Metabolic Brain Disease

, Volume 27, Issue 4, pp 531–539 | Cite as

Methylglyoxal alters glucose metabolism and increases AGEs content in C6 glioma cells

  • Fernanda Hansen
  • Daniela Fraga de Souza
  • Simone da Luz Silveira
  • Ana Lúcia Hoefel
  • Júlia Bijoldo Fontoura
  • Ana Carolina Tramontina
  • Larissa Daniele Bobermin
  • Marina Concli Leite
  • Marcos Luiz Santos Perry
  • Carlos Alberto GonçalvesEmail author
Original Paper


Methylglyoxal is a dicarbonyl compound that is physiologically produced by enzymatic and non-enzymatic reactions. It can lead to cytotoxicity, which is mainly related to Advanced Glycation End Products (AGEs) formation. Methylglyoxal and AGEs are involved in the pathogenesis of Neurodegenerative Diseases (ND) and, in these situations, can cause the impairment of energetic metabolism. Astroglial cells play critical roles in brain metabolism and the appropriate functioning of astrocytes is essential for the survival and function of neurons. However, there are only a few studies evaluating the effect of methylglyoxal on astroglial cells. The aim of this study was to evaluate the effect of methylglyoxal exposure, over short (1 and 3 h) and long term (24 h) periods, on glucose, glycine and lactate metabolism in C6 glioma cells, as well as investigate the glyoxalase system and AGEs formation. Glucose uptake and glucose oxidation to CO2 increased in 1 h and the conversion of glucose to lipids increased at 3 h. In addition, glycine oxidation to CO2 and conversion of glycine to lipids increased at 1 h, whereas the incorporation of glycine in proteins decreased at 1 and 3 h. Methylglyoxal decreased glyoxalase I and II activities and increased AGEs content within 24 h. Lactate oxidation and lactate levels were not modified by methylglyoxal exposure. These data provide evidence that methylglyoxal may impair glucose metabolism and can affect glyoxalase activity. In periods of increased methylglyoxal exposure, such alterations could be exacerbated, leading to further increases in intracellular methylglyoxal and AGEs, and therefore triggering and/or worsening ND.


