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Gliopreventive effects of guanosine against glucose deprivation in vitro

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Abstract

Guanosine, a guanine-based purine, is recognized as an extracellular signaling molecule that is released from astrocytes and confers neuroprotective effects in several in vivo and in vitro studies. Astrocytes regulate glucose metabolism, glutamate transport, and defense mechanism against oxidative stress. C6 astroglial cells are widely used as an astrocyte-like cell line to study the astrocytic function and signaling pathways. Our previous studies showed that guanosine modulates the glutamate uptake activity, thus avoiding glutamatergic excitotoxicity and protecting neural cells. The goal of this study was to determine the gliopreventive effects of guanosine against glucose deprivation in vitro in cultured C6 cells. Glucose deprivation induced cytotoxicity, an increase in reactive oxygen and nitrogen species (ROS/RNS) levels and lipid peroxidation as well as affected the metabolism of glutamate, which may impair important astrocytic functions. Guanosine prevented glucose deprivation-induced toxicity in C6 cells by modulating oxidative and nitrosative stress and glial responses, such as the glutamate uptake, the glutamine synthetase activity, and the glutathione levels. Glucose deprivation decreased the level of EAAC1, the main glutamate transporter present in C6 cells. Guanosine also prevented this effect, most likely through PKC, PI3K, p38 MAPK, and ERK signaling pathways. Taken together, these results show that guanosine may represent an important mechanism for protection of glial cells against glucose deprivation. Additionally, this study contributes to a more thorough understanding of the glial- and redox-related protective properties of guanosine in astroglial cells.

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References

  1. Burnstock G (2009) Purines and sensory nerves. Handb Exp Pharmacol 194:333–392. doi:10.1007/978-3-540-79090-7_10

    PubMed  CAS  Google Scholar 

  2. Ciccarelli R, Ballerini P, Sabatino G, Rathbone MP, D'Onofrio M, Caciagli F, Di Iorio P (2001) Involvement of astrocytes in purine-mediated reparative processes in the brain. Int J Dev Neurosci 19(4):395–414. doi:10.1016/S0736574800000848

    PubMed  CAS  Google Scholar 

  3. Schmidt AP, Lara DR, Souza DO (2007) Proposal of a guanine-based purinergic system in the mammalian central nervous system. Pharmacol Ther 116(3):401–416. doi:10.1016/j.pharmthera.2007.07.004

    PubMed  CAS  Google Scholar 

  4. Schmidt AP, Tort AB, Silveira PP, Bohmer AE, Hansel G, Knorr L, Schallenberger C, Dalmaz C, Elisabetsky E, Crestana RH, Lara DR, Souza DO (2009) The NMDA antagonist MK-801 induces hyperalgesia and increases CSF excitatory amino acids in rats: reversal by guanosine. Pharmacol Biochem Behav 91(4):549–553. doi:10.1016/j.pbb.2008.09.009

    PubMed  CAS  Google Scholar 

  5. Frizzo ME, Lara DR, Dahm KC, Prokopiuk AS, Swanson RA, Souza DO (2001) Activation of glutamate uptake by guanosine in primary astrocyte cultures. Neuroreport 12(4):879–881

    PubMed  CAS  Google Scholar 

  6. Ciccarelli R, Di Iorio P, Giuliani P, D'Alimonte I, Ballerini P, Caciagli F, Rathbone MP (1999) Rat cultured astrocytes release guanine-based purines in basal conditions and after hypoxia/hypoglycemia. Glia 25(1):93–98. doi:10.1002/(SICI)1098-1136(19990101)25:193::AID-GLIA9>3.0.CO;2-N

    PubMed  CAS  Google Scholar 

  7. Lara DR, Schmidt AP, Frizzo ME, Burgos JS, Ramirez G, Souza DO (2001) Effect of orally administered guanosine on seizures and death induced by glutamatergic agents. Brain Res 912(2):176–180. doi:10.1016/S0006-8993(01)02734-2

    PubMed  CAS  Google Scholar 

  8. Schmidt AP, Bohmer AE, Schallenberger C, Antunes C, Pereira MS, Leke R, Wofchuk ST, Elisabetsky E, Souza DO (2009) Spinal mechanisms of antinociceptive action caused by guanosine in mice. Eur J Pharmacol 613(1–3):46–53. doi:10.1016/j.ejphar.2009.04.018

