Amino Acids

, Volume 4, Issue 3, pp 197–235 | Cite as

Aspartame and seizures

  • P. C. Jobe
  • J. W. Dailey
Review Article
  • 101 Downloads

Summary

It has been hypothesized that the dietary sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester) might promote seizures and this hypothesis has been argued in the published literature. The current manuscript reviews the biochemical, neurochemical and behavioral experiments that have been carried out in order to assess the hypothesis linking aspartame with seizure promotion. We conclude that convulsive seizures are not caused by orally administered aspartame in rodents or in primates, including humans. Early reports of seizure facilitation by aspartame in several rodent models were not confirmed by later and more careful experimentation. Proconvulsive effects were absent in humans and other mammals with epilepsy and those without epilepsy. Lack of convulsive liability was evident, even when doses many fold higher than those consumed in the human diet, were used in experimental paradigms. Studies of aspartame in absence seizures are not as complete as those in convulsive seizures, but available evidence in humans does not document an association between absence seizure incidence and aspartame usage.

Keywords

Amino acids Seizures Genetic epilepsy Aspartame Phenylalanine Neurotransmitters 

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References

  1. Abraham R, Dougherty W, Goldberg L, Coulston F (1971) The response of the hypothalamus to high doses of monosodium glutamate in mice and monkeys. Exp Mol Pathol 15: 43–60Google Scholar
  2. Abraham R, Swart J, Golberg L, Coulston F (1975) Electron microscopic observations of hypothalami in neonatal rhesus monkeys (Macaca mulatta) after administration of monosodium L-glutamate. Exp Mol Pathol 23: 203–213Google Scholar
  3. Arauz-Contreras J, Feria-Velasco A (1984) Monosodium-L-glutamate-induced convulsions — I. Differences in seizure pattern and duration of effect as a function of age in rats. Gen Pharmacol 15: 391–395Google Scholar
  4. Axelrod J, Daly J (1965) Pituitary gland: Enzymic formation of methanol from S-adenosylmethionine. Science 150: 892–893Google Scholar
  5. Beas-Zarate C, Arauz-Contreras J, Velazquez A, Feria-Velasco A (1985) Monosodium L-glutamate-induced convulsions. II. Changes in catecholamine concentrations in various brain areas of adult rats. Gen Pharmacol 16: 489–493Google Scholar
  6. Beas-Zarate C, Schliebs R, Morales-Villagran A, Feria-Velasco A (1989) Monosodium L-glutamate-induced convulsions: Changes in uptake and release of catecholamines in cerebral cortex and caudate nucleus of adult rats. Epilepsy Res 4: 20–27Google Scholar
  7. Benninger Ch, Matthis P, de Sonneville LMJ, Lenz-Englert B, Trefz FK, Bickel H (1991) High dose aspartame has no effect on EEG spectral parameters in phenylketonuric heterozygotes (PKUH). Neurosci Abstr 17: 504Google Scholar
  8. Bettendorf AF, Dailey JW, Lasley SM, Jobe PC (1989) Aspartame fails to facilitate bicuculline-induced seizures in DBA/2 mice. Neurosci Abstr 15: 47Google Scholar
  9. Bhagavan HN, Coursin DF, Stewart CN (1971) Monosodium glutamate induces convulsive disorders in rats. Nature 232: 275–276Google Scholar
  10. Bickel H, Trefz FK (1986) Aspartame: ein Süssstoff mit hohem Phenylalaningehalt. Monatsschr Kinderheilkd 134: 478–480Google Scholar
  11. Blasberg R, Lajtha A (1965) Substrate specificity of steady-state amino acid transport in mouse brain slices. Arch Biochem Biophys 112: 361–377Google Scholar
  12. Bradford HF, Dodd PR (1977) Convulsions and activation of epileptic foci induced by monosodium glutamate and related compounds. Biochem Pharmacol 26: 253–254Google Scholar
  13. Bradstock MK, Serdula MK, Marks JS, Barnard RJ, Crane NT, Remington PL, Trowbridge FL (1986) Evaluations of reactions to food additives: the aspartame experience. Am J Clin Nutr 43: 464–469Google Scholar
  14. Browning RA (1987a) The role of neurotransmitters in electroshock seizure models. In: Jobe PC, Laird HE (eds) Neurotransmitters and epilepsy. Humana Press, Clifton, NJ, pp 277–320Google Scholar
  15. Browning RA (1987b) Effect of lesions on seizures in experimental animals. In: Fromm GH, Faingold CL, Browning RA, Burnham WM (eds) Epilepsy and the reticular formation: The role of the reticular core in convulsive seizures. Alan R. Liss, New York, pp 137–162Google Scholar
