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Cellular and Molecular Neurobiology

, Volume 32, Issue 6, pp 1047–1057 | Cite as

Dual Effect of Methylglyoxal on the Intracellular Ca2+ Signaling and Neurite Outgrowth in Mouse Sensory Neurons

  • Beatrice Mihaela Radu
  • Diana Ionela Dumitrescu
  • Cosmin Catalin Mustaciosu
  • Mihai Radu
Original Research

Abstract

The formation of advanced glycation end products is one of the major factors involved in diabetic neuropathy, aging, and neurodegenerative diseases. Reactive carbonyl compounds, such as methylglyoxal (MG), play a key role in cross-linking to various proteins in the extracellular matrix, especially in neurons, which have a high rate of oxidative metabolism. The MG effect was tested on dorsal root ganglia primary neurons in cultures from adult male Balb/c mice. Lower MG doses contribute to an increased adherence of neurons on their support and an increased glia proliferation, as proved by MTS assay and bright-field microscopy. Time-lapse fluorescence microscopy by Fura-2 was performed for monitoring the relative fluorescence ratio changes (ΔR/R 0) upon depolarization and immunofluorescence staining for quantifying the degree of neurites extension. The relative change in fluorescence ratio modifies the amplitude and dispersion depending on the subtype of sensory neurons, the medium-sized neurons are more sensitive to MG treatment when compared to small ones. Low MG concentrations (0–150 μM) increase neuronal viability, excitability, and the capacity of neurite extension, while higher concentrations (250–750 μM) are cytotoxic in a dose-dependent manner. In our opinion, MG could be metabolized by the glyoxalase system inside sensory neurons up to a threshold concentration, afterwards disturbing the cell equilibrium. Our study points out that MG has a dual effect concentration dependent on the neuronal viability, excitability, and neurite outgrowth, but only the excitability changes are soma-sized dependent. In conclusion, our data may partially explain the distinct neuronal modifications in various neurodegenerative pathologies.

Keywords

Methylglyoxal Viability Time-lapse fluorescence microscopy Neurite outgrowth Peripheral sensory neurons 

Notes

Acknowledgments

This work was supported by the national grant PNII 41-074/2007 from the Romanian Ministry of Research. A great thanks to the technicians Cornelia Dragomir, Geanina Haralambie, and Constantin Radulescu for a constant help during the experiments.