    PubMed  CAS  Google Scholar 

  9. Vinade ER, Schmidt AP, Frizzo ME, Izquierdo I, Elisabetsky E, Souza DO (2003) Chronically administered guanosine is anticonvulsant, amnesic and anxiolytic in mice. Brain Res 977(1):97–102

    PubMed  Google Scholar 

  10. Vinade ER, Schmidt AP, Frizzo ME, Portela LV, Soares FA, Schwalm FD, Elisabetsky E, Izquierdo I, Souza DO (2005) Effects of chronic administered guanosine on behavioral parameters and brain glutamate uptake in rats. J Neurosci Res 79(1–2):248–253. doi:10.1002/jnr.20327

    PubMed  CAS  Google Scholar 

  11. Chang R, Algird A, Bau C, Rathbone MP, Jiang S (2008) Neuroprotective effects of guanosine on stroke models in vitro and in vivo. Neurosci Lett 431(2):101–105. doi:10.1016/j.neulet.2007.11.072

    PubMed  CAS  Google Scholar 

  12. Oleskovicz SP, Martins WC, Leal RB, Tasca CI (2008) Mechanism of guanosine-induced neuroprotection in rat hippocampal slices submitted to oxygen-glucose deprivation. Neurochem Int 52(3):411–418. doi:10.1016/j.neuint.2007.07.017

    PubMed  CAS  Google Scholar 

  13. Dal-Cim T, Martins WC, Santos AR, Tasca CI (2011) Guanosine is neuroprotective against oxygen/glucose deprivation in hippocampal slices via large conductance Ca(2)+-activated K+ channels, phosphatidilinositol-3 kinase/protein kinase B pathway activation and glutamate uptake. Neuroscience 183:212–220. doi:10.1016/j.neuroscience.2011.03.022

    PubMed  CAS  Google Scholar 

  14. Pettifer KM, Kleywegt S, Bau CJ, Ramsbottom JD, Vertes E, Ciccarelli R, Caciagli F, Werstiuk ES, Rathbone MP (2004) Guanosine protects SH-SY5Y cells against beta-amyloid-induced apoptosis. Neuroreport 15(5):833–836. doi:10.1097/00001756-200404090-00019

    PubMed  CAS  Google Scholar 

  15. Ganzella M, de Oliveira ED, Comassetto DD, Cechetti F, Cereser VH Jr, Moreira JD, Hansel G, Almeida RF, Ramos DB, Figueredo YN, Souza DG, Oses JP, Worm PV, Achaval M, Netto CA, Souza DO (2012) Effects of chronic guanosine treatment on hippocampal damage and cognitive impairment of rats submitted to chronic cerebral hypoperfusion. Neurol Sci 33(5):985–997. doi:10.1007/s10072-011-0872-1

    PubMed  Google Scholar 

  16. Moretto MB, Boff B, Lavinsky D, Netto CA, Rocha JB, Souza DO, Wofchuk ST (2009) Importance of schedule of administration in the therapeutic efficacy of guanosine: early intervention after injury enhances glutamate uptake in model of hypoxia-ischemia. J Mol Neurosci 38(2):216–219. doi:10.1007/s12031-008-9154-7

    PubMed  CAS  Google Scholar 

  17. Moretto MB, Arteni NS, Lavinsky D, Netto CA, Rocha JB, Souza DO, Wofchuk S (2005) Hypoxic-ischemic insult decreases glutamate uptake by hippocampal slices from neonatal rats: prevention by guanosine. Exp Neurol 195(2):400–406. doi:10.1016/j.expneurol.2005.06.005

    PubMed  CAS  Google Scholar 

  18. Rathbone MP, Saleh TM, Connell BJ, Chang R, Su C, Worley B, Kim M, Jiang S (2011) Systemic administration of guanosine promotes functional and histological improvement following an ischemic stroke in rats. Brain Res 1407:79–89. doi:10.1016/j.brainres.2011.06.027

    PubMed  CAS  Google Scholar 

  19. Schmidt AP, Lara DR, de Faria Maraschin J, da Silveira Perla A, Onofre Souza D (2000) Guanosine and GMP prevent seizures induced by quinolinic acid in mice. Brain Res 864(1):40–43. doi:10.1016/S0006-8993(00)02106-5

