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Branched-Chain Amino Acids and Seizures: A Systematic Review of the Literature

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Abstract

Background

Up to 40% of patients with epilepsy experience seizures despite treatment with antiepileptic drugs; however, branched-chain amino acid (BCAA) supplementation has shown promise in treating refractory epilepsy.

Objectives

The purpose of this systematic review was to evaluate all published studies that investigated the effects of BCAAs on seizures, emphasizing therapeutic efficacy and possible underlying mechanisms.

Methods

On 31 January, 2017, the following databases were searched for relevant studies: MEDLINE (OvidSP), EMBASE (OvidSP), Scopus (Elsevier), the Cochrane Library, and the unindexed material in PubMed (National Library of Medicine/National Institutes of Health). The searches were repeated in all databases on 18 February, 2019. We only included full-length preclinical and clinical studies that were published in the English language that examined the effects of BCAA administration on seizures.

Results

Eleven of 2045 studies met our inclusion criteria: ten studies were conducted in animal models and one study in human subjects. Seven seizure models were investigated: the strychnine (one study), pentylenetetrazole (two studies), flurothyl (one study), picrotoxin (two studies), genetic absence epilepsy in rats (one study), kainic acid (two studies), and methionine sulfoximine (one study) paradigms. Three studies investigated the effect of a BCAA mixture whereas the other studies explored the effects of individual BCAAs on seizures. In most animal models and in humans, BCAAs had potent anti-seizure effects. However, in the methionine sulfoximine model, long-term BCAA supplementation worsened seizure propagation and caused neuron loss, and in the genetic absence epilepsy in rats model, BCAAs exhibited pro-seizure effects.

Conclusions

The contradictory effects of BCAAs on seizure activity likely reflect differences in the complex mechanisms that underlie seizure disorders. Some of these mechanisms are likely mediated by BCAA’s effects on glucose, glutamate, glutamine, and ammonia metabolism, activation of the mechanistic target of rapamycin signaling pathway, and their effects on aromatic amino acid transport and neurotransmitter synthesis. We propose that a better understanding of mechanisms by which BCAAs affect seizures and neuronal viability is needed to advance the field of BCAA supplementation in epilepsy.

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References

  1. Chang BS, Lowenstein DH. Epilepsy. N Engl J Med. 2003;349(13):1257–66.

    Article  PubMed  Google Scholar 

  2. ILAE Commission Report. The epidemiology of the epilepsies: future directions. International League Against Epilepsy. Epilepsia. 1997;38(5):614–8.

    Article  Google Scholar 

  3. Begley CE, Famulari M, Annegers JF, Lairson DR, Reynolds TF, Coan S, et al. The cost of epilepsy in the United States: an estimate from population-based clinical and survey data. Epilepsia. 2000;41(3):342–51.

    Article  CAS  PubMed  Google Scholar 

  4. de Lanerolle NC, Lee TS, Spencer DD. Histopathology of human epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies. 4th ed. Bethesda: National Center for Biotechnology Information; 2012.

    Google Scholar 

  5. Annegers J. The treatment of epilepsy: principles and practice. 2nd ed. Baltimore: Williams and Wilkins; 1996.

    Google Scholar 

  6. Eid T, Gruenbaum SE, Dhaher R, Lee TW, Zhou Y, Danbolt NC. The glutamate-glutamine cycle in epilepsy. Adv Neurobiol. 2016;13:351–400.

    Article  PubMed  Google Scholar 

  7. McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol. 2001;63:815–46.

    Article  CAS  PubMed  Google Scholar 

  8. Zimmerman G, Njunting M, Ivens S, Tolner EA, Behrens CJ, Gross M, et al. Acetylcholine-induced seizure-like activity and modified cholinergic gene expression in chronically epileptic rats. Eur J Neuurosci. 2008;27(4):965–75.

    Article  Google Scholar 

  9. Eid T, Thomas MJ, Spencer DD, Runden-Pran E, Lai JC, Malthankar GV, et al. Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet. 2004;363(9402):28–37.

