet

Cold Spring Harbor Perspectives in Medicine

Volumn 6, Issue 5, 2016, Pages 28-

  Rogawski, Michael A ^a   Löscher, Wolfgang ^b   Rho, Jong M ^c,d  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF VETERINARY MEDICINE HANNOVER   (Germany)

^c UNIVERSITY OF CALGARY   (Canada)

^d UNIVERSITY OF CALGARY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINOBUTYRATE AMINOTRANSFERASE; 4 AMINOBUTYRIC ACID; 4 AMINOBUTYRIC ACID A RECEPTOR; 4 AMINOBUTYRIC ACID B RECEPTOR; ADENOSINE; AMPA RECEPTOR; ANTICONVULSIVE AGENT; BENZODIAZEPINE DERIVATIVE; CALCIUM CHANNEL T TYPE; CORTICOTROPIN; ETHOSUXIMIDE; FELBAMATE; GABA TRANSPORTER 1; GABAPENTIN; GLUTAMIC ACID; KETONE BODY; LEVETIRACETAM; MEDIUM CHAIN TRIACYLGLYCEROL; PERAMPANEL; POLYUNSATURATED FATTY ACID; PREGABALIN; RETIGABINE; RUFINAMIDE; TOPIRAMATE; VALPROIC ACID; VIGABATRIN; VOLTAGE GATED SODIUM CHANNEL; ZONISAMIDE; ION CHANNEL;

4 AMINOBUTYRIC ACID BRAIN LEVEL; ACTION POTENTIAL; ARTICLE; BIOENERGY; CALCIUM CURRENT; DRUG BINDING; DRUG MECHANISM; ENERGY METABOLISM; EPILEPSY; FATTY ACID OXIDATION; GLYCOLYSIS; HIPPOCAMPAL MOSSY FIBER; HUMAN; KETOGENIC DIET; MITOCHONDRION; NONHUMAN; POTASSIUM CURRENT; SODIUM CURRENT; SYNAPSE; SYNAPTIC POTENTIAL; ANIMAL; BRAIN; DIET THERAPY; DRUG EFFECTS; METABOLISM; MOUSE; SEIZURE;

ANIMALS; ANTICONVULSANTS; BRAIN; DIET, KETOGENIC; EPILEPSY; GAMMA-AMINOBUTYRIC ACID; HUMANS; ION CHANNELS; KETONE BODIES; MICE; RECEPTORS, AMPA; SEIZURES;

EID: 84964933211     PISSN: None     EISSN: 21571422     Source Type: Journal    
DOI: 10.1101/cshperspect.a022780     Document Type: Article

References (202)

1. Ahmed GF, Marino SE, Brundage RC, Pakhomov SV, Leppik IE, Cloyd JC, Clark A, Birnbaum AK. 2015. Pharmacoki-netic-pharmacodynamic modelling of intravenous and oral topiramate and its effect on phonemic fluency in adult healthy volunteers. Br J ClinPharmacol 79:820–830.
2. Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Shar-man JL, Catterall WA, Spedding M, Peters JA, Harmar AJ; CGTP Collaborators. 2013. The concise guide to PHAR-MACOLOGY 2013/14: Ion channels. Br J Pharmacol 170: 1607–1651.
3. Avoli M, Kawasaki H, Zona C. 1996. Effects induced by to-piramate on sodium electrogenesis in mammalian central neurons. Epilepsia 37: 51–52.
4. Avoli M, Rogawski MA, Avanzini G. 2001. Generalized epileptic disorders: An update. Epilepsia 42: 445–457.
5. Azzu V, Brand MD. 2010. The on-off switches of the mito-chondrial uncoupling proteins. Trends Biochem Sci 35: 298–307.
6. Berg AT, Levy SR, Testa FM, Blumenfeld H. 2014. Long-term seizure remission in childhood absence epilepsy: Might initial treatment matter? Epilepsia 55: 551–557.
7. Biton V. 2007. Clinical pharmacology and mechanism of action of zonisamide. Clin Neuropharmacol 30: 230–240.
8. Blumenfeld H, Klein JP, Schridde U, Vestal M, Rice T, Khera DS, Bashyal C, Giblin K, Paul-Laughinghouse C, Wang F, et al. 2008. Early treatment suppresses the development of spike-wave epilepsy in a rat model. Epilepsia 49: 400–409.
9. Blumenfeld H, Varghese GI, Purcaro MJ, Motelow JE, Enev M, McNally KA, Levin AR, Hirsch LJ, Tikofsky R, Zubal IG, et al. 2009. Cortical and subcortical networks in hu-man secondarily generalized tonicclonic seizures. Brain 132: 999–1012.
10. Borges K, Sonnewald U. 2012. Triheptanoin-A medium chain triglyceride with odd chain fatty acids: A new ana-plerotic anticonvulsant treatment? Epilepsy Res 100: 239–244.
11. Bough KJ, Wetherington J, Hassel B, Pare JF, Gawryluk JW, Greene JG, Shaw R, Smith Y, Geiger JD, Dingledine RJ. 2006. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol 60: 223–235.
12. 2+ channel antagonist on thalamic relay and local circuit interneurons in a rat model of absence epilepsy. Neuropharmacology 53: 431–446.
13. Bromfield E, Dworetzky B, Hurwitz S, Eluri Z, Lane L, Re-plansky S, Mostofsky D. 2008. A randomized trial of polyunsaturated fatty acids for refractory epilepsy. Epilep-sy Behav 12: 187–190.