AGEs Methylglyoxal C6 glioma cells Energetic metabolism Glyoxalase system 



We would like to thank Ms. Gisele Souza for technical support with cell culture. This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), FINEP/ Rede IBN 01.06.0842-00 and INCT-National Institute of Science and Technology for Excitotoxicity and Neuroprotection.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abordo EA, Minhas HS, Thornalley PJ (1999) Accumulation of alpha-oxoaldehydes during oxidative stress: a role in cytotoxicity. Biochem Pharmacol 58:641–648PubMedCrossRefGoogle Scholar
  2. Ahmed N, Battah S, Karachalias N, Babaei-Jadidi R, Horanyi M, Baroti K, Hollan S, Thornalley PJ (2003) Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency. Biochim Biophys Acta 1639:121–132PubMedCrossRefGoogle Scholar
  3. Alexander CL, Fitzgerald UF, Barnett SC (2002) Identification of growth factors that promote long-term proliferation of olfactory ensheathing cells and modulate their antigenic phenotype. Glia 37:349–364PubMedCrossRefGoogle Scholar
  4. Amicarelli F, Colafarina S, Cattani F, Cimini A, Di Ilio C, Ceru MP, Miranda M (2003) Scavenging system efficiency is crucial for cell resistance to ROS-mediated methylglyoxal injury. Free Radic Biol Med 35:856–871PubMedCrossRefGoogle Scholar
  5. Baber Z, Haghighat N (2010) Glutamine synthetase gene expression and glutamate transporters in C6-glioma cells. Metab Brain Dis 25:413–418PubMedCrossRefGoogle Scholar
  6. Bouzier AK, Voisin P, Goodwin R, Canioni P, Merle M (1998) Glucose and lactate metabolism in C6 glioma cells: evidence for the preferential utilization of lactate for cell oxidative metabolism. Dev Neurosci 20:331–338PubMedCrossRefGoogle Scholar
  7. Dalfo E, Portero-Otin M, Ayala V, Martinez A, Pamplona R, Ferrer I (2005) Evidence of oxidative stress in the neocortex in incidental Lewy body disease. J Neuropathol Exp Neurol 64:816–830PubMedCrossRefGoogle Scholar
  8. Davey GE, Murmann P, Heizmann CW (2001) Intracellular Ca2+ and Zn2+ levels regulate the alternative cell density-dependent secretion of S100B in human glioblastoma cells. J Biol Chem 276:30819–30826PubMedCrossRefGoogle Scholar
  9. de Arriba SG, Stuchbury G, Yarin J, Burnell J, Loske C, Munch G (2007) Methylglyoxal impairs glucose metabolism and leads to energy depletion in neuronal cells–protection by carbonyl scavengers. Neurobiol Aging 28:1044–1050PubMedCrossRefGoogle Scholar
  10. de Souza DF, Leite MC, Quincozes-Santos A, Nardin P, Tortorelli LS, Rigo MM, Gottfried C, Leal RB, Goncalves CA (2009) S100B secretion is stimulated by IL-1beta in glial cultures and hippocampal slices of rats: Likely involvement of MAPK pathway. J Neuroimmunol 206:52–57PubMedCrossRefGoogle Scholar
  11. Di Loreto S, Zimmitti V, Sebastiani P, Cervelli C, Falone S, Amicarelli F (2008) Methylglyoxal causes strong weakening of detoxifying capacity and apoptotic cell death in rat hippocampal neurons. Int J Biochem Cell Biol 40:245–257PubMedCrossRefGoogle Scholar
  12. Dmitriev LF, Titov VN (2010) Lipid peroxidation in relation to ageing and the role of endogenous aldehydes in diabetes and other age-related diseases. Ageing Res Rev 9:200–210PubMedCrossRefGoogle Scholar
  13. dos Santos Fagundes I, Rotta LN, Schweigert ID, Valle SC, de Oliveira KR, Huth Kruger A, Souza KB, Souza DO, Perry ML (2001) Glycine, serine, and leucine metabolism in different regions of rat central nervous system. Neurochem Res 26:245–249CrossRefGoogle Scholar
  14. Dringen R, Hamprecht B (1996) Glutathione content as an indicator for the presence of metabolic pathways of amino acids in astroglial cultures. J Neurochem 67:1375–1382PubMedCrossRefGoogle Scholar