    Article  CAS  PubMed  Google Scholar 

  10. Yudkoff M. Brain metabolism of branched-chain amino acids. Glia. 1997;21(1):92–8.

    Article  CAS  PubMed  Google Scholar 

  11. Fernstrom JD. Branched-chain amino acids and brain function. J Nutr. 2005;135(6):1539S–46S.

    Article  CAS  PubMed  Google Scholar 

  12. Matsuo H, Tsukada S, Nakata T, Chairoungdua A, Kim DK, Cha SH, et al. Expression of a system L neutral amino acid transporter at the blood–brain barrier. Neuroreport. 2000;11(16):3507–11.

    Article  CAS  PubMed  Google Scholar 

  13. Takanaga H, Mackenzie B, Peng JB, Hediger MA. Characterization of a branched-chain amino-acid transporter SBAT1 (SLC6A15) that is expressed in human brain. Biochem Biophys Res Commun. 2005;337(3):892–900.

    Article  CAS  PubMed  Google Scholar 

  14. Giorgi FS, Pizzanelli C, Biagioni F, Murri L, Fornai F. The role of norepinephrine in epilepsy: from the bench to the bedside. Neurosci Biobehav Rev. 2004;28(5):507–24.

    Article  CAS  PubMed  Google Scholar 

  15. Kumar U, Medel-Matus JS, Redwine HM, Shin D, Hensler JG, Sankar R, et al. Effects of selective serotonin and norepinephrine reuptake inhibitors on depressive- and impulsive-like behaviors and on monoamine transmission in experimental temporal lobe epilepsy. Epilepsia. 2016;57(3):506–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Svob Strac D, Pivac N, Smolders IJ, Fogel WA, De Deurwaerdere P, Di Giovanni G. Monoaminergic mechanisms in epilepsy may offer innovative therapeutic opportunity for monoaminergic multi-target drugs. Front Neurosci. 2016;10(10):492.

    PubMed  PubMed Central  Google Scholar 

  17. Fernstrom JD. Aromatic amino acids and monoamine synthesis in the central nervous system: influence of the diet. J Nutr Biochem. 1990;1(10):508–17.

    Article  CAS  PubMed  Google Scholar 

  18. Smith QR, Momma S, Aoyagi M, Rapoport SI. Kinetics of neutral amino acid transport across the blood–brain barrier. J Neurochem. 1987;49(5):1651–8.

    Article  CAS  PubMed  Google Scholar 

  19. Pardridge WM, Choi TB. Neutral amino acid transport at the human blood–brain barrier. Fed Proc. 1986;45(7):2073–8.

    CAS  PubMed  Google Scholar 

  20. Fernstrom MH, Volk EA, Fernstrom JD. In vivo inhibition of tyrosine uptake into rat retina by large neutral but not acidic amino acids. Am J Physiol. 1986;251(4 Pt 1):E393–9.

    CAS  PubMed  Google Scholar 

  21. Blomstrand E, Eliasson J, Karlsson HK, Kohnke R. Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise. J Nutr. 2006;136(1 Suppl.):269S–73S.

    Article  CAS  PubMed  Google Scholar 

  22. Rothman DL, De Feyter HM, Maciejewski PK, Behar KL. Is there in vivo evidence for amino acid shuttles carrying ammonia from neurons to astrocytes? Neurochem Res. 2012;37(11):2597–612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol. 2014;10(12):723–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. De Simone R, Vissicchio F, Mingarelli C, De Nuccio C, Visentin S, Ajmone-Cat MA, et al. Branched-chain amino acids influence the immune properties of microglial cells and their responsiveness to pro-inflammatory signals. Biochim Biophys Acta. 2013;1832(5):650–9.

    Article  CAS  PubMed  Google Scholar 

  25. Scarna A, McTavish SF, Cowen PJ, Goodwin GM, Rogers RD. The effects of a branched chain amino acid mixture supplemented with tryptophan on biochemical indices of neurotransmitter function and decision-making. Psychopharmacology (Berl). 2005;179(4):761–8.

    Article  CAS  Google Scholar 

  26. Contrusciere V, Paradisi S, Matteucci A, Malchiodi-Albedi F. Branched-chain amino acids induce neurotoxicity in rat cortical cultures. Neurotox Res. 2010;17(4):392–8.

    Article  CAS  PubMed  Google Scholar 

  27. Testa D, Caraceni T, Fetoni V. Branched-chain amino acids in the treatment of amyotrophic lateral sclerosis. J Neurol. 1989;236(8):445–7.