14. Brown DA, Passmore GM. 2009. Neural KCNQ (Kv7) channels. Br J Pharmacol 156: 1185–1195.
15. Chang P, Orabi B, Deranieh RM, Dham M, Hoeller O, Shim-shoni JA, Yagen B, Bialer M, Greenberg ML, Walker MC, et al. 2012. The antiepileptic drug valproic acid and other medium-chain fatty acids acutely reduce phosphoinositide levels independently of inositol in Dictyostelium. Dis Model Mech 5: 115–124.
16. Chang P, Terbach N, Plant N, Chen PE, Walker MC, Wil-liams RS. 2013. Seizure control by ketogenic diet-associated medium chain fatty acids. Neuropharmacology 69: 105–114.
17. Chang P, Zuckermann AM, Williams S, Close AJ, Cano-Jaimez M, McEvoy JP, Spencer J, Walker MC, Williams RS. 2015. Seizure control by derivatives of medium chain fatty acids associated with the ketogenic diet show novel branching-point structure for enhanced potency. J Phar-macol Exp Ther 352: 43–52.
18. Charlier C, Singh NA, Ryan SG, Lewis TB, Reus BE, Leach RJ, Leppert M. 1998. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet 18: 53–55.
19. Chen CY, Matt L, Hell JW, Rogawski MA. 2014. Perampanel inhibition of AMPA receptor currents in cultured hippo-campal neurons. PLoS ONE 9: e108021.
20. Cheng CM, Wang K, Eagles DA, Bondy CA. 2004. Caloric restriction augments brain glutamic acid decarboxylase-65 and -67 expression. J Neurosci Res 77: 270–276.
21. Cooper EC. 2012. Potassium channels (including KCNQ) and epilepsy. In Jasper’s basic mechanismsoftheepilepsies, 4th ed. (ed. Noebels JL, et al.), pp. 55–65. Oxford Uni-versity Press, New York.
22. Coulter DA, Huguenard JR, Prince DA. 1989. Characterization of ethosuximide reduction of low-threshold calcium current in thalamic relay neurons. Ann Neurol 25: 582–593.
23. 2+ channels in sleep waves. Pflugers Arch 466: 735–745.
24. Cullingford TE, Eagles DA, Sato H. 2002. The ketogenic diet upregulates expression of the gene encoding the key ketogenic enzyme mitochondrial 3-hydroxy-3-methylglu-taryl-CoA synthase in rat brain. Epilepsy Res 49: 99–107.
25. Dahlin M, Elfving A, Ungerstedt U, Amark P. 2005. The ketogenic diet influences the levels of excitatory and in-hibitory amino acids in the CSF in children with refractory epilepsy. Epilepsy Res 64: 115–125.
26. Danober L, Deransart C, Depaulis A, Vergnes M, Marescaux C. 1998. Pathophysiological mechanisms of genetic ab-sence epilepsy in the rat. Prog Neurobiol 55: 27–57.
27. 2δ sub-units of voltage-gated calcium channels. Trends Pharmacol Sci 28: 220–228.
28. Deckers CL, Czuczwar SJ, Hekster YA, Keyser A, Kubova H, Meinardi H, Patsalos PN, Renier WO, Van Rijn CM. 2000. Selection of antiepileptic drug polytherapy based on mechanisms of action: The evidence reviewed. Epilepsia 41: 1364–1374.
29. Dezsi G, Ozturk E, Stanic D, Powell KL, Blumenfeld H, O’Brien TJ, Jones NC. 2013. Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy. Epilepsia 54: 635–643.
30. Ding Y, Wang S, Zhang MM, Guo Y, Yang Y, Weng SQ, Wu JM, Qiu X, Ding MP. 2010. Fructose-1,6-diphosphate inhibits seizure acquisition in fast hippocampal kindling. Neurosci Lett 477: 33–36.
31. Dodgson SJ, Shank RP, Maryanoff BE. 2000. Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia 41: S35–S39.
32. 2δ subunits of voltage-gated calci-um channels. Biochim Biophys Acta 1828: 1541–1549.
33. Dunwiddie TV, Masino SA. 2001. The role and regulation of adenosine in the central nervous system. Annu Rev Neu-rosci 24: 31–55.
34. Eid T, Kovacs I, Spencer DD, de Lanerolle NC. 2002. Novel expression of AMPA-receptor subunit GluR1 on mossy cells and CA3 pyramidal neurons in the human epilep-togenic hippocampus. Eur J Neurosci 15: 517–527.
35. Englund M, Hyllienmark L, Brismar T. 2011. Effect of val-proate, lamotrigine and levetiracetam on excitability and firing properties of CA1 neurons in rat brain slices. Cell Mol Neurobiol 31: 645–652.
36. - current. J Neurosci 13: 3211–3221.
37. 2-δ-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci 103: 17537–17542.
38. Frahm C, Engel D, Draguhn A. 2001. Efficacy of background GABA uptake in rat hippocampal slices. NeuroReport 12: 1593–1596.
39. Fraser DD, Whiting S, Andrew RD, Macdonald EA, Musa-Veloso K, Cunnane SC. 2003. Elevated polyunsaturated fatty acids in blood serum obtained from children on the ketogenic diet. Neurology 60: 1026–1029.
40. Freeman JM, Kossoff EH. 2010. Ketosis and the ketogenic diet, 2010: Advances in treating epilepsy and other disorders. Adv Pediatr 57: 315–329.