  16. Browning RA (1991) Overview of neurotransmission: relationship to the action of antiepileptic drugs. In: Faingold CL, Fromm GH (eds) Drugs for the control of epilepsy: Actions on neuronal networks involved in seizure disorders. CRC Press, Boca Raton, FL, pp 23–56Google Scholar
  17. Browning RA, Maynert EW (1978) Effect of intracisternal 6-hydroxydopamine on seizure susceptibility in rats. Eur J Pharmacol 50: 97–101Google Scholar
  18. Browning RA, Wang C, Jobe PC (1989) Effect of regional CNS norepinephrine (NE) depletion on seizure severity in the genetically epilepsy-prone rat (GEPR). Epilepsia 30: 651Google Scholar
  19. Burns TS, Stargel WW, Tschanz C, Kotsonis FN, Hurwitz A (1991) Aspartame and sucrose produce a similar increase in the plasma phenylalanine to large neutral amino acid ratio in healthy subjects. Pharmacology 43: 210–219Google Scholar
  20. Butchko HH, Kotsonis FN (1989) Aspartame: review of recent research. Comm Toxicol 3: 253–278Google Scholar
  21. Butchko HH, Kotsonis FN (1991) Acceptable daily intake vs actual intake: The aspartame example. J Am Coll Nutr 10: 258–266Google Scholar
  22. Cain DP, Boon F, Bevan M (1989) Failure of aspartame to affect seizure susceptibility in kindled rats. Neuropharmacology 28: 433–435Google Scholar
  23. Camfield PR, Camfield CS, Dooley JM, Gordon K, Jollymore S, Weaver DF (1992) Aspartame exacerbates EEG spike-wave discharge in children with generalized absence epilepsy: A double-blind controlled study. Neurology 42: 1000–1003Google Scholar
  24. Chapman AG, Meldrum BS (1987) Epilepsy-prone mice: genetically determined soundinduced seizures. In Jobe PC, Laird HE (eds) Neurotransmitters and epilepsy. Human Press, Clifton, NJ, pp 9–40Google Scholar
  25. Chiu P, Woodbury DM (1988) Effects of aspartame (ASM) and its metabolites on seizure susceptibility in mice. Pharmacologist 30: A119Google Scholar
  26. Clough RW, Browning RA, Maring ML, Jobe PC (1991) Intracerebral grafting of fetal dorsal pons in genetically epilepsy-prone rats: Effects on audiogenic-induced seizures. Exp Neurol 112: 195–199Google Scholar
  27. Corcoran ME (1988) Characteristics and mechanisms of kindling. In: Kalivas P, Barnes C (eds) Sensitization of the nervous system. The Telford Press, Caldwell, NJ, pp 81–116Google Scholar
  28. Daabees TT, Finkelstein MW, Stegink LD, Applebaum AE (1985) Correlation of glutamate plus aspartate dose, plasma amino acid concentration and neuronal necrosis in infant mice. Food Chem Toxicol 23: 887–895Google Scholar
  29. Dailey JW, Lasley SM, Frasca J, Jobe PC (1987) Aspartame (ASM) is not pro-convulsant in the genetically epilepsy-prone rat (GEPR). Pharmacologist 29: 142Google Scholar
  30. Dailey JW, Lasley SM, Bettendorf AF, Burger RL, Jobe PC (1988) Aspartame does not facilitate pentylenetetrazol-induced seizures in genetically epilepsy-prone rats. Epilepsia 29: 651Google Scholar
  31. Dailey JW, Lasley SM, Mishra PK, Bettendorf AF, Burger RL, Jobe PC (1989a) Aspartame fails to facilitate pentylenetetrazol-induced convulsions in CD-1 mice. Toxicol Appl Pharmacol 98: 475–486Google Scholar
  32. Dailey JW, Reigel CE, Mishra PK, Jobe PC (1989b) Neurobiology of seizure predisposition in the genetically epilepsy-prone rats. Epilepsy Res 3: 3–17Google Scholar
  33. Dailey JW, Bettendorf AF, Lasley SM, Jobe PC (1989c) Aspartame does not facilitate bicuculline-induced seizures in C57 mice. Pharmacologist 31: 187Google Scholar
  34. Dailey JW, Lasley SM, Burger RL, Bettendorf AF, Mishra PK, Jobe PC (1991) Amino acids, monoamines and audiogenic seizures in genetically epilepsy-prone rats: effects of aspartame. Epilepsy Res 8: 122–133Google Scholar
  35. Dailey JW, Mishra PK, Ko KH, Penny JE, Jobe PC (1992a) Serotonergic abnormalities in the central nervous system of seizure naive genetically epilepsy-prone rats. Life Sci 50: 319–326Google Scholar
  36. Dailey JW, Yan QS, Mishra PK, Burger RL, Jobe PC (1992b) Effects of fluoxetine on convulsions and on dialyzable brain serotonin in genetically epilepsy-prone rats. J Pharmacol Exp Ther 260: 533–540Google Scholar