    Article  CAS  PubMed  Google Scholar 

  28. Mayers JR, Vander Heiden MG. BCAT1 defines gliomas by IDH status. Nat Med. 2013;19(7):816–7.

    Article  CAS  PubMed  Google Scholar 

  29. Bastone A, Micheli A, Beghi E, Salmona M. The imbalance of brain large-chain aminoacid availability in amyotrophic lateral sclerosis patients treated with high doses of branched-chain aminoacids. Neurochem Int. 1995;27(6):467–72.

    Article  CAS  PubMed  Google Scholar 

  30. Aquilani R, Iadarola P, Contardi A, Boselli M, Verri M, Pastoris O, et al. Branched-chain amino acids enhance the cognitive recovery of patients with severe traumatic brain injury. Arch Phys Med Rehabil. 2005;86(9):1729–35.

    Article  PubMed  Google Scholar 

  31. Korein J, Sansaricq C, Kalmijn M, Honig J, Lange B. Maple syrup urine disease: clinical, eeg, and plasma amino acid correlations with a theoretical mechanism of acute neurotoxicity. Int J Neurosci. 1994;79(1–2):21–45.

    Article  CAS  PubMed  Google Scholar 

  32. Carlson H, Ronne-Engstrom E, Ungerstedt U, Hillered L. Seizure related elevations of extracellular amino acids in human focal epilepsy. Neurosci Lett. 1992;140(1):30–2.

    Article  CAS  PubMed  Google Scholar 

  33. Gietzen DW, Dixon KD, Truong BG, Jones AC, Barrett JA, Washburn DS. Indispensable amino acid deficiency and increased seizure susceptibility in rats. Am J Physiol. 1996;271(1 Pt 2):R18–24.

    CAS  PubMed  Google Scholar 

  34. Eid T, Ghosh A, Wang Y, Beckstrom H, Zaveri HP, Lee TS, et al. Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats. Brain. 2008;131(Pt 8):2061–70.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gruenbaum SE, Dhaher R, Rapuano A, Zaveri HP, Tang A, de Lanerolle N, et al. Effects of branched-chain amino acid supplementation on spontaneous seizures and neuronal viability in a model of mesial temporal lobe epilepsy. J Neurosurg Anesthesiol. 2019;31(2):247–56.

    Article  PubMed  Google Scholar 

  36. Rho JM, Donevan SD, Rogawski MA. Direct activation of GABAA receptors by barbiturates in cultured rat hippocampal neurons. J Physiol. 1996;497(Pt 2):509–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Qian H, Pan Y, Zhu Y, Khalili P. Picrotoxin accelerates relaxation of GABAC receptors. Mol Pharmacol. 2005;67(2):470–9.

    Article  CAS  PubMed  Google Scholar 

  38. Skeie B, Petersen AJ, Manner T, Askanazi J, Jellum E, Steen PA. Branched-chain amino acids increase the seizure threshold to picrotoxin in rats. Pharmacol Biochem Behav. 1992;43(3):669–71.

    Article  CAS  PubMed  Google Scholar 

  39. Skeie B, Petersen AJ, Manner T, Askanazi J, Steen PA. Effects of valine, leucine, isoleucine, and a balanced amino acid solution on the seizure threshold to picrotoxin in rats. Pharmacol Biochem Behav. 1994;48(1):101–3.

    Article  CAS  PubMed  Google Scholar 

  40. Kandratavicius L, Balista PA, Lopes-Aguiar C, Ruggiero RN, Umeoka EH, Garcia-Cairasco N, et al. Animal models of epilepsy: use and limitations. Neuropsychiatr Dis Treat. 2014;10:1693–705.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Bogdanov NN, Poletaeva II, Popova NV. Pentylenetetrazol and strychnine convulsions in brain weight selected mice. Seizure. 1997;6(2):135–8.

    Article  CAS  PubMed  Google Scholar 

  42. Curtis DR, Duggan AW, Johnston GAR. The specificity of strychnine as a glycine antagonist in the mammalian spinal cord. Exp Brain Res. 1971;12(5):547–65.