41. Fritsch B, Reis J, Gasior M, Kaminski RM, Rogawski MA. 2014. Role of GluK1 kainate receptors in seizures, epilep-tic discharges, and epileptogenesis. J Neurosci 34: 5765–5775.
42. García-Pérez E, Lo DC, Wesseling JF. 2008. Kinetic isolation of a slowly recovering component of short-term depression during exhaustive use at excitatory hippocampal synapses. J Neurophysiol 100: 781–795.
43. García-Pérez E, Mahfooz K, Covita J, Zandueta A, Wesseling JF. 2015. Levetiracetam accelerates the onset of supply rate depression in synaptic vesicle trafficking. Epilepsia 56: 535–545.
44. Garriga-Canut M, Schoenike B, Qazi R, Bergendahl K, Da-ley TJ, Pfender RM, Morrison JF, Ockuly J, Stafstrom C, Sutula T, et al. 2006. 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-Ct BP-dependent metabolic regula-tion of chromatin structure. Nat Neurosci 9: 1382–1387.
45. Gasior M, Rogawski MA, Hartman AL. 2006. Neuroprotec-tive and disease-modifying effects of the ketogenic diet. Behav Pharmacol 17: 431–439.
46. Gasior M, French A, Joy MT, Tang RS, Hartman AL, Rogaw-ski MA. 2007. The anticonvulsant activity of acetone, the major ketone body in the ketogenic diet, is not de-pendent on its metabolites acetol, 1,2-propanediol, methylglyoxal, or pyruvic acid. Epilepsia 48: 793–800.
47. Gasior M, Yankura J, Hartman AL, French A, Rogawski MA. 2010. Anticonvulsant and proconvulsant actions of 2-deoxy-D-glucose. Epilepsia 51: 1385–1394.
48. Gibbs JW 3rd, Sombati S, DeLorenzo RJ, Coulter DA. 2000. Cellular actions of topiramate: Blockade of kai-nate-evoked inward currents in cultured hippocampal neurons. Epilepsia 41: S10–S16.
49. v1.1 modulation by a novel triazole compound attenuates ep-ileptic seizures in rodents. ACS Chem Biol 9: 1204–1212.
50. Gomora JC, Daud AN, Weiergräber M, Perez-Reyes E. 2001. Block of cloned human T-type calcium channels by suc-cinimide antiepileptic drugs. Mol Pharmacol 60: 1121–1132.
51. Gören MZ, Onat F. 2007. Ethosuximide: From bench to bedside. CNS Drug Rev 13: 224–239.
52. Grigorov A, Moskalyuk A, Kravchenko M, Veselovsky N, Verkhratsky A, Fedulova S. 2014. Kv7 potassium channel subunits and M currents in cultured hippocampal inter-neurons. Pflugers Arch 466:1747–1758.
53. Grunnet M, Strøbæk D, Hougaard C, Christophersen P. 2014. Kv7 channels as targets for anti-epileptic and psy-chiatric drug-development. Eur J Pharmacol 726: 133–137.
54. Ca2/SK channels, contribute to the somatic medium after-hyperpolarization and excit-ability control in CA1 hippocampal pyramidal cells. J Physiol 566: 689–715.
55. + channel opener for the treatment of epilepsy. Epilepsia 53: 412–424.
56. Hadera MG, Smeland OB, McDonald TS, Tan KN, Sonne-wald U, Borges K. 2014. Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epilepsy. J Neurochem 129: 107–119.
57. Hanada T, Hashizume Y, Tokuhara N, Takenaka O, Koh-mura N, Ogasawara A, Hatakeyama S, Ohgoh M, Ueno M, Nishizawa Y. 2011. Perampanel: A novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy. Epilepsia 52: 1331–1340.
58. Hassel B, Dingledine R. 2012. Glutamate and glutamate receptors. In Basic neurochemistry: Principlesofmolecu-lar,cellular, and medical neurobiology, 8th ed. (ed. ScottT, Brady ST, Siegel GJ, et al.), pp. 343–366. Elsevier, Am-sterdam.
59. Hermann R, Ferron GM, Erb K, Knebel N, Ruus P, Paul J, Richards L, Cnota HP, Troy S. 2003. Effects of age and sex on the disposition of retigabine. Clin Pharmacol Ther 73: 61–70.
60. 2δ Expression sets presynaptic calcium channel abun-dance and release probability. Nature 486: 122–125.
61. Houser CR. 2014. Do structural changes in GABA neurons give rise to the epileptic state? Adv Exp Med Biol 813: 151–160.
62. Hu H, Vervaeke K, Storm JF. 2007. M-channels (Kv7/KCNQ channels) that regulate synaptic integration, excitability, and spike pattern of CA1 pyramidal cells are located in the perisomatic region. J Neurosci 27: 1853–1867.
63. + (Kir2.1) channel. Pflugers Arch 467: 1733–1746.
64. Hughes JR. 2009. Absence seizures: A review of recent re-ports with new concepts. Epilepsy Behav 15: 404–412.
65. Huguenard JR. 1996. Low-threshold calcium currents in central nervous system neurons. Annu Rev Physiol 58: 329–358.
66. 2+ channels is an important action of succinimide antiabsence drugs. Epilepsy Curr 2: 49–52.