  15. Dunlop DS, van Elden W, Lajtha A (1975) Optimal conditions for protein synthesis in incubated slices of rat brain. Brain Res 99:303–318PubMedCrossRefGoogle Scholar
  16. Freemantle E, Vandal M, Tremblay-Mercier J, Tremblay S, Blachere JC, Begin ME, Brenna JT, Windust A, Cunnane SC (2006) Omega-3 fatty acids, energy substrates, and brain function during aging. Prostaglandins Leukot Essent Fatty Acids 75:213–220PubMedCrossRefGoogle Scholar
  17. Fuller S, Steele M, Munch G (2010) Activated astroglia during chronic inflammation in Alzheimer’s disease–do they neglect their neurosupportive roles? Mutat Res 690:40–49PubMedCrossRefGoogle Scholar
  18. Goldin A, Beckman JA, Schmidt AM, Creager MA (2006) Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 114:597–605PubMedCrossRefGoogle Scholar
  19. Gundersen RY, Vaagenes P, Breivik T, Fonnum F, Opstad PK (2005) Glycine–an important neurotransmitter and cytoprotective agent. Acta Anaesthesiol Scand 49:1108–1116PubMedCrossRefGoogle Scholar
  20. Haghighat N, McCandless DW (1997) Effect of 6-aminonicotinamide on metabolism of astrocytes and C6-glioma cells. Metab Brain Dis 12:29–45PubMedCrossRefGoogle Scholar
  21. Hertz L, Peng L, Dienel GA (2007) Energy metabolism in astrocytes: high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. J Cereb Blood Flow Metab 27:219–249PubMedCrossRefGoogle Scholar
  22. Hu G, Jousilahti P, Bidel S, Antikainen R, Tuomilehto J (2007) Type 2 diabetes and the risk of Parkinson’s disease. Diabetes Care 30:842–847PubMedCrossRefGoogle Scholar
  23. Ikeda K, Higashi T, Sano H, Jinnouchi Y, Yoshida M, Araki T, Ueda S, Horiuchi S (1996) N (epsilon)-(carboxymethyl)lysine protein adduct is a major immunological epitope in proteins modified with advanced glycation end products of the Maillard reaction. Biochemistry 35:8075–8083PubMedCrossRefGoogle Scholar
  24. Krautwald M, Munch G (2010) Advanced glycation end products as biomarkers and gerontotoxins—A basis to explore methylglyoxal-lowering agents for Alzheimer’s disease? Exp Gerontol 45:744–751PubMedCrossRefGoogle Scholar
  25. Kroner Z (2009) The relationship between Alzheimer’s disease and diabetes: Type 3 diabetes? Altern Med Rev 14:373–379PubMedGoogle Scholar
  26. Kuhla B, Luth HJ, Haferburg D, Boeck K, Arendt T, Munch G (2005) Methylglyoxal, glyoxal, and their detoxification in Alzheimer’s disease. Ann N Y Acad Sci 1043:211–216PubMedCrossRefGoogle Scholar
  27. Kuhla B, Luth HJ, Haferburg D, Weick M, Reichenbach A, Arendt T, Munch G (2006) Pathological effects of glyoxalase I inhibition in SH-SY5Y neuroblastoma cells. J Neurosci Res 83:1591–1600PubMedCrossRefGoogle Scholar
  28. Kuhla B, Boeck K, Schmidt A, Ogunlade V, Arendt T, Munch G, Luth HJ (2007) Age- and stage-dependent glyoxalase I expression and its activity in normal and Alzheimer’s disease brains. Neurobiol Aging 28:29–41PubMedCrossRefGoogle Scholar
  29. Lapolla A, Reitano R, Seraglia R, Sartore G, Ragazzi E, Traldi P (2005) Evaluation of advanced glycation end products and carbonyl compounds in patients with different conditions of oxidative stress. Mol Nutr Food Res 49:685–690PubMedCrossRefGoogle Scholar
  30. Leite MC, Galland F, de Souza DF, Guerra MC, Bobermin L, Biasibetti R, Gottfried C, Goncalves CA (2009) Gap junction inhibitors modulate S100B secretion in astrocyte cultures and acute hippocampal slices. J Neurosci Res 87:2439–2446PubMedCrossRefGoogle Scholar
  31. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  32. Lüth HJ, Ogunlade V, Kuhla B, Kientsch-Engel R, Stahl P, Webster J, Arendt T, Munch G (2005) Age- and Stage-dependent accumulation of Advanced Glycation End Products in intracellular deposits in normal and Alzheimer’s Disease brains. Cereb Cortex 15:211–220PubMedCrossRefGoogle Scholar
