Neurotoxicity Research

, Volume 21, Issue 3, pp 245–255 | Cite as

Effect of Aspartame on Oxidative Stress and Monoamine Neurotransmitter Levels in Lipopolysaccharide-Treated Mice

  • Omar M. E. Abdel-SalamEmail author
  • Neveen A. Salem
  • Jihan Seid Hussein


This study aimed at investigating the effect of the sweetener aspartame on oxidative stress and brain monoamines in normal circumstances and after intraperitoneal (i.p.) administration of lipopolysaccharide (LPS; 100 μg/kg) in mice. Aspartame (0.625–45 mg/kg) was given via subcutaneous route at the time of endotoxin administration. Mice were euthanized 4 h later. Reduced glutathione (GSH), lipid peroxidation (thiobarbituric acid-reactive substances; TBARS), and nitrite concentrations were measured in brain and liver. Tumor necrosis factor-alpha (TNF-α) and glucose were determined in brain. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were measured in liver. The administration of only aspartame (22.5 and 45 mg/kg) increased brain TBARS by 17.7–32.8%, decreased GSH by 25.6–31.6%, and increased TNF-α by 16.7–44%. Aspartame caused dose-dependent inhibition of brain serotonin, noradrenaline, and dopamine. Aspartame did not alter liver TBARS, nitrite, GSH, AST, ALT, or ALP. The administration of LPS increased nitrite in brain and liver by 26.8 and 37.1%, respectively; decreased GSH in brain and liver by 21.6 and 31.1%, respectively; increased brain TNF-α by 340.4%, and glucose by 39.9%, and caused marked increase in brain monoamines. LPS increased AST, ALT, and ALP in liver tissue by 84.4, 173.7, and 258.9%, respectively. Aspartame given to LPS-treated mice at 11.25 and 22.5 mg/kg increased brain TBARS by 15.5–16.9%, nitrite by 12.6–20.1%, and mitigated the increase in monoamines. Aspartame did not alter liver TBARS, nitrite, GSH, ALT, AST, or ALP. Thus, the administration of aspartame alone or in the presence of mild systemic inflammatory response increases oxidative stress and inflammation in the brain, but not in the liver.


Aspartame Lipopolysaccharide Oxidative stress Brain Liver Mice 


Conflicts of interest

The authors declare that there are no conflicts of interest relevant to the subject of their manuscript.