67. Huttenlocher PR. 1976. Ketonemia and seizures: Metabolic and anticonvulsant effects of two ketogenic diets in child-hood epilepsy. Pediatr Res 10: 536–540.
68. Huttenlocher PR, Wilbourn AJ, Signore JM. 1971. Medium-chain triglycerides as a therapy for intractable childhood epilepsy. Neurology 21: 1097–1103.
69. Jarrett SG, Milder JB, Liang LP, Patel M. 2008. The ketogenic diet increases mitochondrial glutathione levels. J Neuro-chem 106: 1044–1051.
70. Juge N, Gray JA, Omote H, Miyaji T, Inoue T, Hara C, Un-eyama H, Edwards RH, Nicoll RA, Moriyama Y. 2010. Metabolic control of vesicular glutamate transport and release. Neuron 68: 99–112.
71. Kaminski RM, Gillard M, Klitgaard H. 2012. Targeting SV2A for discovery of antiepileptic drugs. In Jasper’s basic mechanismsoftheepilepsies, 4th ed. (ed. Noebels JL, et al.), pp. 974–983. Oxford University Press, New York.
72. Kaminski RM, Rogawski MA, Klitgaard H. 2014. The potential of antiseizure drugs and agents that act on novel molecular targets as antiepileptogenic treatments. Neuro-therapeutics 11: 385–400.
73. Kapetanovic IM, Yonekawa WD, Kupferberg HJ. 1995. The effects of D-23129, a new experimental anticonvulsant drug, on neurotransmitter amino acids in the rat hippo-campus in vitro. Epilepsy Res 22: 167–173.
74. Kasteleijn-Nolst Trenité D, Brandt C, Mayer T, Rosenow F, Schmidt B, Steinhoff BJ, Gardin A, Imbert G, Johns D, Sagkriotis A, et al. 2015. Dose-dependent suppression of human photoparoxysmal response with the competitive AMPA/kainate receptor antagonist BGG492: Clear PK/ PD relationship. Epilepsia 56: 924–932.
75. Keith HM. 1933. Factors influencing experimentally produced convulsions. Arch Neurol Psychiatry 29: 148–154.
76. Kim DY, Davis LM, Sullivan PG, Maalouf M, Simeone TA, van Brederode J, Rho JM. 2007. Ketone bodies are protective against oxidative stress in neocortical neurons. J Neurochem 101: 1316–1326.
77. Kim DY, Vallejo J, Rho JM. 2010. Ketones prevent synaptic dysfunction induced by mitochondrial respiratory complex inhibitors. J Neurochem 114: 130–141.
78. Kim TH, Borges K, Petrou S, Reid CA. 2013. Triheptanoin reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy. Epilepsy Res 103: 101–105.
79. Kim DY, Simeone KA, Simeone TA, Pandya JD, Wilke JC, Ahn Y, Geddes JW, Sullivan PG, Rho JM. 2015. Ketone bodies mediate antiseizure effects through mitochondrial permeability transition. Ann Neurol 78: 77–87.
80. Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, Kobayashi M, Hirasawa A, Tsujimoto G.: Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). 2011. Proc Natl Acad Sci 108: 8030–8035.
81. Lambert RC, Bessaïh T, Crunelli V, Leresche N. 2014. The many faces of T-type calcium channels. Pflugers Arch 466: 415–423.
82. Lawrence JJ, Saraga F, Churchill JF, Statland JM, Travis KE, Skinner FK, McBain CJ. 2006. Somatodendritic Kv7/ KCNQ/M channels control interspike interval in hippo-campal interneurons. J Neurosci 26: 12325–12338.
83. Lennox WG, Cobb S. 1928. Epilepsy: From the standpoint of physiology and treatment. Medicine 7: 105–290.
84. Leppik IE, Sherwin AL. 1977. Anticonvulsant activity of phenobarbital and phenytoin in combination. J Pharma-col Exp Ther 200: 570–575.
85. Li G, Nowak M, Bauer S, Schlegel K, Stei S, Allenhöfer L, Waschbisch A, Tackenberg B, Höllerhage M, Höglinger GU, et al. 2013. Levetiracetam but not valproate inhibits function of CD8+ T lymphocytes. Seizure 22: 462–466.
86. Lian XY, Khan FA, Stringer JL. 2007. Fructose-1,6-bisphos-phate has anticonvulsant activity in models of acute seizures in adult rats. J Neurosci 27: 12007–12011.
87. Likhodii SS, Serbanescu I, Cortez MA, Murphy P, Snead OC III, Burnham WM. 2003. Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet. Ann Neurol 54: 219–226.
88. Liu YM, Wang HS. 2013. Medium-chain triglyceride ketogenic diet, an effective treatment for drug-resistant epilepsy and a comparison with other ketogenic diets. Biomed J 36: 9–15.
89. Löscher W. 1989. Valproate enhances GABA turnover in the substantia nigra. Brain Res 501: 198–203.
90. Löscher W. 1998. Pharmacology of glutamate receptor an-tagonists in the kindling model. In Kindling 5 (ed. Cor-coran ME, Moshé SL), pp. 435–449. Plenum, New York.
91. Löscher W. 2002. Basic pharmacology of valproate: A review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 16: 669–694.
92. Löscher W, Rogawski MA. 2012. How theories evolved con-cerning the mechanism of action of barbiturates. Epilep-sia 53: 12–25.
93. Löscher W, Jäckel R, Müller F. 1989. Anticonvulsant and proconvulsant effects of inhibitors of GABA degradation in the amygdala-kindling model. Eur J Pharmacol 163: 1–14.