  37. Davis WM, King WT (1966) Pharmacogenetic factor in the convulsive responses of mice to flurothyl. Experientia 23: 214–215Google Scholar
  38. Delgado-Escueta AV, Ward Jr AA, Woodbury DM, Porter RJ (1986) New wave of research in the epilepsies. In: Delgado-Escueta AV, Ward AA Jr, Woodbury DM, Porter RJ (eds) Advances in neurology, vol 44. Raven Press, New York, pp 3–55Google Scholar
  39. Dreisbach RH (1983) Handbook of poisoning: Prevention diagnosis and treatment, 11th edn. Lange Medical Publications, Los Altos CA, pp 452–467Google Scholar
  40. Eriksen SP, Kulkarni AB (1963) Methanol in normal human breath. Science 141: 639–640Google Scholar
  41. Faingold CL, Meldrum BS (1990) Excitant amino acids in epilepsy. In: Avoli M, Gloor P, Kostopoulos G, Naquet R (eds) Generalized epilepsy: Neurobiological approaches. Birkhäuser, Boston, pp 102–117Google Scholar
  42. Faingold CL, Naritoku DK (1991) The genetically epilepsy-prone rat: neuronal networks and actions of amino acid neurotransmitters. In: Faingold CL, Fromm GH (eds) Drugs for the control of epilepsy: Actions on neuronal networks involved in seizure disorders. CRC Press Boca Raton, FL, pp 277–308Google Scholar
  43. Fernstrom JD (1983) Role of precursor availability in the control of monoamine biosynthesis in brain. Physiol Rev 63: 484–546Google Scholar
  44. Fernstrom JD (1989) Oral aspartame and plasma phenylalanine: pharmacokinetic difference between rodents and man, and relevance to CNS effects of phenylalanine. J Neural Transm 75: 159–164Google Scholar
  45. Fernstrom JD, Wurtman RJ, Hammarstrom-Wiklund B, Rand WM, Munro HN, Davidson CS (1979) Diurnal variations in plasma concentrations of tryptophan, tyrosine and other neutral amino acids: Effect of dietary protein intake. Am J Clin Nutr 32: 1912–1922Google Scholar
  46. Fernstrom JD, Fernstrom MH, Gillis MA (1983) Acute effects of aspartame on large neutral amino acids and monoamines in rat brain. Life Sci 32: 1651–1658Google Scholar
  47. Fishbein DH, Thatcher RW, Cantor DS (1990) Ingestion of carbohydrates varying in complexity produce differential brain responses. Clin Electroencephalogr 21: 5–11Google Scholar
  48. Fisher RS (1989) Aspartame, neurotoxicity, and seizures: A review. J Epilepsy 2: 55–64Google Scholar
  49. Fisher RS (1991) Glutamate and epilepsy. In Fisher RS, Coyle JT (eds) Neurotransmitters and epilepsy. John Wiley & Sons, New York, pp 131–145Google Scholar
  50. Fisher RS, Coyle JT (1991) Summary: neurotransmitters and epilepsy. In: Fisher RS, Coyle JT (eds) Neurotransmitters and epilepsy. John Wiley & Sons, New York, pp 247–252Google Scholar
  51. Fountain SB, Hennes SK, Teyler TJ (1988) Aspartame exposure andin vitro hippocampal slice excitability and plasticity. Fund Appl Toxicol 11: 221–228Google Scholar
  52. Frasca MA, Aldag JC (1988) The single-patient clinical trial. Am Fam Physician 37: 195–199Google Scholar
  53. Gagnon C (1979) Presence of a protein methylesterase in mamalian tissues. Biochem Biophys Res Commun 88: 847–853Google Scholar
  54. Gagnon C, Heisler S (1979) Protein carboxy-methylation: Role in exocytosis and chemotaxis. Life Sci 25: 993–1000Google Scholar
  55. Garattini S, Caccia S, Romano M, Diomede L, Guiso G, Vezzani A, Salmona M (1988) Studies on the susceptibility to convulsions in animals receiving abuse doses of aspartame. In: Wurtman RJ, Rittar-Walker E (eds) Dietary phenylalanine and brain function. Birkhäuser, Boston, pp 131–143Google Scholar
  56. Gibbs FA, Gibbs EL, Lennox WG (1939) Influence of the blood sugar level on the wave and spike formation in petit mal epilepsy. Arch Neurol Psychiat 41: 1111–1116Google Scholar
  57. Giroud M, Duman R, Dauvergne M, D'Athis P, Rochette P, Beley L, Bralet J (1990) 5-Hydroxyindoleacetic acid and homo-vanillic acid in cerebrospinal fluid of children with febrile convulsions. Epilepsia 31: 178–181Google Scholar
  58. Goddard GV (1967) Development of epileptic seizures through brain stimulation at low intensity. Nature 214: 1020–1021Google Scholar
  59. Goddard GV, McIntyre DC, Leech CK (1969) A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 25: 295–330Google Scholar
  60. Green MC, Sidman RL (1962) Tottering — a neuromuscular mutation in the mouse. J Hered 53: 233–237Google Scholar