References

  1. 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 Rad Biol Med 35(8):856–871PubMedCrossRefGoogle Scholar
  2. Armati P (2007) The biology of Schwann cells: development differentiation and immunomodulation. Cambridge University Press, Cambridge, pp 2–4CrossRefGoogle Scholar
  3. Bélanger M, Yang J, Petit JM, Laroche T, Magistretti PJ, Allaman I (2011) Role of the glyoxalase system in astrocyte-mediated neuroprotection. J Neurosci 31(50):18338–18352PubMedCrossRefGoogle Scholar
  4. Best L, Miley HE, Brown PD, Cook LJ (1999) Methylglyoxal causes swelling and activation of a volume-sensitive anion conductance in rat pancreatic beta-cells. J Membr Biol 167(1):65–71PubMedCrossRefGoogle Scholar
  5. Chan WH, Wu HJ (2008) Methylglyoxal and high glucose co-treatment induces apoptosis or necrosis in human umbilical vein endothelial cells. J Cell Biochem 103(4):1144–1157PubMedCrossRefGoogle Scholar
  6. Chen YJ, Huang XB, Li ZX, Yin LL, Chen WQ, Li L (2010) Tenuigenin protects cultured hippocampal neurons against methylglyoxal-induced neurotoxicity. Eur J Pharmacol 645(1–3):1–8PubMedCrossRefGoogle Scholar
  7. de Arriba SG, Stuchbury G, Yarin J, Burnell J, Loske C, Münch G (2007) Methylglyoxal impairs glucose metabolism and leads to energy depletion in neuronal cells—protection by carbonyl scavengers. Neurobiol Aging 28(7):1044–1050PubMedCrossRefGoogle Scholar
  8. 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(2):245–257PubMedCrossRefGoogle Scholar
  9. Du J, Suzuki H, Nagase F, Akhand AA, Yokoyama T, Miyata T, Kurokawa K, Nakashima I (2000) Methylglyoxal induces apoptosis in Jurkat leukemia T cells by activating c-Jun N-terminal kinase. J Cell Biochem 77:333–344PubMedCrossRefGoogle Scholar
  10. Duran-Jimenez B, Dobler D, Moffatt S, Rabbani N, Streuli CH, Thornalley PJ, Tomlinson DR, Gardiner NJ (2009) Advanced glycation end products in extracellular matrix proteins contribute to the failure of sensory nerve regeneration in diabetes. Diabetes 58(12):2893–2903PubMedCrossRefGoogle Scholar
  11. Engel MA, Leffler A, Niedermirtl F, Babes A, Zimmermann K, Filipović MR, Izydorczyk I, Eberhardt M, Kichko TI, Mueller-Tribbensee SM, Khalil M, Siklosi N, Nau C, Ivanović-Burmazović I, Neuhuber WL, Becker C, Neurath MF, Reeh PW (2011) TRPA1 and substance P mediate colitis in mice. Gastroenterology 141(4):1346–1358PubMedCrossRefGoogle Scholar
  12. Fleming TH, Humpert PM, Nawroth PP, Bierhaus A (2011) Reactive metabolites and AGE/RAGE-mediated cellular dysfunction affect the aging process: a mini-review. Gerontology 57(5):435–443PubMedGoogle Scholar
  13. Forster AB, Reeh PW, Messlinger K, Fischer MJ (2009) High concentrations of morphine sensitize and activate mouse dorsal root ganglia via TRPV1 and TRPA1 receptors. Mol Pain 5:17PubMedCrossRefGoogle Scholar
  14. Han Y, Randell E, Vasdev S, Gill V, Gadag V, Newhook LA, Grant M, Hagerty D (2007) Plasma methylglyoxal and glyoxal are elevated and related to early membrane alteration in young, complication-free patients with Type 1 diabetes. Mol Cell Biochem 305(1–2):123–131PubMedCrossRefGoogle Scholar
  15. Hiruma H, Saito A, Ichikawa T, Kiriyama Y, Hoka S, Kusakabe T, Kobayashi H, Kawakami T (2000) Effects of substance P and calcitonin gene-related peptide on axonal transport in isolated and cultured adult mouse dorsal root ganglion neurons. Brain Res 883(2):184–191PubMedCrossRefGoogle Scholar
  16. Hsieh MS, Chan WH (2009) Impact of methylglyoxal and high glucose co-treatment on human mononuclear cells. Int J Mol Sci 10(4):1445–1464PubMedCrossRefGoogle Scholar
  17. Huang SM, Chuang HC, Wu CH, Yen GC (2008) Cytoprotective effects of phenolic acids on methylglyoxal-induced apoptosis in Neuro-2A cells. Mol Nutr Food Res 52(8):940–949PubMedCrossRefGoogle Scholar
  18. Ibi M, Matsuno K, Shiba D, Katsuyama M, Iwata K, Kakehi T, Nakagawa T, Sango K, Shirai Y, Yokoyama T, Kaneko S, Saito N, Yabe-Nishimura C (2008) Reactive oxygen species derived from NOX1/NADPH oxidase enhance inflammatory pain. J Neurosci 28(38):9486–9494PubMedCrossRefGoogle Scholar
  19. Jack MM, Ryals JM, Wright DE (2011) Characterisation of glyoxalase I in a streptozocin-induced mouse model of diabetes with painful and insensate neuropathy. Diabetologia 54(8):2174–2182PubMedCrossRefGoogle Scholar
  20. Jan CR, Chen CH, Wang SC, Kuo SY (2005) Effect of methylglyoxal on intracellular calcium levels and viability in renal tubular cells. Cell Signal 17(7):847–855PubMedCrossRefGoogle Scholar
  21. Jimenez-Andrade JM, Herrera MB, Ghilardi JR, Vardanyan M, Melemedjian OK, Mantyh PW (2008) Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: implications for chemical-induced peripheral sensory neuropathies. Mol Pain 4:10PubMedCrossRefGoogle Scholar