94. Löscher W, Hönack D, Taylor CP. 1991. Gabapentin increas-es aminooxyacetic acid-induced GABA accumulation in several regions of rat brain. Neurosci Lett 128: 150–154.
95. Löscher W, Hönack D, Bloms-Funke P. 1996. The novel antiepileptic drug levetiracetam (ucb L059) induces al-terations in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in sub-stantia nigra pars reticulata. Brain Res 735: 208–216.
96. 2δ-2 (R279A) mouse mutants. J Pharmacol Exp Ther 338: 615–621.
97. Lynch BA, Matagne A, Brännström A, von Euler A, Jansson M, Hauzenberger E, Söderhäll JA. 2008. Visualization of SV2A conformations in situ by the use of protein tomog-raphy. Biochem Biophys Res Commun 375: 491–495.
98. Lyseng-Williamson KA. 2011. Spotlight on levetiracetam in epilepsy. CNS Drugs 25: 901–905.
99. Ma W, Berg J, Yellen G. 2007. Ketogenic diet metabolites reduce firing in central neurons by opening KATP channels. J Neurosci 27: 3618–3625.
100. Maalouf M, Rho JM. 2008. Oxidative impairment of hip-pocampal long-term potentiation involves activation of protein phosphatase 2A and is prevented by ketone bodies. J Neurosci Res 86: 3322–3330.
101. Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM. 2007. Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotox-icity by increasing NADH oxidation. Neuroscience 145: 256–264.
102. Mantegazza M, Curia G, Biagini G, Ragsdale DS, Avoli M. 2010. Voltage-gated sodium channels as therapeutic tar-gets in epilepsy and other neurological disorders. Lancet Neurol 9: 413–424.
103. Mantis JG, Centeno NA, Todorova MT, McGowan R, Sey-fried TN. 2004. Management of multifactorial idiopathic epilepsy in EL mice with caloric restriction and the keto-genic diet: Role of glucose and ketone bodies. Nutr Metab (Lond) 1: 11.
104. Margolis JM, Chu BC, Wang ZJ, Copher R, Cavazos JE. 2014. Effectiveness of antiepileptic drug combination therapy for partial-onset seizures based on mechanisms of action. JAMA Neurol 71: 985–993.
105. Martire M, Castaldo P, D’Amico M, Preziosi P, Annunziato L, Taglialatela M. 2004. M channels containing KCNQ2 subunits modulate norepinephrine, aspartate, and GABA release from hippocampal nerve terminals. J Neurosci 24: 592–597.
106. Masino SA, Rho JM. 2012. Mechanisms of ketogenic diet action. In Jasper’s basic mechanismsoftheepilepsies, 4th ed. (ed. Noebels JL, et al.), pp. 1003–1024. Oxford University Press, New York.
107. Masino SA, Li T, Theofilas P, Sandau US, Ruskin DN, Fred-holm BB, Geiger JD, Aronica E, Boison D. 2011. A ketogenic diet suppresses seizures in mice through adenosine A1 receptors. J Clin Invest 121: 2679–2683.
108. Masino SA, Kawamura M Jr, Ruskin DN, Geiger JD, Boison D. 2012. Purines and neuronal excitability: Links to the ketogenic diet. Epilepsy Res 100: 229–238.
109. Matar N, Jin W, Wrubel H, Hescheler J, Schneider T, Weier-gräber M. 2009. Zonisamide block of cloned human T-type voltage-gated calcium channels. Epilepsy Res 83: 224–234.
110. Mathern GW, Pretorius JK, Mendoza D, Lozada A, Leite JP, Chimelli L, Fried I, Sakamoto AC, Assirati JA, Adelson PD. 1998. Increased hippocampal AMPA and NMDA receptor subunit immunoreactivity in temporal lobe epilepsy patients. J Neuropathol Exp Neurol 57: 615–634.
111. Mazzuferi M, Kumar G, van Eyll J, Danis B, Foerch P, Ka-minski RM. 2013. Nrf2 defense pathway: Experimental evidence for its protective role in epilepsy. Ann Neurol 74: 560–568.
112. Medina-Kauwe LK, Tobin AJ, De Meirleir L, Jaeken J, Jakobs C, Nyhan WL, Gibson KM. 1999. 4-Aminobutyrate ami-notransferase (GABA-transaminase) deficiency. J Inherit Metab Dis 22: 414–427.
113. Meehan AL, Yang X, McAdams BD, Yuan L, Rothman SM. 2011. A new mechanism for antiepileptic drug action: Vesicular entry may mediate the effects of levetiracetam. J Neurophysiol 106: 1227–1239.
114. Meehan AL, Yang X, Yuan LL, Rothman SM. 2012. Leveti-racetam has an activity-dependent effect on inhibitory transmission. Epilepsia 53: 469–476.
115. Meldrum BS, Rogawski MA. 2007. Molecular targets for antiepileptic drug development. Neurotherapeutics 4: 18–61.
116. Melo TM, Nehlig A, Sonnewald U. 2006. Neuronal-glial interactions in rats fed a ketogenic diet. Neurochem Int 48: 498–507.
117. Michael-Titus AT, Priestley JV. 2013. Omega-3 fatty acids and traumatic neurological injury: From neuroprotec-tion to neuroplasticity? Trends Neurosci 37: 30–38.
118. Milder JB, Liang LP, Patel M. 2010. Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet. Neu-robiol Dis 40: 238–244.