    Article  CAS  PubMed  Google Scholar 

  43. Loscher W. Animal models of intractable epilepsy. Prog Neurobiol. 1997;53(2):239–58.

    Article  CAS  PubMed  Google Scholar 

  44. Jeske J, Misterek K, Dorociak A. Some pharmacological effects of amino acid 4 aminoantipyrine derivatives. Bull Pol Med Sci Hist. 1974;15:II.

    Google Scholar 

  45. Dhir A. Pentylenetetrazol (PTZ) kindling model of epilepsy. Curr Protoc Neurosci. 2012;Chapter 9:Unit 9.37.

    Google Scholar 

  46. Dufour F, Nalecz KA, Nalecz MJ, Nehlig A. Modulation of pentylenetetrazol-induced seizure activity by branched-chain amino acids and alpha-ketoisocaproate. Brain Res. 1999;815(2):400–4.

    Article  CAS  PubMed  Google Scholar 

  47. Pinto JMB, Maher TJ. Administration of aspartame potentiates pentylenetetrazole- and fluorothyl-induced seizures in mice. Neuropharmacology. 1988;27(1):51–5.

    Article  CAS  PubMed  Google Scholar 

  48. Kadiyala SB, Yannix JQ, Nalwalk JW, Papandrea D, Beyer BS, Herron BJ, et al. Eight flurothyl-induced generalized seizures lead to the rapid evolution of spontaneous seizures in mice: a model of epileptogenesis with seizure remission. J Neurosci. 2016;36(28):7485–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sperber EF, Veliskova J, Germano IM, Friedman LK, Moshe SL. Age-dependent vulnerability to seizures. Adv Neurol. 1999;79:161–9.

    CAS  PubMed  Google Scholar 

  50. Hashimoto Y, Araki H, Suemaru K, Gomita Y. Effects of drugs acting on the GABA-benzodiazepine receptor complex on flurothyl-induced seizures in Mongolian gerbils. Eur J Pharmacol. 2006;536(3):241–7.

    Article  CAS  PubMed  Google Scholar 

  51. Marescaux C, Vergnes M, Depaulis A. Genetic absence epilepsy in rats from Strasbourg—a review. J Neural Transm Suppl. 1992;35:37–69.

    CAS  PubMed  Google Scholar 

  52. Snead OC 3rd. Basic mechanisms of generalized absence seizures. Ann Neurol. 1995;37(2):146–57.

    Article  PubMed  Google Scholar 

  53. Dufour F, Nalecz KA, Nalecz MJ, Nehlig A. Metabolic approach of absence seizures in a genetic model of absence epilepsy, the GAERS: Study of the leucine-glutamate cycle. J Neurosci Res. 2001;66(5):923–30.

    Article  CAS  PubMed  Google Scholar 

  54. Dufour F, Nalecz KA, Nalecz MJ, Nehlig A. Modulation of absence seizures by branched-chain amino acids: correlation with brain amino acid concentrations. Neurosci Res. 2001;40(3):255–63.

    Article  CAS  PubMed  Google Scholar 

  55. Zhang XM, Zhu J. Kainic Acid-induced neurotoxicity: targeting glial responses and glia-derived cytokines. Curr Neuropharmacol. 2011;9(2):388–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Levesque M, Avoli M. The kainic acid model of temporal lobe epilepsy. Neurosci Biobehav Rev. 2013;37(10 Pt 2):2887–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hartman AL, Santos P, O’Riordan KJ, Stafstrom CE, Hardwick JM. Potent anti-seizure effects of d-leucine. Neurobiol Dis. 2015;82:46–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Holden K, Hartman AL. d-Leucine: evaluation in an epilepsy model. Epilepsy Behav. 2018;78:202–9.

    Article  PubMed  Google Scholar 

  59. Yudkoff M, Daikhin Y, Nissim I, Lazarow A, Nissim I. Ketogenic diet, brain glutamate metabolism and seizure control. Prostaglandins Leukot Essent Fatty Acids. 2004;70(3):277–85.

    Article  CAS  PubMed  Google Scholar 

  60. Evangeliou A, Spilioti M, Doulioglou V, Kalaidopoulou P, Ilias A, Skarpalezou A, et al. Branched chain amino acids as adjunctive therapy to ketogenic diet in epilepsy: pilot study and hypothesis. J Child Neurol. 2009;24(10):1268–72.