  61. Guiso G, Caccia S, Vezzani A, Stasi MA, Salmona M, Romano M, Garattini S (1988) Effect of aspartame on seizures in various models of experimental epilepsy. Toxicol Appl Pharmacol 96: 485–493Google Scholar
  62. Guey J, Bureau M, Dravet C, Roger J (1969) A study of the rhythm of petit mal absences in children in relation to prevailing situations. Epilepsia 10: 441–451Google Scholar
  63. Guyatt G, Sackett D, Taylor DW, Chong J, Robers R, Pugsley S (1986) Determining optimal therapy — randomized trials in individual patients. N Eng J Med 314: 889–892Google Scholar
  64. Harper AE (1984) Phenylalanine metabolism. In: Stegink LD, Filer LJ Jr (eds) Aspartame physiology and biochemistry. Marcel Dekker, New York, pp 509–553Google Scholar
  65. Heatherbell DA, Wrolstad RE, Libbey LM (1971) Carrot volatiles: Characterization and effects of canning and freeze drying. J Food Sci 36: 219–224Google Scholar
  66. Heywood R, James RW (1979) An attempt to induce neurotoxicity in an infant rhesus monkey with monosodium glutamate. Toxicol Lett 4: 285–286Google Scholar
  67. Hjelle JJ, Dudley RE, Marietta MP, Sanders PG, Dickie BC, Brisson J, Kotsonis FN (1992) Plasma concentrations and pharmacokinetics of phenylalanine in rats and mice administered aspartame. Pharmacology 44: 48–60Google Scholar
  68. Jimenez-Rivera CA, Waterhouse BD (1991) The role of central noradrenergic systems in seizure disorders. In: Fisher RS, Coyle JT (eds) Neurotransmitters and epilepsy. John Wiley & Sons, New York, pp 109–129Google Scholar
  69. Jobe PC, Laird H (1987) Neurotransmitter systems and the epilepsy models: distinguishing features and unifying principles. In: Jobe PC, Laird HE (eds) Neurotransmitters and epilepsy. Humana Press, Clifton NJ, pp 339–366Google Scholar
  70. Jobe PC, Picchioni AL, Chin L (1973a) Role of 5-hydroxytryptamine in audiogenic seizure in the rat. Life Sci 13: 1–13Google Scholar
  71. Jobe PC, Piccioni AL, Chin L (1973b) Role of brain norepinephrine in audiogenic seizure in the rat. J Pharmacol Exp Ther 184: 1–10Google Scholar
  72. Jobe PC, Laird HE, Ko KH, Ray T, Dailey JW (1982) Abnormalities in monoamine levels in the central nervous system of the genetically epilepsy-prone rat. Epilepsia 23: 359–366Google Scholar
  73. Jobe PC, Ko KH, Dailey JW (1984) Abnormalities in norepinephrine turnover rate in the central nervous system of the genetically epilepsy-prone rat. Brain Res 290: 357–360Google Scholar
  74. Jobe PC, Bettendorf AF, Lasley SM, Dailey JW (1989a) Audiogenic seizures in DBA/2 mice are not facilitated by aspartame. Neurosci Abstr 15: 47Google Scholar
  75. Jobe PC, Bettendorf AF, Lasley SM, Dailey JW (1989b) Multiple exposures to audiogenic stimuli in DBA/2 mice: lack of effect of aspartame. Epilepsia 30: 653Google Scholar
  76. Jobe PC, Mishra PK, Dailey JW (1991a) Genetically epilepsy-prone rats: Actions of antiepileptic drugs and monoaminergic neurotransmitters. In: Faingold CL, Fromm GH (eds) Drugs for the control of epilepsy: Actions on neuronal networks involved in seizure disorders. CRC Press, Boca Raton, FL, pp 253–276Google Scholar
  77. Jobe PC, Mishra PK, Ludvig N, Dailey JW (1991b) Scope and contribution of genetic models to an understanding of the epilepsies. CRC Crit Rev Neurobiol 6: 183–220Google Scholar
  78. Jobe PC, Mishra PK, Bettendorf AF, Burger RL, Dailey JW, Wang C, Browning RA (1991c) Noradrenergic system also regulates forebrain seizures in the genetically epilepsy-prone rat (GEPR). Epilepsia 32: 31Google Scholar
  79. Jobe PC, Lasley SM, Burger RL, Bettendorf AF, Mishra PK, Dailey JW (1992a) Absence of an effect of aspartame on seizures induced by electroshock in epileptic and nonepileptic rats. Amino Acids 3: 155–172Google Scholar
  80. Jobe PC, Mishra PK, Ludvig N, Dailey JW (1992b) Genetic models of the epilepsies. In: Schwartzkroin PA (ed) Concepts and models in epilepsy research. Cambridge University Press (In press)Google Scholar
  81. Johnston GAR (1973) Convulsions induced in 10-day-old rats by intraperitoneal injection of monosodium glutamate and related excitant amino acids. Biochem Pharmacol 22: 137–140Google Scholar
  82. Kazdin AE (1982) Single-case research designs: Methods for clinical and applied settings. Oxford University Press, New YorkGoogle Scholar
  83. Kazeniac SJ, Hall RM (1970) Flavor chemistry of tomato volatiles. J Food Sci 35: 519–530Google Scholar