119. Morris AA. 2005. Cerebral ketone body metabolism. J Inherit Metab Dis 28: 109–121.
120. 1H-MRS. Neurology 57: 1422–1427.
121. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. 2008. The ketogenic diet for the treatment of childhood epilepsy: A randomised controlled trial. Lancet Neurol 7: 500–506.
122. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. 2009. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia 50: 1109–1117.
123. Neuman R, Cherubini E, Ben-Ari Y. 1988. Epileptiform bursts elicited in CA3 hippocampal neurons by a variety of convulsants are not blocked by N-methyl-D-aspartate antagonists. Brain Res 459: 265–274.
124. Oliva M, Berkovic SF, Petrou S. 2012. Sodium channels and the neurobiology of epilepsy. Epilepsia 53: 1849–1859.
125. Olsen RW, Sieghart W. 2009. GABAA receptors: Subtypes provide diversity of function and pharmacology. Neuro-pharmacology 56: 141–148.
126. Otto JF, Kimball MM, Wilcox KS. 2002. Effects of the anticonvulsant retigabine on cultured cortical neurons: Changes in electroresponsive properties and synaptic transmission. Mol Pharmacol 61: 921–927.
127. Overstreet LS, Westbrook GL. 2001. Paradoxical reduction of synaptic inhibition by vigabatrin. J Neurophysiol 86: 596–603.
128. Pascual JM, Liu P, Mao D, Kelly DI, Hernandez A, Sheng M, Good LB, Ma Q, Marin-Valencia I, Zhang X, et al. 2014. Triheptanoin for glucose transporter type I deficiency (G1D): Modulation of human ictogenesis, cerebral met-abolic rate, and cognitive indices by a food supplement. JAMA Neurol 71: 1255–1265.
129. + channel β subunits in development and disease. Neurosci Lett 486: 53–59.
130. Peterman MG. 1924. The ketogenic diet in the treatment of epilepsy: A preliminary report. Am J Dis Child 28: 28–33.
131. Petroff OAC, Behar KL, Mattson RH, Rothman DL. 1996a. Human brain γ-aminobutyric acid levels and seizure control following initiation of vigabatrin therapy. J Neu-rochem 67: 2399–4404.
132. Petroff OAC, Rothman DL, Behar KL, Lamoureux D, Matt-son RH. 1996b. The effect of gabapentin on brain γ-aminobutyric acid in patients with epilepsy. Ann Neurol 39: 95–99.
133. Pierre K, Pellerin L. 2005. Monocarboxylate transporters in the central nervous system: Distribution, regulation and function. J Neurochem 94: 1–14.
134. Porta N, Vallee L, Lecointe C, Bouchaert E, Staels B, Bordet R, Auvin S. 2009. Fenofibrate, a peroxisome proliferator-activated receptor-a agonist, exerts anticonvulsive properties. Epilepsia 50: 943–948.
135. Powell KL, Cain SM, Snutch TP, O’Brien TJ. 2014. Low threshold T-type calcium channels as targets for novel epilepsy treatments. Br J Clin Pharmacol 77: 729–739.
136. + channels. Proc Natl Acad Sci 93: 9270–9275.
137. A receptor function and seizure susceptibility. J Neurosci 22: 3795–3805.
138. A receptors. Ann Neurol 35: 229–234.
139. Rho JM, Donevan SD, Rogawski MA. 1996. Direct activation of GABAA receptors by barbiturates in cultured rat hippocampal neurons. J Physiol 497: 509–522.
140. Rigoulot MA, Boehrer A, Nehlig A. 2003. Effects of topiramate in two models of genetically determined generalized epilepsy, the GAERS and the Audiogenic Wistar AS. Epilepsia 44: 14–19.
141. Rogawski MA. 2006. Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Res 69: 273–294.
142. Rogawski MA. 2013. AMPA receptors as a molecular target inepilepsy therapy. Acta Neurol Scand Suppl 197: 9–18.
143. Rogawski MA, Cavazos JE. 2015. Mechanisms of action of antiepileptic drugs. In Wyllie’s treatment ofepilepsy: Prin-ciples and practice, 6th ed. (ed. Wyllie E.), pp. 522–529. Wolters Kluwer, Philadelphia.
144. Rogawski MA, Hanada T. 2013. Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol Scand 127: 19–24.
145. Rogawski MA, Porter RJ. 1990. Antiepileptic drugs: Pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage com-pounds. Pharmacol Rev 42: 223–286.
146. Rogawski MA, Kurzman PS, Yamaguchi SI, Li H. 2001. Role of AMPA and GluR5 kainate receptors in the develop-ment and expression of amygdala kindling in the mouse. Neuropharmacology 40: 28–35.
147. Rogawski MA, Tofighy A, White HS, Matagne A, Wolff C. 2015. Current understanding of the mechanism of action of the antiepileptic drug lacosamide. Epilepsy Res 110: 189–205.
148. Rowley S, Patel M. 2013. Mitochondrial involvement and oxidative stress in temporal lobe epilepsy. Free Radic Biol Med 62: 121–131.
149. Rundfeldt C, Netzer R. 2000. Investigations into the mechanism of action of the new anticonvulsant retigabine. Interaction with GABA ergic and glutamatergic neuro-transmission and with voltage gated ion channels. Arz-neimittelforschung 50: 1063–1070.