    PubMed  CAS  Google Scholar 

  20. Schmidt AP, Avila TT, Souza DO (2005) Intracerebroventricular guanine-based purines protect against seizures induced by quinolinic acid in mice. Neurochem Res 30(1):69–73. doi:10.1007/s11064-004-9687-2

    PubMed  CAS  Google Scholar 

  21. Roos DH, Puntel RL, Santos MM, Souza DO, Farina M, Nogueira CW, Aschner M, Burger ME, Barbosa NB, Rocha JB (2009) Guanosine and synthetic organoselenium compounds modulate methylmercury-induced oxidative stress in rat brain cortical slices: involvement of oxidative stress and glutamatergic system. Toxicol In Vitro 23(2):302–307. doi:10.1016/j.tiv.2008.12.020

    PubMed  CAS  Google Scholar 

  22. Tarozzi A, Merlicco A, Morroni F, Bolondi C, Di Iorio P, Ciccarelli R, Romano S, Giuliani P, Hrelia P (2010) Guanosine protects human neuroblastoma cells from oxidative stress and toxicity induced by Amyloid-beta peptide oligomers. J Biol Regul Homeost Agents 24(3):297–306

    PubMed  CAS  Google Scholar 

  23. Molz S, Dal-Cim T, Budni J, Martin-de-Saavedra MD, Egea J, Romero A, del Barrio L, Rodrigues AL, Lopez MG, Tasca (2011) CI Neuroprotective effect of guanosine against glutamate-induced cell death in rat hippocampal slices is mediated by the phosphatidylinositol-3 kinase/Akt/ glycogen synthase kinase 3beta pathway activation and inducible nitric oxide synthase inhibition. J Neurosci Res 89(9):1400–1408. doi:10.1002/jnr.22681

    PubMed  CAS  Google Scholar 

  24. Wang DD, Bordey A (2008) The astrocyte odyssey. Prog Neurobiol 86(4):342–367. doi:10.1016/j.pneurobio.2008.09.015

    PubMed  CAS  PubMed Central  Google Scholar 

  25. Belanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 14(6):724–738. doi:10.1016/j.cmet.2011.08.016

    PubMed  CAS  Google Scholar 

  26. Nedergaard M, Ransom B, Goldman SA (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26(10):523–530

    PubMed  CAS  Google Scholar 

  27. Maragakis NJ, Rothstein JD (2006) Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2(12):679–689. doi:10.1038/ncpneuro0355

    PubMed  CAS  Google Scholar 

  28. Anderson CM, Swanson RA (2000) Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32(1):1–14. doi:10.1002/1098-1136(200010)32:1<1::AID-GLIA10>3.0.CO;2-W

    PubMed  CAS  Google Scholar 

  29. Ransom BR, Ransom CB (2012) Astrocytes: multitalented stars of the central nervous system. Methods Mol Biol 814:3–7. doi:10.1007/978-1-61779-452-0_1

    PubMed  CAS  Google Scholar 

  30. Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF Jr, Spray DC, Reichenbach A, Pannicke T, Pekny M, Pekna M, Zorec R, Verkhratsky A (2012) Glial cells in (patho)physiology. J Neurochem 121(1):4–27. doi:10.1111/j.1471-4159.2012.07664.x

    PubMed  CAS  PubMed Central  Google Scholar 

  31. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65(1):1–105. doi:10.1016/S0301-0082(00)00067-8

    PubMed  CAS  Google Scholar 

  32. Trotti D, Danbolt NC, Volterra A (1998) Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration? Trends Pharmacol Sci 19(8):328–334. doi:10.1016/S0165-6147(98)01230-9

    PubMed  CAS  Google Scholar 

  33. Coulter DA, Eid T (2012) Astrocytic regulation of glutamate homeostasis in epilepsy. Glia 60(8):1215–1226. doi:10.1002/glia.22341

    PubMed  PubMed Central  Google Scholar 

  34. Hertz L, Zielke HR (2004) Astrocytic control of glutamatergic activity: astrocytes as stars of the show. Trends Neurosci 27(12):735–743. doi:10.1016/j.tins.2004.10.008

    PubMed  CAS  Google Scholar 

  35. Mates JM, Perez-Gomez C, NunezdeCastro I, Asenjo M, Marquez J (2002) Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death. Int J Biochem Cell Biol 34(5):439–458