    Article  PubMed  Google Scholar 

  61. During MJ, Spencer DD. Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet. 1993;341(8861):1607–10.

    Article  CAS  PubMed  Google Scholar 

  62. Hutson SM, Lieth E, LaNoue KF. Function of leucine in excitatory neurotransmitter metabolism in the central nervous system. J Nutr. 2001;131(3):846S–50S.

    Article  CAS  PubMed  Google Scholar 

  63. Hutson SM, Berkich D, Drown P, Xu B, Aschner M, LaNoue KF. Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism. J Neurochem. 1998;71(2):863–74.

    Article  CAS  PubMed  Google Scholar 

  64. Norenberg MD, Martinez-Hernandez A. Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res. 1979;161(2):303–10.

    Article  CAS  PubMed  Google Scholar 

  65. Su TZ, Campbell GW, Oxender DL. Glutamine transport in cerebellar granule cells in culture. Brain Res. 1997;757(1):69–78.

    Article  CAS  PubMed  Google Scholar 

  66. Hogstad S, Svenneby G, Torgner IA, Kvamme E, Hertz L, Schousboe A. Glutaminase in neurons and astrocytes cultured from mouse brain: kinetic properties and effects of phosphate, glutamate, and ammonia. Neurochem Res. 1988;13(4):383–8.

    Article  CAS  PubMed  Google Scholar 

  67. Broer S, Brookes N. Transfer of glutamine between astrocytes and neurons. J Neurochem. 2001;77(3):705–19.

    Article  CAS  PubMed  Google Scholar 

  68. Plaitakis A. Abnormal glutamatergic mechanisms and branched-chain aminoacids in amyotrophic lateral sclerosis. Lancet. 1989;1(8630):157.

    Article  CAS  PubMed  Google Scholar 

  69. Plaitakis A, Smith J, Mandeli J, Yahr MD. Pilot trial of branched-chain aminoacids in amyotrophic lateral sclerosis. Lancet. 1988;1(8593):1015–8.

    Article  CAS  PubMed  Google Scholar 

  70. Dhaher R, Damisah EC, Wang H, Gruenbaum SE, Ong C, Zaveri HP, et al. 5-aminovaleric acid suppresses the development of severe seizures in the methionine sulfoximine model of mesial temporal lobe epilepsy. Neurobiol Dis. 2014;67:18–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fritsche E, Humm A, Huber R. The ligand-induced structural changes of human l-arginine:glycine amidinotransferase: a mutational and crystallographic study. J Biol Chem. 1999;274(5):3026–32.

    Article  CAS  PubMed  Google Scholar 

  72. Nanavati SM, Silverman RB. Design of potential anticonvulsant agents: mechanistic classification of GABA aminotransferase inactivators. J Med Chem. 1989;32(11):2413–21.

    Article  CAS  PubMed  Google Scholar 

  73. Tasaka J, Sakai S, Tosaka T, Yoshihama I. Glial uptake system of GABA distinct from that of taurine in the bullfrog sympathetic ganglia. Neurochem Res. 1989;14(3):271–7.

    Article  CAS  PubMed  Google Scholar 

  74. Levy RG, Cooper PN, Giri P. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst Rev. 2012;3:CD001903.

    Google Scholar 

  75. Kinsman SL, Vining EP, Quaskey SA, Mellits D, Freeman JM. Efficacy of the ketogenic diet for intractable seizure disorders: review of 58 cases. Epilepsia. 1992;33(6):1132–6.

    Article  CAS  PubMed  Google Scholar 

  76. Bixel MG, Hamprecht B. Generation of ketone bodies from leucine by cultured astroglial cells. J Neurochem. 1995;65(6):2450–61.

    Article  CAS  PubMed  Google Scholar 

  77. Yudkoff M, Daikhin Y, Nissim I, Lazarow A, Nissim I. Brain amino acid metabolism and ketosis. J Neurosci Res. 2001;66(2):272–81.

    Article  CAS  PubMed  Google Scholar 

  78. Yudkoff M, Daikhin Y, Nissim I, Lazarow A, Nissim I. Ketogenic diet, amino acid metabolism, and seizure control. J Neurosci Res. 2001;66(5):931–40.