150. Sahara S, Yanagawa Y, O’Leary DD, Stevens CF. 2012. The fraction of cortical GABA ergic neurons is constant from near the start of cortical neurogenesis to adulthood. J Neurosci 32: 4755–4761.
151. Schlanger S, Shinitzky M, Yam D. 2002. Diet enriched with omega-3 fatty acids alleviates convulsion symptoms in epilepsy patients. Epilepsia 43: 103–104.
152. Schousboe A, Madsen KK, Barker-Haliski ML, White HS. 2014. The GABA synapse as a target for antiepileptic drugs: A historical overview focused on GABA transporters. Neurochem Res 39: 1980–1987.
153. Shank RP, Maryanoff BE. 2008. Molecular pharmacody-namics, clinical therapeutics, and pharmacokinetics of topiramate. CNS Neurosci Ther 14: 120–142.
154. Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, et al. 2013. Suppression of oxidative stress by 3-hydroxy‑butyrate, an endogenous histone deacetylase inhibitor. Science 339: 211–214.
155. Silverman RB, Andruszkiewicz R, Nanavati SM, Taylor CP, Vartanian MG. 1991. 3-Alkyl-4-aminobutyric acids: The first class of anticonvulsant agents that activates L-glutamic acid decarboxylase. J Med Chem 34: 2295–2298.
156. Simeone TA, Wilcox KS, White HS. 2011. Topiramate modulation of β1- and β3-homomeric GABAA receptors. Pharmacol Res 64: 44–52.
157. Sohal VS, Keist R, Rudolph U, Huguenard JR. 2003. Dynamic GABAA receptor subtype-specific modulation of the synchrony and duration of thalamic oscillations. J Neuro-sci 23: 3649–3657.
158. Stafstrom CE. 2007. Persistent sodium current and its role in epilepsy. Epilepsy Curr 7: 15–22.
159. Stafstrom CE, Rho JM. 2012. The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol 3: 59.
160. Stafstrom CE, Ockuly JC, Murphree L, Valley MT, Roopra A, Sutula TP. 2009. Anticonvulsant and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models. Ann Neurol 65: 435–447.
161. Stafstrom CE, Arnason BG, Baram TZ, Catania A, Cortez MA, Glauser TA, Pranzatelli MR, Riikonen R, Rogawski MA, Shinnar S, et al. 2011. Treatment of infantile spasms: Emerging insights from clinical and basic science perspectives. J Child Neurol 26: 1411–1421.
162. Stahl SM, Porreca F, Taylor CP, Cheung R, Thorpe AJ, Clair A. 2013. The diverse therapeutic actions of pregabalin: Is a single mechanism responsible for several pharmacological activities? Trends Pharmacol Sci 34: 332–339.
163. Steinhoff BJ, Ben-Menachem E, Ryvlin P, Shorvon S, Kramer L, Satlin A, Squillacote D, Yang H, Zhu J, Laurenza A. 2013. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: A pooled analysis of three phase III studies. Epilepsia 54: 1481–1499.
164. Stuchlík A, Kubová H, Mares P. 2001. Single systemic dose of vigabatrin induces early proconvulsant and later anticon-vulsant effect in rats. Neurosci Lett 312: 37–40.
165. Sullivan PG, Dube C, Dorenbos K, Steward O, Baram TZ. 2003. Mitochondrial uncoupling protein-2 protects the immature brain from excitotoxic neuronal death. Ann Neurol 53: 711–717.
166. Sullivan PG, Rippy NA, Dorenbos K, Concepcion RC, Agarwal AK, Rho JM. 2004. The ketogenic diet increases mi-tochondrial uncoupling protein levels and activity. Ann Neurol 55: 576–580.
167. v1.3 α-subunit. Epilepsia 48: 774–782.
168. Suzuki S, Rogawski MA. 1989. T-type calcium channels mediate the transition between tonic and phasic firing in thalamic neurons. Proc Natl Acad Sci 86: 7228–7232.
169. Suzuki T, Motohashi H, Yamamoto M. 2013. Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol Sci 34: 340–346.
170. Sveinbjornsdottir S, Sander JW, Upton D, Thompson PJ, Patsalos PN, Hirt D, Emre M, Lowe D, Duncan JS. 1993. The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy. Epilepsy Res 16: 165–174.
171. Taha AY, Ryan MA, Cunnane SC. 2005. Despite transient ketosis, the classic high-fat ketogenic diet induces marked changes in fatty acid metabolism in rats. Metabolism 54: 1127–1132.
172. Taha AY, Burnham WM, Auvin S. 2010. Polyunsaturated fatty acids and epilepsy. Epilepsia 51: 1348–1358.
173. Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, Bayliss DA. 1999. Differential distribution of three members of a gene family encoding low voltage-activated (T-type) cal-cium channels. J Neurosci 19: 1895–1911.
174. Tanner GR, Lutas A, Martinez-Francois JR, Yellen G. 2011. Single KATP channel opening in response to action po-tential firing in mouse dentate granule neurons. J Neuro-sci 31: 8689–8696.
175. Tatulian L, Brown DA. 2003. Effect of the KCNQ potassium channel opener retigabine on single KCNQ2/3 channels expressed in CHO cells. J Physiol 549: 57–63.
176. Taylor CP, Vartanian MG, Andruszkiewiewicz R, Silverman RB. 1992. 3-Alkyl GABA and 3-alkylglutamic acid analogues: Two new classes of anticonvulsant agents. Epilepsy Res 11: 103–110.