  1. Abdel Salam OME, Sleem AA, Shaffie NM (2009) Hepatoprotective effects of citric acid and aspartame on carbon tetrachloride-induced hepatic damage in rats. EXCLI J 8:41–49Google Scholar
  2. Belfield A, Goldberg DM (1971) Human serum glucose-6 phosphatase activity: confirmation of its presence and lack of diagnostic value. Clin Chim Acta 31:81–85PubMedCrossRefGoogle Scholar
  3. Bergstrom BP, Cummings DR, Skaggs TA (2007) Aspartame decreases evoked extracellular dopamine levels in the rat brain: an in vivo voltammetry study. Neuropharmacology 53:967–974PubMedCrossRefGoogle Scholar
  4. Beurel E, Jope RS (2009) Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain. J Neuroinflamm 6:9CrossRefGoogle Scholar
  5. Borowski T, Kokkinidis L, Merali Z, Anisman H (1998) Lipopolysaccharide, central in vivo biogenic amine variations, and anhedonia. Neuroreport 9:3797–3801PubMedCrossRefGoogle Scholar
  6. Buchanan JB, Sparkman NL, Johnson RW (2010) Methamphetamine sensitization attenuates the febrile and neuroinflammatory response to a subsequent peripheral immune stimulus. Brain Behav Immun 24:502–511PubMedCrossRefGoogle Scholar
  7. Butchko HH, Stargel WW, Comer CP et al (2002) Aspartame: review of safety. Regul Toxicol Pharmacol 35:S1–S93PubMedCrossRefGoogle Scholar
  8. Butterfield DA (2002) Amyloid β-peptide (1–42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review. Free Radic Res 36:1307–1313PubMedCrossRefGoogle Scholar
  9. Butterfield DA, Kanski J (2001) Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins. Mech Ageing Dev 122:945–962PubMedCrossRefGoogle Scholar
  10. Buttini M, Mir A, Appel K et al (1997) Lipopolysaccharide induces expression of tumour necrosis factor alpha in rat brain: inhibition by methylprednisolone and by rolipram. Br J Pharmacol 122:1483–1489PubMedCrossRefGoogle Scholar
  11. Calabrese V, Boyd-Kimball D, Scapagnini G et al (2004) Nitric oxide and cellular stress response in brain aging and neurodegenerative disorders: the role of vitagenes. In Vivo 18:245–267PubMedGoogle Scholar
  12. Cao C, Matsumura K, Yamagata K et al (1995) Induction by lipopolysaccharide of cyclooxygenase-2 mRNA in rat brain; its possible role in the febrile response. Brain Res 697:187–196PubMedCrossRefGoogle Scholar
  13. Chen K, Inoue M, Okada A (1996) Expression of inducible nitric oxide synthase mRNA in rat digestive tissues after endotoxin and its role in intestinal mucosal injury. Biochem Biophys Res Commun 224:703–708PubMedCrossRefGoogle Scholar
  14. Chen W, Jin W, Cook M et al (1998) Oral delivery of group a streptococcal cell walls augments circulating TGF-beta and suppresses streptococcal cell wall arthritis. J Immunol 161:6297–6304PubMedGoogle Scholar
  15. Collins AR (2005) Assays for oxidative stress and antioxidant status: applications to research into the biological effectiveness of polyphenols. Am J Clin Nutr 81(suppl):261S–267SPubMedGoogle Scholar
  16. Coulombe RA Jr, Sharma RP (1986) Neurobiochemical alterations induced by the artificial sweetener aspartame (NutraSweet). Toxicol Appl Pharmacol 83:79–85PubMedCrossRefGoogle Scholar
  17. Cunningham C, Wilcockson DC, Campion S et al (2005) Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 25:9275–9284PubMedCrossRefGoogle Scholar
  18. Czapski GA, Cakala M, Chalimoniuk M et al (2007) Role of nitric oxide in the brain during lipopolysaccharide-evoked systemic inflammation. J Neurosci Res 85:1694–1703PubMedCrossRefGoogle Scholar
  19. Dailey JW, Lasley SM, Burger RL et al (1991) Amino acids, monoamines and audiogenic seizures in genetically epilepsy-prone rats: effects of aspartame. Epilepsy Res 8:122–133PubMedCrossRefGoogle Scholar
  20. Dunn AJ (1992) Endotoxin-induced activation of cerebral catecholamine and serotonin metabolism: comparison with interleukin-1. J Pharmacol Exp Ther 261:964–969PubMedGoogle Scholar
  21. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem 82:70–77PubMedCrossRefGoogle Scholar
  22. Fiorucci S, Mencarelli A, Meneguzzi A et al (2002) NCX-4016 (NO-Aspirin) inhibits lipopolysaccharide-induced tissue factor expression in vivo. Role of nitric oxide. Circulation 106:3120–3125PubMedCrossRefGoogle Scholar
  23. Gibbons SS (2000) Antidepressants. In: Edmunds MW, Mayhew MS (eds) Pharmacology for the primary care provider. Mosby Inc., St. Louis, pp 602–620Google Scholar
  24. Goerss AL, Wagner GC, Hill WL (2000) Acute effects of aspartame on aggression and neurochemistry of rats. Life Sci 67:1325–1329PubMedCrossRefGoogle Scholar