    Article  CAS  PubMed  Google Scholar 

  79. Jirapinyo P, Kankirawatana P, Densupsoontorn N, Thamonsiri N, Wongarn R. High plasma branched-chain amino acids: aromatic amino acids ratio in children on the ketogenic diet: a mechanism in controlling epilepsy. J Med Assoc Thail. 2004;87(4):432–7.

    Google Scholar 

  80. Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, et al. Hypothalamic mTOR signaling regulates food intake. Science. 2006;312(5775):927–30.

    Article  CAS  PubMed  Google Scholar 

  81. Arrieta-Cruz I, Su Y, Gutiérrez-Juárez R. Suppression of endogenous glucose production by isoleucine and valine and impact of diet composition. Nutrients. 2016;8(2):79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Arieff AI, Doerner T, Zelig H, Massry SG. Mechanisms of seizures and coma in hypoglycemia evidence for a direct effect of insulin on electrolyte transport in brain. J Clin Investig. 1974;54(3):654–63.

    Article  CAS  PubMed  Google Scholar 

  83. Stafstrom CE. Hyperglycemia lowers seizure threshold. Epilepsy Curr. 2003;3(4):148–9.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Koltai M, Minker E. Changes of electro-shock seizure threshold in alloxan diabetic rats. Experientia. 1975;31(11):1369.

    Article  CAS  PubMed  Google Scholar 

  85. Schwechter EM, Veliskova J, Velisek L. Correlation between extracellular glucose and seizure susceptibility in adult rats. Ann Neurol. 2003;53(1):91–101.

    Article  CAS  PubMed  Google Scholar 

  86. Berkovic SF, Johns JA, Bladin PF. Focal seizures and systemic metabolic disorders. Aust N Z J Med. 1982;12(6):620–3.

    Article  CAS  PubMed  Google Scholar 

  87. Huang CW, Huang CC, Cheng JT, Tsai JJ, Wu SN. Glucose and hippocampal neuronal excitability: role of ATP-sensitive potassium channels. J Neurosci Res. 2007;85(7):1468–77.

    Article  CAS  PubMed  Google Scholar 

  88. Weber JD, Gutmann DH. Deconvoluting mTOR biology. Cell Cycle. 2012;11(2):236–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cho CH. Frontier of epilepsy research: mTOR signaling pathway. Exp Mol Med. 2011;43(5):231–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yang Z, Ming XF. mTOR signalling: the molecular interface connecting metabolic stress, aging and cardiovascular diseases. Obes Rev. 2012;13(Suppl. 2):58–68.

    Article  CAS  PubMed  Google Scholar 

  91. Meng X-F, Yu J-T, Song J-H, Chi S, Tan L. Role of the mTOR signaling pathway in epilepsy. J Neurol Sci. 2013;332(1):4–15.

    Article  CAS  PubMed  Google Scholar 

  92. Amara S, Fontana A. Excitatory amino acid transporters: keeping up with glutamate. Neurochem Int. 2002;41(5):313–8.

    Article  CAS  PubMed  Google Scholar 

  93. Almilaji A, Pakladok T, Guo A, Munoz C, Föller M, Lang F. Regulation of the glutamate transporter EAAT3 by mammalian target of rapamycin mTOR. Biochem Biophys Res Commun. 2012;421(2):159–63.

    Article  CAS  PubMed  Google Scholar 

  94. Erecińska M, Nelson D. Activation of glutamate dehydrogenase by leucine and its nonmetabolizable analogue in rat brain synaptosomes. J Neurochem. 1990;54(4):1335–43.

    Article  PubMed  Google Scholar 

  95. Sugimoto H, Koehler RC, Wilson DA, Brusilow SW, Traystman RJ. Methionine sulfoximine, a glutamine synthetase inhibitor, attenuates increased extracellular potassium activity during acute hyperammonemia. J Cereb Blood Flow Metab. 1997;17(1):44–9.

    Article  CAS  PubMed  Google Scholar 

  96. Cavus I, Kasoff WS, Cassaday MP, Jacob R, Gueorguieva R, Sherwin RS, et al. Extracellular metabolites in the cortex and hippocampus of epileptic patients. Ann Neurol. 2005;57(2):226–35.