177. 2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res 73: 137–150.
178. Thio LL, Wong M, Yamada KA. 2000. Ketone bodies do not directly alter excitatory or inhibitory hippocampal syn-aptic transmission. Neurology 54: 325–331.
179. Thompson SM, Gähwiler BH. 1992. Effects of the GABA uptake inhibitor tiagabine on inhibitory synaptic potentials in rat hippocampal slice cultures. J Neurophysiol 67: 1698–1701.
180. Treven M, Koenig X, Assadpour E, Gantumur E, Meyer C, Hilber K, Boehm S, Kubista H. 2015. The anticonvulsant retigabine is a subtype selective modulator of GABAA receptors. Epilepsia 56: 647–657.
181. Turner JP, Salt TE. 1998. Characterization of sensory and corticothalamic excitatory inputs to rat thalamocortical neurones in vitro. J Physiol 510: 829–843.
182. Twele F, Bankstahl M, Klein S, Römermann K, Löscher W. 2015. The AMPA receptor antagonist NBQX exerts anti-seizure but not antiepileptogenic effects in the intrahip-pocampal kainate mouse model of mesial temporal lobe epilepsy. Neuropharmacology 95: 234–242.
183. Tzingounis AV, Heidenreich M, Kharkovets T, Spitzmaul G, Jensen HS, Nicoll RA, Jentsch TJ. 2010. The KCNQ5 potassium channel mediates a component of the after-hyperpolarization current in mouse hippocampus. Proc Natl Acad Sci 107: 10232–10237.
184. U.S. Food and Drug Administration 2010. Ezogabine for partial seizures in epilepsy (NDA-022345). Peripheral and Central Nervous System Drugs Advisory Committee Briefing Document U.S. Food and Drug Administration, Jersey City, NJ.
185. Vacher H, Mohapatra DP, Trimmer JS. 2008. Localization and targeting of voltage-dependent ion channels in mammalian central neurons. Physiol Rev 88: 1407–1447.
186. Vervaeke K, Gu N, Agdestein C, Hu H, Storm JF. 2006. Kv7/ KCNQ/M-channels in rat glutamatergic hippocampal axons and their role in regulation of excitability and transmitter release. J Physiol 576.1: 235–256.
187. Vreugdenhil M, Bruehl C, Voskuyl RA, Kang JX, Leaf A, Wadman WJ. 1996. Polyunsaturated fatty acids modulate sodium and calcium currents in CA1 neurons. Proc Natl Acad Sci 93: 12559–12563.
188. +-dependent GABA type A receptor-mediated presynaptic modulation. J Pharmacol Exp Ther 348: 246–259.
189. Waldmeier PC, Baumann PA, Wicki P, Feldtrauer JJ, Stierlin C, Schmutz M. 1995. Similar potency of carbamazepine, oxcarbazepine, and lamotrigine in inhibiting the release of glutamate and other neurotransmitters. Neurology 45: 1907–1913.
190. Walker MC, Kullmann DM. 2012. Tonic GABAA receptor-mediated signaling in epilepsy. In Jasper’s basic mecha-nisms of the epilepsies, 4th ed. (Noebels JL, et al., eds.), pp. 111–121. Oxford University Press, New York.
191. Walker MC, Williams RS. 2013. The search for better epilepsy treatments: From slime mould to coconuts. Biochem Soc Trans 41: 1625–1628.
192. V2.1 in HEK293t cells. Brain Res Bull 90: 107–113.
193. Wheless JW. 2008. History of the ketogenic diet. Epilepsia 49: 3–5.
194. Willis S, Stoll J, Sweetman L, Borges K. 2010. Anticonvulsant effects of a triheptanoin diet in two mouse chronic seizure models. Neurobiol Dis 40: 565–572.
195. Won YJ, Lu VB, Puhl HL 3rd, Ikeda SR. 2013. β-Hy-droxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3. J Neurosci 33: 19314–19325.
196. Wu Y, Wang W, Richerson GB. 2003. Vigabatrin induces tonic inhibition via GABA transporter reversal without increasing vesicular GABA release. J Neurophysiol 89: 2021–2034.
197. Yamaguchi S, Donevan SD, Rogawski MA. 1993. Anticon-vulsant activity of AMPA/kainate antagonists: Comparison of GYKI 52466 and NBOX in maximal electroshock and chemoconvulsant seizure models. Epilepsy Res 15: 179–184.
198. Yu FH, Catterall WA. 2003. Overview of the voltage-gated sodium channel family. Genome Biol 4: 207.
199. Yudkoff M, Daikhin Y, Nissim I, Horyn O, Lazarow A, Lu-hovyy B, Wehrli S. 2005. Response of brain amino acid metabolism to ketosis. Neurochem Int 47: 119–128.
200. v7/ M channels differentially regulate the intrinsic excitability of adult rat CA1 pyramidal cells. J Neurophysiol 95: 3480–3495.
201. Yuen AW, Sander JW, Fluegel D, Patsalos PN, Bell GS, John-son T, Koepp MJ. 2005. Omega-3 fatty acid supplemen-tation in patients with chronic epilepsy: A randomized trial. Epilepsy Behav 7: 253–258.
202. Zilles K, Qü MS, Köhling R, Speckmann EJ. 1999. Ionotropic glutamate and GABA receptors in human epileptic neocortical tissue: Quantitative in vitro receptor autoradiography. Neuroscience 94: 1051–1061.