  25. Gutteridge JMC (1995) Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin Chem 41:1819–1828PubMedGoogle Scholar
  26. Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59:1609–1623PubMedCrossRefGoogle Scholar
  27. Halliwell B (1996) Free radicals, protein and DNA: oxidative damage versus redox regulation. Biochem Soc Trans 24:1023–1027PubMedGoogle Scholar
  28. Halliwell B (2001) Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging 18:685–716PubMedCrossRefGoogle Scholar
  29. Holder MD, Yirmiya R (1989) Behavioral assessment of the toxicity of aspartame. Pharmacol Biochem Behav 32:17–26PubMedCrossRefGoogle Scholar
  30. Hollis JH, Lemus M, Evetts MJ et al (2010) Central interleukin-10 attenuates lipopolysaccharide-induced changes in food intake, energy expenditure and hypothalamic Fos expression. Neuropharmacology 58:730–738PubMedCrossRefGoogle Scholar
  31. Jacewicz M, Czapski GA, Katkowska I et al (2009) Systemic administration of lipopolysaccharide impairs glutathione redox state and object recognition in male mice. The effect of PARP-1 inhibitor. Folia Neuropathol 47:321–328PubMedGoogle Scholar
  32. Jeong H-K, Jou I, Joe E-h (2010) Systemic LPS administration induces brain inflammation but not dopaminergic neuronal death in the substantia nigra. Exp Mol Med 42:823–832PubMedCrossRefGoogle Scholar
  33. Koprich JB, Reske-Nielsen C, Mithal P et al (2008) Neuroinflammation mediated by IL-1β increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson’s disease. J Neuroinflamm 5:8CrossRefGoogle Scholar
  34. Lee HY, Noh HJ, Gang JG et al (2002) Inducible nitric oxide synthase (iNOS) expression is increased in lipopolysaccharide (LPS)-stimulated diabetic rat glomeruli: effect of ACE inhibitor and angiotensin II receptor blocker. Yonsei Med J 43:183–192PubMedGoogle Scholar
  35. Li L, Whiteman M, Moore PK (2009) Dexamethasone inhibits lipopolysaccharide-induced hydrogen sulphide biosynthesis in intact cells and in an animal model of endotoxic shock. J Cell Mol Med 13(8B):2684–2692PubMedCrossRefGoogle Scholar
  36. Lim U, Subar AF, Mouw T et al (2006) Consumption of aspartame-containing beverages and incidence of hematopoietic and brain malignancies. Cancer Epidemiol Biomarkers Prev 15:1654–1659PubMedCrossRefGoogle Scholar
  37. Maes M (2008) The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuro Endocrinol Lett 29:287–291PubMedGoogle Scholar
  38. Møller SE (1991) Effect of aspartame and protein, administered in phenylalanine-equivalent doses, on plasma neutral amino acids, aspartate, insulin and glucose in man. Pharmacol Toxicol 68:408–412PubMedCrossRefGoogle Scholar
  39. Moncada S, Bolanos JP (2006) Nitric oxide, cell bioenergetics and neurodegeneration. J Neurochem 97:1676–1689PubMedCrossRefGoogle Scholar
  40. Mori K, Kaneko YS, Nakashima A et al (2003) Effect of peripheral lipopolysaccharide injection on dopamine content in murine anterior olfactory nucleus. J Neural Transm 110:31–50PubMedGoogle Scholar
  41. Moshage H, Kok B, Huizenga JR (1995) Nitrite and nitrate determination in plasma: a critical evaluation. Clin Chem 41:892–896PubMedGoogle Scholar
  42. Noble F, Rubira E, Boulanouar M et al (2007) Acute systemic inflammation induces central mitochondrial damage and mnesic deficit in adult Swiss mice. Neurosci Lett 424:106–110PubMedCrossRefGoogle Scholar
  43. Olney JW, Farber NB, Spitznagel E et al (1996) Increasing brain cancer rates: is there a link to aspartame? J Neuropathol Exp Neurol 55:1115–1123PubMedCrossRefGoogle Scholar
  44. Olsson LE, Wheeler MA, Sessa WC et al (1998) Bladder instillation and intraperitoneal injection of Escherichia coli lipopolysaccharide up-regulate cytokines and iNOS in rat urinary bladder. JPET 284:1203–1208Google Scholar
  45. Opperman JA (1984) Aspartame metabolism in animals. In: Stegink LD, Filer LJ Jr (eds) Aspartame: physiology and biochemistry. Marcel Dekker, New YorkGoogle Scholar
  46. Ota A, Kaneko YS, Mori K et al (2007) Effect of peripherally administered lipopolysaccharide (LPS) on GTP cyclohydrolase I, tetrahydrobiopterin and norepinephrine in the locus coeruleus in mice. Stress 10:131–136PubMedCrossRefGoogle Scholar
  47. Paget GE, Barnes JM (1964) Toxicity tests. In: Laurence DR, Bacharach AL (eds) Evaluation of drug activities pharmacometics. Academic Press, London and New YorkGoogle Scholar