  84. Killam EK (1976) Measurement of anticonvulsant activity in thePapio papio model of epilepsy. Fed Proc 35: 2264–2269Google Scholar
  85. Killam EK, Killam KF (1984) Evidence for neurotransmitter abnormalities related to seizure activity in the epileptic baboon. Fed Proc 43: 2510–2515Google Scholar
  86. Killam KF, Killam EK, Naquet R (1966a) Etudes pharmacologiques realisees chez des singes presentant une activite EEG paroxystique particuliere a la stimulation lumineuse intermittente. J Physiol (Paris) 58: 543–544Google Scholar
  87. Killam KF, Naquet R, Bert J (1966b) Paroxysmal responses to intermittent light stimulation in a population of baboons (Papio papio). Epilepsia 7: 215–219Google Scholar
  88. Killam KF, Killam EK, Naquet R (1967) An animal model of light sensitive epilepsy. Electroencephalograph Clin Neurophysiol 22: 497–513Google Scholar
  89. Kim KC, Tasch MD, Kim SH (1988) The effect of aspartame on 50% convulsion doses of lidocaine. In: Wurtman RJ, Ritter-Walker E (eds) Dietary phenylalanine and brain function. Birkhäuser, Boston, pp 127–130Google Scholar
  90. Kim S (1973) Purification and properties of protein methylase II. Arch Biochem Biophys 157: 476–484Google Scholar
  91. Kirchner JG, Miller JM (1957) Volatile water-soluble and oil constituents of Valencia orange juice. J Agric Food Chem 5: 283–291Google Scholar
  92. Laird II HE (1989) The genetically epilepsy-prone rat. A valuable model for the study of the epilepsies. Mol Chem Neuropathol 11: 45–59Google Scholar
  93. Larsson BT (1965) Gas chromatography of organic volatiles in human breath and saliva. Acta Chem Scand 19: 159–164Google Scholar
  94. Lemkey-Johnston N, Reynolds WA (1974) Nature and extent of brain lesions in mice related to ingestion of monosodium glutamate. A light and electron microscope study. J Neuropathol Exp Neurol 33: 74–97Google Scholar
  95. Leon AS, Hunninghake DB, Bell C, Rassin DK, Tephly TR (1989) Safety of long-term large doses of aspartame. Arch Intern Med 149: 2318–2324Google Scholar
  96. Levitt P, Noebels JL (1981) Mutant mouse tottering: selective increase of locus ceruleus axons in a defined single-locus mutation. Proc Nat Acad Sci 78: 4630–4634Google Scholar
  97. Loscher W, Schmidt D (1988) Which models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations. Epilepsy Res 2: 145–181Google Scholar
  98. Loscher W, Nolting B, Fassbender CP (1990) The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. I. The influence of administration vehicles. Epilepsy Res 7: 173–181Google Scholar
  99. Loscher W, Fassbender CP, Nolting B (1991a) The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models. Epilepsy Res 8: 79–94Google Scholar
  100. Loscher W, Honack D, Fassbender CP, Nolting B (1991b) The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models. Epilepsy Res 8: 171–189Google Scholar
  101. Ludvig N, Gyorgy L, Folly G, Vizi ES (1985) Yohimbine can not exert its anticonvulsant action in genetically audiogenic seizure-prone mice. Eur J Pharmacol 115: 123–124Google Scholar
  102. Lund ED, Kirkland CL, Shaw PE (1981) Methanol, ethanol, and acetaldehyde contents of citrus products. J Agric Food Chem 29: 361–366Google Scholar
  103. Maher TJ, Wurtman RJ (1987) Possible neurologic effects of aspartame, a widely used food additive. Environ Health Persp 75: 53–57Google Scholar
  104. Maynert EW, Marczynski TJ, Browning RA (1975) The role of neurotransmitters in the epilepsies. In: Friedlander WJ (ed) Advances in neurology vol 13. Raven Press, New York, pp 79–147Google Scholar
  105. Marley RJ, Gaffney D, Wehner JM (1986) Genetic influences on GABA-related seizures. Pharmacol Biochem Behav 24: 665–672Google Scholar
  106. Martin-Du Pan R, Mauron C, Glaeser B, Wurtman RJ (1982) Effect of various oral glucose doses on plasma neutral amino acid levels. Metabolism 31: 937–943Google Scholar
  107. McGeer PL, McGeer EG (1989) Amino acid neurotransmitters. In: Siegel GJ, Agranoff BW, Albers RW, Molinoff PB (eds) Basic neurochemistry: Molecular, cellular, and medical aspects. Raven Press, New York, pp 311–332Google Scholar
  108. McLeod RS, Taylor DW, Cohen Z, Cullen JB (1986) Single-patient randomised clinical trial. Use in determining optimum treatment for patient with inflammation of Kock continent ileostomy reservoir. Lancet (8483): 726–728Google Scholar