    Article  CAS  PubMed  Google Scholar 

  97. Laake JH, Slyngstad TA, Haug FM, Ottersen OP. Glutamine from glial cells is essential for the maintenance of the nerve terminal pool of glutamate: immunogold evidence from hippocampal slice cultures. J Neurochem. 1995;65(2):871–81.

    Article  CAS  PubMed  Google Scholar 

  98. Erecinska M, Nelson D. Activation of glutamate dehydrogenase by leucine and its nonmetabolizable analogue in rat brain synaptosomes. J Neurochem. 1990;54(4):1335–43.

    Article  CAS  PubMed  Google Scholar 

  99. Burrage LC, Nagamani SC, Campeau PM, Lee BH. Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Hum Mol Genet. 2014;23(R1):R1–8.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Coulter DA, Eid T. Astrocytic regulation of glutamate homeostasis in epilepsy. Glia. 2012;60(8):1215–26.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Tripathi PP, Bozzi Y. The role of dopaminergic and serotonergic systems in neurodevelopmental disorders: a focus on epilepsy and seizure susceptibility. Bioimpacts. 2015;5(2):97–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Yan QS, Mishra PK, Burger RL, Bettendorf AF, Jobe PC, Dailey JW. Evidence that carbamazepine and antiepilepsirine may produce a component of their anticonvulsant effects by activating serotonergic neurons in genetically epilepsy-prone rats. J Pharmacol Exp Ther. 1992;261(2):652–9.

    CAS  PubMed  Google Scholar 

  103. Ahmad S, Fowler LJ, Whitton PS. Lamotrigine, carbamazepine and phenytoin differentially alter extracellular levels of 5-hydroxytryptamine, dopamine and amino acids. Epilepsy Res. 2005;63(2–3):141–9.

    Article  CAS  PubMed  Google Scholar 

  104. Kanner AM. Association between selective serotonin-reuptake inhibitor antidepressants and increased risk of poststroke epilepsy. Mayo Clin Proc. 2017;92(2):179–81.

    Article  PubMed  Google Scholar 

  105. Favale E, Rubino V, Mainardi P, Lunardi G, Albano C. Anticonvulsant effect of fluoxetine in humans. Neurology. 1995;45(10):1926–7.

    Article  CAS  PubMed  Google Scholar 

  106. Krahl SE, Clark KB, Smith DC, Browning RA. Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia. 1998;39(7):709–14.

    Article  CAS  PubMed  Google Scholar 

  107. Suryawan A, Hawes JW, Harris RA, Shimomura Y, Jenkins AE, Hutson SM. A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr. 1998;68(1):72–81.

    Article  CAS  PubMed  Google Scholar 

  108. Daikhin Y, Yudkoff M. Compartmentation of brain glutamate metabolism in neurons and glia. J Nutr. 2000;130(4S Suppl.):1026s–31s.

    Article  CAS  PubMed  Google Scholar 

  109. Pardridge WM. Brain metabolism: a perspective from the blood–brain barrier. Physiol Rev. 1983;63(4):1481–535.

    Article  CAS  PubMed  Google Scholar 

  110. Young SN, Ervin FR, Pihl RO, Finn P. Biochemical aspects of tryptophan depletion in primates. Psychopharmacology (Berl). 1989;98(4):508–11.

    Article  CAS  Google Scholar 

  111. Williams WA, Shoaf SE, Hommer D, Rawlings R, Linnoila M. Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers. J Neurochem. 1999;72(4):1641–7.

    Article  CAS  PubMed  Google Scholar 

  112. Fernstrom MH, Fernstrom JD. Acute tyrosine depletion reduces tyrosine hydroxylation rate in rat central nervous system. Life Sci. 1995;57(9):97–102.

    Article  CAS  Google Scholar 

  113. Smith GS, Barrett FS, Joo JH, Nassery N, Savonenko A, Sodums DJ, et al. Molecular imaging of serotonin degeneration in mild cognitive impairment. Neurobiol Dis. 2017;105:33–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. von Coelln R, Thomas B, Savitt JM, Lim KL, Sasaki M, Hess EJ, et al. Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proc Natl Acad Sci. 2004;101(29):10744–9.

    Article  Google Scholar 

  115. Vilela TC, Scaini G, Furlanetto CB, Pasquali MA, Santos JP, Gelain DP, et al. Apoptotic signaling pathways induced by acute administration of branched-chain amino acids in an animal model of maple syrup urine disease. Metab Brain Dis. 2017;32(1):115–22.