  48. Perego C, De Simoni MG, Fodritto F et al (1988) Aspartame and the rat brain monoaminergic system. Toxicol Lett 44:331–339PubMedCrossRefGoogle Scholar
  49. Pérez-Nievas BG, Madrigal JL, García-Bueno B et al (2010) Corticosterone basal levels and vulnerability to LPS-induced neuroinflammation in the rat brain. Brain Res 1315:159–168PubMedCrossRefGoogle Scholar
  50. Qin L, Wu X, Block ML et al (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453–462PubMedCrossRefGoogle Scholar
  51. Reitman S, Frankel S (1957) The colorimetric method for determination of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase. Am J Clin Pathol 28:56–63PubMedGoogle Scholar
  52. Rothwell NJ (1997) Sixteenth Gaddum Memorial Lecture December 1996. Neuroimmune interactions: the role of cytokines. Pro-inflammatory cytokines are important mediators of inflammation and injury and are known contributors to excitotoxic damage. Br J Pharmacol 121:841–847PubMedCrossRefGoogle Scholar
  53. Ruiz-Larrea MB, Leal AM, Liza M et al (1994) Antioxidant effects of estradiol and 2-hydroxyestradiol on iron-induced lipid peroxidation of rat liver microsomes. Steroids 59:383–388PubMedCrossRefGoogle Scholar
  54. Saito Y, Nishio K, Yoshida Y et al (2010) Cytotoxic effect of formaldehyde with free radicals via increment of cellular reactive oxygen species. Toxicology 2–3:235–245Google Scholar
  55. Schulz JB, Lindenau J, Seyfried J et al (2000) Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 267:4904–4911PubMedCrossRefGoogle Scholar
  56. Simintzi I, Schulpis KH, Angelogianni P et al (2007) The effect of aspartame on acetylcholinesterase activity in hippocampal homogenates of suckling rats. Pharmacol Res 56:155–159PubMedCrossRefGoogle Scholar
  57. Soffritti M, Belpoggi F, Esposti DD et al (2005) Aspartame induces lymphomas and leukaemias in rats. Eur J Oncol 10:107–116Google Scholar
  58. Spiers PA, Sabounjian L, Reiner A et al (1998) Aspartame: neuropsychologic and neurophysiologic evaluation of acute and chronic effects. Am J Clin Nutr 68:531–537PubMedGoogle Scholar
  59. Stegink LD (1984) Aspartame metabolism in humans: acute dosing studies. In: Stegink LD, Filer LJ Jr (eds) Aspartame: physiology and biochemistry. Marcel Dekker, New YorkGoogle Scholar
  60. Tabner BJ, El-Agnaf OMA, German MJ et al (2005) Protein aggregation, metals and oxidative stress in neurodegenerative diseases. Biochem Soc Trans 33:1082–1086PubMedCrossRefGoogle Scholar
  61. Thompson WL, Karpus WJ, Van Eldik LJ (2008) MCP-1-deficient mice show reduced neuroinflammatory responses and increased peripheral inflammatory responses to peripheral endotoxin insult. J Neuroinflamm 5:35CrossRefGoogle Scholar
  62. Torii K, Mimura T, Takasaki Y et al (1985) Dietary aspartame with protein on plasma and brain amino acids, brain monoamines and behavior in rats. Physiol Behav 36:765–771CrossRefGoogle Scholar
  63. Trinder P (1969) Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem 6:24–25Google Scholar
  64. Trocho C, Pardo R, Rafecas I et al (1998) Formaldehyde derived from dietary aspartame binds to tissue components in vivo. Life Sci 63:337–349PubMedCrossRefGoogle Scholar
  65. Tsakiris S, Giannoulia-Karantana A, Simintzi I et al (2006) The effect of aspartame metabolites on human erythrocyte membrane acetylcholinesterase activity. Pharmacol Res 53:1–5PubMedCrossRefGoogle Scholar
  66. Turrin NP, Gayle D, Ilyin SE et al (2001) Pro-inflammatory and anti-inflammatory cytokine mRNA induction in the periphery and brain following intraperitoneal administration of bacterial lipopolysaccharide. Brain Res Bull 54:443–453PubMedCrossRefGoogle Scholar
  67. Vona-Davis L, Wearden P, Hill J et al (2002) Cardiac response to nitric oxide synthase inhibition using aminoguanidine in a rat model of endotoxemia. Shock 17:404–410PubMedCrossRefGoogle Scholar
  68. Wood SJ, Yücel M, Pantelis C et al (2009) Neurobiology of schizophrenia spectrum disorders: the role of oxidative stress. Ann Acad Med Singap 38:396–401PubMedGoogle Scholar
  69. Yokogoshi H, Wurtman RJ (1986) Acute effects of oral or parenteral aspartame on catecholamine metabolism in various regions of rat brain. J Nutr 116:356–364PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Omar M. E. Abdel-Salam
    • 1
    Email author
  • Neveen A. Salem
    • 1
  • Jihan Seid Hussein
    • 2
  1. 1.Department of Toxicology and NarcoticsNational Research CentreCairoEgypt
  2. 2.Department of Medical BiochemistryNational Research CentreCairoEgypt

Personalised recommendations