  22. Kikuchi S, Shinpo K, Moriwaka F, Makita Z, Miyata T, Tashiro K (1999) Neurotoxicity of methylglyoxal and 3-deoxyglucosone on cultured cortical neurons: synergism between glycation and oxidative stress, possibly involved in neurodegenerative diseases. J Neurosci Res 57(2):280–289PubMedCrossRefGoogle Scholar
  23. Koivisto A, Hukkanen M, Saarnilehto M, Chapman H, Kuokkanen K, Wei H, Viisanen H, Akerman KE, Lindstedt K, Pertovaara A (2012) Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: Sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy. Pharmacol Res 65(1):149–158PubMedCrossRefGoogle Scholar
  24. Kuhla B, Lüth HJ, Haferburg D, Weick M, Reichenbach A, Arendt T, Münch G (2006) Pathological effects of glyoxalase I inhibition in SH-SY5Y neuroblastoma cells. J Neurosci Res 83(8):1591–1600PubMedCrossRefGoogle Scholar
  25. Li G, Chang M, Jiang H, Xie H, Dong Z, Hu L (2011) Proteomics analysis of methylglyoxal-induced neurotoxic effects in SH-SY5Y cells. Cell Biochem Funct 29(1):30–35PubMedCrossRefGoogle Scholar
  26. Lu SG, Zhang X, Gold MS (2006) Intracellular calcium regulation among subpopulations of rat dorsal root ganglion neurons. J Physiol 577(Pt 1):169–190PubMedCrossRefGoogle Scholar
  27. Lu J, Randell E, Han Y, Adeli K, Krahn J, Meng QH (2011) Increased plasma methylglyoxal level, inflammation, and vascular endothelial dysfunction in diabetic nephropathy. Clin Biochem 44(4):307–311PubMedCrossRefGoogle Scholar
  28. Lupachyk S, Shevalye H, Maksimchyk Y, Drel VR, Obrosova IG (2011) PARP inhibition alleviates diabetes-induced systemic oxidative stress and neural tissue 4-hydroxynonenal adduct accumulation: correlation with peripheral nerve function. Free Radic Biol Med 50(10):1400–1409PubMedCrossRefGoogle Scholar
  29. Mukohda M, Yamawaki H, Okada M, Hara Y (2010) Methylglyoxal enhances sodium nitroprusside-induced relaxation in rat aorta. J Pharmacol Sci 112(2):176–183PubMedCrossRefGoogle Scholar
  30. Nascimento RS, Santiago MF, Marques SA, Allodi S, Martinez AMB (2008) Diversity among satellite glial cells in dorsal root ganglia of the rat. Braz J Med Biol Res 41(11):1011–1017PubMedCrossRefGoogle Scholar
  31. Naziroğlu M (2007) New molecular mechanisms on the activation of TRPM2 channels by oxidative stress and ADP-ribose. Neurochem Res 32(11):1990–2001PubMedCrossRefGoogle Scholar
  32. Naziroğlu M, Özgül C, Çiğ B, Doğan S, Uğuz AC (2011) Glutathione modulates Ca(2+) influx and oxidative toxicity through TRPM2 channel in rat dorsal root ganglion neurons. J Membr Biol 242(3):109–118PubMedCrossRefGoogle Scholar
  33. Noble M, Fok-Seang J, Cohen J (1984) Glia are a unique substrate for the in vitro growth of central nervous system neurons. J Neurosci 4(7):1892–1903PubMedGoogle Scholar
  34. Reid G, Babes A, Pluteanu F (2002) A cold- and menthol-activated current in rat dorsal root ganglion neurones: properties and role in cold transduction. J Physiol 545:595–614PubMedCrossRefGoogle Scholar
  35. Ren YS, Qian NS, Tang Y, Liao YH, Yang YL, Dou KF, Toi M (2012) Sodium channel Nav1.6 is up-regulated in the dorsal root ganglia in a mouse model of type 2 diabetes. Brain Res Bull 87(2–3):244–249PubMedCrossRefGoogle Scholar
  36. Thornalley PJ (2005) Dicarbonyl intermediates in the Maillard reaction. Ann N Y Acad Sci 1043:111–117PubMedCrossRefGoogle Scholar
  37. Toth C, Brussee V, Cheng C, Zochodne DW (2004) Diabetes mellitus and the sensory neuron. J Neuropathol Exp Neurol 63:561–573PubMedGoogle Scholar
  38. Webber C, Zochodne D (2010) The nerve regenerative microenvironment: early behavior and partnership of axons and Schwann cells. Exp Neurol 223(1):51–59PubMedCrossRefGoogle Scholar
  39. Webber CA, Christie KJ, Cheng C, Martinez JA, Singh B, Singh V, Thomas D, Zochodne DW (2011) Schwann cells direct peripheral nerve regeneration through the Netrin-1 receptors, DCC and Unc5H2. Glia 59(10):1503–1517PubMedCrossRefGoogle Scholar
  40. WO/2010/136182 WIPO patent application, Newroth P, Bierhaus A, Fleming T (2010) Methylglyoxal-scavenging compounds and their use for the prevention and treatment of pain and/or hyperalgesiaGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Beatrice Mihaela Radu
    • 1
    • 2
  • Diana Ionela Dumitrescu
    • 2
  • Cosmin Catalin Mustaciosu
    • 3
  • Mihai Radu
    • 1
    • 3
  1. 1.Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Anatomy and HistologyUniversity of VeronaVeronaItaly
  2. 2.Department of Anatomy, Animal Physiology and Biophysics, Faculty of BiologyUniversity of BucharestBucharestRomania
  3. 3.Department of Life and Environmental PhysicsHoria Hulubei National Institute for Physics and Nuclear EngineeringBucharest-MagureleRomania

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