  109. McMartin KE, Martin-Amat G, Makar AB, Tephly TR (1977) Methanol poisoning. V. Role of formate metabolism in the monkey. J Pharmacol Exp Therap 201: 564–572Google Scholar
  110. McNamara JO, Bonhaus DW, Shin C, Crain BJ, Gellman RL, Giacchino JL (1985) The kindling model of epilepsy: a critical review. CRC Crit Rev Clin Neurobiol 1: 341–392Google Scholar
  111. McNamara JO, Byrne MC, Dasheiff RM, Fitz JG (1980) The kindling model of epilepsy: a review. Progr Neurobiol 15: 139–159Google Scholar
  112. Meldrum BS (1991) Anticonvulsant drugs with new mechanisms of action. In: Faingold CL, Fromm GH (eds) Drugs for control of epilepsy: Actions on neuronal networks involved in seizure disorders. CRC Press, Boca Raton, pp 485–495Google Scholar
  113. Meldrum BS, Nanji N, Cornell RG (1989) Lack of effect of aspartame or of L-phenylalanine on photically induced myoclonus in the baboon,Papio papio. Epilepsy Res 4: 1–7Google Scholar
  114. Micheletti G, Warter J-M, Marescaux C, Depaulis A, Tranchant C, Rumbach L, Vergnes M (1987) Effects of drugs affecting noradrenergic neurotransmission in rats with spontaneous petit mal-like seizures. Eur J Pharmacol 135: 397–402Google Scholar
  115. Mishra PK, Burger RL, Yan QS, Dailey JW, Jobe PC (1989) Characteristics of extracellular norepinephrine: A microdialysis study in genetically epilepsy-prone rats. FASEB J 3: A747Google Scholar
  116. Mishra PK, Bettendorf AF, Burger RL, Dailey JW, Eldadah MK, Wang C, Browning RA, Jobe PC (1991) Noradrenergic regulation of forebrain and brainstem seizures in nonepileptic and genetically epilepsy-prone rats (GEPRs). Neurosci Abstr 17: 172Google Scholar
  117. Morin AM, Lis M (1973) Evidence for a methylated protein intermediate in pituitary methanol formation. Biochem Biophys Res Commun 52: 373–378Google Scholar
  118. Mushahwar IK, Koeppe RE (1971) The toxicity of monosodium glutamate in young rats. Biochim Biophys Acta 244: 318–321Google Scholar
  119. Neame KD (1968) A comparison of the transport systems for amino acids in brain, intestine, kidney and tumor. Prog Brain Res 29: 185–199Google Scholar
  120. Nemeroff CB, Crisley FD (1975) Monosodium L-glutamate-induced convulsions: temporary alteration in blood-brain barrier permeability to plasma proteins. Environ Physiol Biochem 5: 389–395Google Scholar
  121. Newman AJ, Heywood R, Palmer AK, Barry DH, Edwards FP, Worden AN (1973) The administration of monosodium L-glutamate to neonatal and pregnant rhesus monkeys. Toxicology 1: 197–204Google Scholar
  122. Nevins ME, Arnolde SM, Haigler HJ (1986a) Aspartame: lack of effect on convulsant thresholds in mice. Fed Proc 45: 1096Google Scholar
  123. Nevins ME, Arnolde SM, Haigler JJ (1986b) Aspartame: lack of effect on convulsant thresholds in mice. In: Kaufman S (Ed) Amino acids in health and diseases: New perspectives. Alan R. Liss, New York, pp 437–449Google Scholar
  124. Noebels JL, Sidman RL (1979) Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering. Science 204: 1334–1336Google Scholar
  125. Okaniwa, A, Hori M, Masuda M, Takeshita M, Hayashi N, Wada I, Doi K, Ohara Y (1979) Histopathological study on effects of potassium aspartate on the hypothalamus of rats. J Toxicol Sci 4: 31–45Google Scholar
  126. Olney JW (1969) Brain lesions, obesity and other disturbances in mice treated with monosodium glutamate. Science 164: 719–721Google Scholar
  127. Olney JW, Sharpe LG (1969) Brain lesions in an infant rhesus monkey treated with monosodium glutamate. Science 166: 386–388Google Scholar
  128. Olney JW, Sharpe LG, Feigin RD (1972) Glutamate-induced brain damage in infant primates. Neuropathol Exp Neurol 31: 464–488Google Scholar
  129. Perego C, De Simoni MG, Fodritto F, Raimondi L, Diomede L, Salmona M, Algeri S, Garattini S (1988) Aspartame and the rat brain monoaminergic system. Toxicol Lett 44: 331–339Google Scholar
  130. Pinto JMB, Maher TJ (1988) Administration of aspartame potentiates pentylenetetrazoleand fluorothyl-induced seizures in mice. Neuropharmacology 27: 51–55Google Scholar
  131. Porszasz J, Worum I (1971) Seasonal variations of electroshock seizure susceptibility in the rat. Acta Physiol Acad Sci Hungar 40: 93–100Google Scholar