  33. Mangoura D, Sakellaridis N, Jones J, Vernadakis A (1989) Early and late passage C-6 glial cell growth: similarities with primary glial cells in culture. Neurochem Res 14:941–947PubMedCrossRefGoogle Scholar
  34. Mannervik B, Aronsson AC, Marmstal E, Tibbelin G (1981) Glyoxalase I (rat liver). Methods Enzymol 77:297–301PubMedCrossRefGoogle Scholar
  35. Munch G, Taneli Y, Schraven E, Schindler U, Schinzel R, Palm D, Riederer P (1994) The cognition-enhancing drug tenilsetam is an inhibitor of protein crosslinking by advanced glycosylation. J Neural Transm Park Dis Dement Sect 8:193–208PubMedCrossRefGoogle Scholar
  36. Munch G, Thome J, Foley P, Schinzel R, Riederer P (1997) Advanced glycation endproducts in ageing and Alzheimer’s disease. Brain Res Brain Res Rev 23:134–143PubMedCrossRefGoogle Scholar
  37. Oray B, Norton SJ (1982) Glyoxalase II from mouse liver. Methods Enzymol 90(Pt E):547–551PubMedCrossRefGoogle Scholar
  38. Pellerin L, Magistretti PJ (1994) Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci USA 91:10625–10629PubMedCrossRefGoogle Scholar
  39. Pellerin L, Magistretti PJ (1996) Excitatory amino acids stimulate aerobic glycolysis in astrocytes via an activation of the Na+/K+ ATPase. Dev Neurosci 18:336–342PubMedCrossRefGoogle Scholar
  40. Phillips SA, Thornalley PJ (1993) The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal. Eur J Biochem 212:101–105PubMedCrossRefGoogle Scholar
  41. Quincozes-Santos A, Abib RT, Leite MC, Bobermin D, Bambini-Junior V, Goncalves CA, Riesgo R, Gottfried C (2008) Effect of the atypical neuroleptic risperidone on morphology and S100B secretion in C6 astroglial lineage cells. Mol Cell Biochem 314:59–63PubMedCrossRefGoogle Scholar
  42. Quincozes-Santos A, Bobermin LD, Kleinkauf-Rocha J, Souza DO, Riesgo R, Goncalves CA, Gottfried C (2009) Atypical neuroleptic risperidone modulates glial functions in C6 astroglial cells. Prog Neuropsychopharmacol Biol Psychiatry 33:11–15PubMedCrossRefGoogle Scholar
  43. Quincozes-Santos A, Bobermin LD, Tonial RP, Bambini-Junior V, Riesgo R, Gottfried C (2010) Effects of atypical (risperidone) and typical (haloperidol) antipsychotic agents on astroglial functions. Eur Arch Psychiatry Clin Neurosci 260:475–481PubMedCrossRefGoogle Scholar
  44. Ramasamy R, Vannucci SJ, Yan SS, Herold K, Yan SF, Schmidt AM (2005) Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology 15:16R–28RPubMedCrossRefGoogle Scholar
  45. Schmidt B, de Assis AM, Battu CE, Rieger DK, Hansen F, Sordi F, Longoni A, Hoefel AL, Farina M, Goncalves CA, Souza DO, Perry ML (2010) Effects of glyoxal or methylglyoxal on the metabolism of amino acids, lactate, glucose and acetate in the cerebral cortex of young and adult rats. Brain Res 1315:19–24PubMedCrossRefGoogle Scholar
  46. Tabernero A, Medina JM, Giaume C (2006) Glucose metabolism and proliferation in glia: role of astrocytic gap junctions. J Neurochem 99:1049–1061PubMedCrossRefGoogle Scholar
  47. Vander Jagt DL, Hunsaker LA (2003) Methylglyoxal metabolism and diabetic complications: roles of aldose reductase, glyoxalase-I, betaine aldehyde dehydrogenase and 2-oxoaldehyde dehydrogenase. Chem Biol Interact 144:341–351CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Fernanda Hansen
    • 1
  • Daniela Fraga de Souza
    • 1
  • Simone da Luz Silveira
    • 1
  • Ana Lúcia Hoefel
    • 1
  • Júlia Bijoldo Fontoura
    • 2
  • Ana Carolina Tramontina
    • 1
  • Larissa Daniele Bobermin
    • 1
  • Marina Concli Leite
    • 1
  • Marcos Luiz Santos Perry
    • 1
  • Carlos Alberto Gonçalves
    • 1
    Email author
  1. 1.Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Faculdade de FarmáciaUniversidade Federal do Rio Grande do SulPorto AlegreBrazil

Personalised recommendations