    Article  CAS  PubMed  Google Scholar 

  116. Tonjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med. 2013;19(7):901–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yudkoff M, Daikhin Y, Nissim I, Horyn O, Lazarow A, Nissim I. Metabolism of brain amino acids following pentylenetetrazole treatment. Epilepsy Res. 2003;53(1–2):151–62.

    Article  CAS  PubMed  Google Scholar 

  118. Treacy E, Clow CL, Reade TR, Chitayat D, Mamer OA, Scriver CR. Maple syrup urine disease: Interrelations between branched-chain amino-, oxo- and hydroxyacids; implications for treatment; associations with CNS dysmyelination. J Inherit Metab Dis. 1992;15(1):1–35.

    Article  Google Scholar 

  119. Jouvet P, Rustin P, Taylor DL, Pocock JM, Felderhoff-Mueser U, Mazarakis ND, et al. Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: implications for neurological impairment associated with maple syrup urine disease. Mol Biol Cell. 2000;11(5):1919–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Bridi R, Araldi JN, Sgarbi MB, Testa CG, Durigon K, Wajner M, et al. Induction of oxidative stress in rat brain by the metabolites accumulating in maple syrup urine disease. Int J Dev Neurosci. 2003;21(6):327–32.

    Article  CAS  PubMed  Google Scholar 

  121. Bible E. Neuro-oncology: BCAT1 promotes cell proliferation in aggressive gliomas. Nat Rev Neurol. 2013;9(8):420.

    Article  PubMed  Google Scholar 

  122. Schauwecker PE. The effects of glycemic control on seizures and seizure-induced excitotoxic cell death. BMC Neurosci. 2012;13:94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wang X. Nonketotic hyperglycemia-related epileptic seizures. Chin Neurosurg J. 2017;3(1):16.

    Article  Google Scholar 

  124. Hennis A, Corbin D, Fraser H. Focal seizures and non-ketotic hyperglycaemia. J Neurol Neurosurg Psychiatry. 1992;55(3):195–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Yoon M-S. The emerging role of branched-chain amino acids in insulin resistance and metabolism. Nutrients. 2016;8(7):E405.

    Article  CAS  PubMed  Google Scholar 

  126. Vary TC, Lynch CJ. Nutrient signaling components controlling protein synthesis in striated muscle. J Nutr. 2007;137(8):1835–43.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors gratefully acknowledge Garrett Sendlewski (Yale Media Laboratory Associate) for his outstanding illustrative work for Fig. 4, and Alexandria Brackett, MA, MLIS (Clinical Librarian) for her assistance in performing the literature review.

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Authors and Affiliations

  1. Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL, USA

    Shaun E. Gruenbaum

  2. Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA

    Eric C. Chen, Mani Ratnesh Singh Sandhu, Ketaki Deshpande, Roni Dhaher & Tore Eid

  3. Lewis Science Library, Princeton University, Princeton, NJ, USA

    Denise Hersey

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  1. Shaun E. Gruenbaum
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Correspondence to Shaun E. Gruenbaum.

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Funding

Tore Eid and Roni Dhaher are supported by grants from the National Institute of Health (NIH): NINDS K08 NS058674 and R01 NS070824. Tore Eid is supported by an Innovator Award from Citizens United for Research in Epilepsy (CURE). Shaun E. Gruen is supported by grants from the NIH: T32 GM086287 and the Foundation of Anesthesia Education and Research (FAER). This work was also made possible by a grant from the National Center for Advancing Translational Science (NCATS; UL1 TR000142), a component of the NIH and the NIH roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NIH.

Conflict of interest

Shaun E. Gruenbaum, Eric C. Chen, Mani Ratnesh S. Sandhu, Ketaki Deshpande, Roni Dhaher, Denise Hersey, and Tore Eid have no conflicts of interest that are directly relevant to the content of this article.

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Gruenbaum, S.E., Chen, E.C., Sandhu, M.R.S. et al. Branched-Chain Amino Acids and Seizures: A Systematic Review of the Literature. CNS Drugs 33, 755–770 (2019). https://doi.org/10.1007/s40263-019-00650-2

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