  132. Porta MS (1986) The search for more clinical meaningful research designs: single-patient random-mized clinical trials. J Gen Intern Med 1: 418–419Google Scholar
  133. Racine RJ (1972) Modification of seizure activity by electrical stimulation: II. motor seizure. Electroencephalogr Clin Neurophysio 32: 281–294Google Scholar
  134. Racine R (1978) Related disciplines. Kindling: the first decade. Neurosurgery 3: 234–252Google Scholar
  135. Racine R, Okujava V, Chipashvili S (1972) Modification of seizure activity by electrical stimulation: III. mechanisms. Electroencephalogr Clin Neurophysiol 32: 295–299Google Scholar
  136. Rall TW, Schleifer LS (1990) Drugs effective in the therapy of the epilepsies. In: Gilman AG, Rall TW, Nies AS, Taylor P (eds) Goodman and Gilman's the pharmacological basis of therapeutics, 8th edn. Pergamon Press, New York, pp 436–462Google Scholar
  137. Ranney RE, Opperman JA, Muldoon E (1976) Comparative metabolism of aspartame in experimental animals and humans. J Toxicol Environ Health 2: 441–451Google Scholar
  138. Reynolds WA, Lemkey-Johnston N, Filer LJ Jr, Pitkin RM (1971) Monosodium glutamate: Absence of hypothalamic lesions after ingestion by newborn primates. Science 172: 1342–1344Google Scholar
  139. Reynolds WA, Lemkey-Johnston N, Stegink LD (1979) Morphology of the fetal monkey hypothalamus after in utero exposure to monosodium glutamate. In: Filer LJ Jr, Garattini S, Kare MR, Reynolds WA, Wurtman RJ (eds) Glutamic acid: Advances in biochemistry and physiology. Raven Press, New York, pp 217–229Google Scholar
  140. Reynolds WA, Parsons L, Stegink LD (1984) Neuropathology studies following aspartame ingestion by infant nonhuman primates. In: Stegink LD, Filer LJ Jr., (eds) Aspartame: Physiology and biochemistry. Marcel Dekker, New York, pp 363–378Google Scholar
  141. Roberts HJ (1988) Aspartame (NutraSweet)-associated epilepsy. Clin Res 36: 349AGoogle Scholar
  142. Rowan AJ, Shaywitz BA (1992) Aspartame has no effect on seizure incidence or EEG epileptiform discharges in children and adults who reportedly had seizures due to aspartame consumption. J Clin Neurophysiol (In press)Google Scholar
  143. Segal M (1991) Serotonin and epilepsy. In: Fisher RS, Coyle JT (eds) Neurotransmitters and epilepsy. John Wiley & Sons, New York, pp 103–108Google Scholar
  144. Shaywitz BA, Novotny EJ, Ebersole JS, Anderson GM, Sullivan CM, Gillespie SM (1992) Aspartame does not provoke seizures in children with epilepsy. Pediatr Res 31: 354AGoogle Scholar
  145. Smialowski A (1983) Excitatory effect of intrahippocampal injection of glutamic acid on rabbit EEG. J Neural Transm 58: 205–211Google Scholar
  146. Snead OC (1988) Gamma-hydroxybutyrate model of generalized absence seizures: Further characterization and comparison with other absence models. Epilepsia 29/4: 361–368Google Scholar
  147. Statnick MA, Dailey JW, Jobe PC, Browning RA (1991) Abnormalities in brain serotonin uptake and steady state concentration in the genetically epilepsy-prone rat (GEPR). Soc Neurosci Abstr 17: 171Google Scholar
  148. Stegink LD (1984) Aspartame metabolism in humans: Acute dosing studies. In: Stegink LD, Filer LJ Jr (eds) Aspartame: Physiology and biochemistry. Marcel Dekker, New York, pp 509–553Google Scholar
  149. Stegink LD, Brummel MC, McMartin K, Martin-Amat G, Filer LJ Jr, Baker GL, Tephly TR (1981) Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame. J Toxicol Environ Health 7: 281–290Google Scholar
  150. Stegink LD, Filler LJ, Baker GL (1977) Effect of aspartame and aspartate loading upon plasma and erythrocyte free amino acid levels in normal adult volunteers. J Nutr 107: 1837–1845Google Scholar
  151. Stegink LD, Filer LJ Jr, Bell EF, Ziegler EE, Tephly TR (1989) Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults. Metabolism 38: 357–363Google Scholar
  152. Stegink LD, Filer LJ Jr, Bell EF, Ziegler EE, Tephly TR, Krause WL (1990) Repeated ingestion of aspartame-sweetened beverages: Further observations in individuals heterozygous for phenylketonuria. Metabolism 39: 1076–1081Google Scholar
  153. Stegink LD, Reynolds WA, Filer LJ Jr, Pitkin RM, Boaz DP, Brummel MC (1975) Monosodium glutamate metabolism in the neonatal monkey. Am J Physiol 229: 246–250Google Scholar
  154. Stewart CN, Coursin DB, Bhagavan HN (1972) Electroencephalographic study of L-glutamate induced seizures in rats. Toxicol Appl Pharmacol 23: 635–639Google Scholar
  155. Stone WE (1972) Systemic chemical convulsants and metabolic derangements. In: Purpura DP, Penry JK, Tower DB, Woodbury DM, Walter RD (eds) Experimental models of epilepsy — A manual for the laboratory worker. Raven Press, New York, pp 407–432Google Scholar
  156. Swinyard EA (1972) Electrically induced convulsions. In: Purpura DP, Penry JK, Tower DB, Woodbury DM, Walter RD (eds) Experimental models of epilepsy — A manual for the laboratory worker. Raven Press, New York, pp 433–458Google Scholar
  157. Sze PY (1989) Pharmacological effects of phenylalanine on seizure susceptibility: an overview. Neurochemical Res 14: 103–111Google Scholar
  158. Tephly TR, McMartin KE (1984) Methanol metabolism and toxicity. In: Stegink LD, Filer LJ Jr (eds) Aspartame physiology and biochemistry. Marcel Dekker, New York, pp 111–140Google Scholar
  159. Tilson HA, Thai L, Zhao D, Sobotka TJ, Hong JS (1989) Oral administration of aspartame is not proconvulsant in rats. Neurotoxicology 10: 229–238Google Scholar
  160. Tollefson L, Barnard RJ, Glinsmann HW (1988) Monitoring of adverse reactions to aspartame reported to the US Food and Drug Administration. In: Wurtman RJ, Ritter-Walker E (eds) Dietary phenylalanine and brain function. Birkhäuser, Boston, pp 317–337Google Scholar
  161. Vergnes M, Marescaux Ch, Depaulis A, Micheletti G, Warter JM (1990) Spontaneous spike-and-wave discharges in wistar rats: A model of genetic generalized nonconvulisve epilepsy. In: Avoli M, Gloor P, Kostopoulos G, Naquet R (eds) Generalized epilepsy: Neurobiological approaches. Birkhäuser, Boston, pp 238–253Google Scholar
  162. Walton RG (1986) Seizure and mania after high intake of aspartame. Psychosomatics 27: 218–219Google Scholar
  163. Wang C, Jobe PC, Browning RA (1990) Effect of 6-OHDA-induced lesions of the medial forebrain bundle (MFB) on audiogenic seizures in genetically epilepsy-prone rats (GEPR-3s). Soc Neurosci Abstr 16: 781Google Scholar
  164. Ward AA (1972) Topical convulsant metals. In: Purpura DP, Penry JK, Tower DB, Woodbury DM, Walter RD (eds) Experimental models of epilepsy: A manual for the laboratory worker. Raven Press, New York, pp 14–35Google Scholar
  165. Wasterlain C (1988) Epileptic seizures. In: Siegel GJ, Agranoff B, Albers RW, Molinoff P (eds) Basic neurochemistry: Molecular, cellular, and medical aspects, 4th edn. Raven Press, New York, pp 797–810Google Scholar
  166. Wen C, Hayes KC, Gershoff SN (1973) Effects of dietary supplementation of monosodium glutamate on infant monkeys, weanling rats and suckling mice. Am J Clin Nutr 26: 803–813Google Scholar
  167. Wolf-Novak LC, Stegink LD, Brummel MC, Persoon TJ, Filer LJ Jr, Bell EF, Ziegler EE, Krause WL (1990) Aspartame ingestion with and without carbohydrate in phenylketonuric and normal subjects: Effect on plasma concentrations of amino acids, glucose, and insulin. Metabolism 39: 391–396Google Scholar
  168. Wurtman RJ (1985) Aspartame: possible effect on seizure susceptibility. Lancet November 9: 1060Google Scholar
  169. Wurtman RJ, Maher TJ (1987) Effects of oral aspartame on plasma phenylalanine in humans and experimental rodents. J Neural Transm 70: 169–173Google Scholar
  170. Yan QS, Jobe PC, Dailey JW (1992a) Effects of desipramine and yohimbine on convulsions and onin vivo norepinephrine release in genetically epilepsy-prone rats. FASEB J 6: A1879Google Scholar
  171. Yan QS, Mishra PK, Burger RL, Bettendorf AF, Jobe PC, Dailey JW (1992b) 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 261: 652–659Google Scholar
  172. Yokogoshi H, Roberts CH, Caballero B, Wurtman RJ (1984) Effects of aspartame and glucose metabolism on brain and plasma levels of large neutral amino acids and brain 5-hydroxyindoles. Am J Clin Nutr 40: 1–7Google Scholar
  173. Zhi J, Levy G (1989) Aspartame and phenylalanine do not enhance theophylline-induced seizures in rats. Res Commun Chem Path Pharmacol 66: 171–174Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • P. C. Jobe
    • 1
  • J. W. Dailey
    • 1
  1. 1.Department of Basic SciencesCollege of Medicine of PeoriaPeoriaUSA

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