    PubMed  CAS  Google Scholar 

  36. McKenna MC (2007) The glutamate-glutamine cycle is not stoichiometric: fates of glutamate in brain. J Neurosci Res 85(15):3347–3358. doi:10.1002/jnr.21444

    PubMed  CAS  Google Scholar 

  37. Hertz L (2006) Glutamate, a neurotransmitter—and so much more, a synopsis of Wierzba III. Neurochem Int 48(6–7):416–425. doi:10.1016/j.neuint.2005.12.021

    PubMed  CAS  Google Scholar 

  38. Dringen R, Pfeiffer B, Hamprecht B (1999) Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione. J Neurosci 19(2):562–569

    PubMed  CAS  Google Scholar 

  39. Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62(6):649–671

    PubMed  CAS  Google Scholar 

  40. Banerjee R, Vitvitsky V, Garg SK (2008) The undertow of sulfur metabolism on glutamatergic neurotransmission. Trends Biochem Sci 33(9):413–419. doi:10.1016/j.tibs.2008.06.006

    PubMed  CAS  Google Scholar 

  41. dos Santos AQ, Nardin P, Funchal C, de Almeida LM, Jacques-Silva MC, Wofchuk ST, Goncalves CA, Gottfried C (2006) Resveratrol increases glutamate uptake and glutamine synthetase activity in C6 glioma cells. Arch Biochem Biophys 453(2):161–167. doi:10.1016/j.abb.2006.06.025

    PubMed  Google Scholar 

  42. Bobermin LD, Quincozes-Santos A, Guerra MC, Leite MC, Souza DO, Goncalves CA, Gottfried C (2012) Resveratrol prevents ammonia toxicity in astroglial cells. PLoS One 7(12):e52164. doi:10.1371/journal.pone.0052164PONE-D-12-13584

    PubMed  CAS  PubMed Central  Google Scholar 

  43. Quincozes-Santos A, Gottfried C (2011) Resveratrol modulates astroglial functions: neuroprotective hypothesis. Ann N Y Acad Sci 1215:72–78. doi:10.1111/j.1749-6632.2010.05857.x

    PubMed  CAS  Google Scholar 

  44. Quincozes-Santos A, Nardin P, de Souza DF, Gelain DP, Moreira JC, Latini A, Goncalves CA, Gottfried C (2009) The janus face of resveratrol in astroglial cells. Neurotox Res 16(1):30–41. doi:10.1007/s12640-009-9042-0

    PubMed  CAS  Google Scholar 

  45. Benda P, Davidson RL (1971) Regulation of specific functions of glial cells in somatic hybrids. I. Control of S100 protein. J Cell Physiol 78(2):209–216. doi:10.1002/jcp.1040780207

    PubMed  CAS  Google Scholar 

  46. Benda P, Lightbody J, Sato G, Levine L, Sweet W (1968) Differentiated rat glial cell strain in tissue culture. Science 161(839):370–371. doi:10.1126/science.161.3839.370

    PubMed  CAS  Google Scholar 

  47. Funchal C, Latini A, Jacques-Silva MC, Dos Santos AQ, Buzin L, Gottfried C, Wajner M, Pessoa-Pureur R (2006) Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Neurochem Int 49(7):640–650. doi:10.1016/j.neuint.2006.05.007

    PubMed  CAS  Google Scholar 

  48. Allaman I, Belanger M, Magistretti PJ (2011) Astrocyte–neuron metabolic relationships: for better and for worse. Trends Neurosci 34(2):76–87. doi:10.1016/j.tins.2010.12.001

    PubMed  CAS  Google Scholar 

  49. Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10(11):1369–1376. doi:10.1038/nn2003

    PubMed  CAS  Google Scholar 

  50. Pellerin L, Bonvento G, Chatton JY, Pierre K, Magistretti PJ (2002) Role of neuron–glia interaction in the regulation of brain glucose utilization. Diabetes Nutr Metab 15(5):268–273

    PubMed  CAS  Google Scholar 

  51. Suh SW, Shin BS, Ma H, Van Hoecke M, Brennan AM, Yenari MA, Swanson RA (2008) Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann Neurol 64(6):654–663. doi:10.1002/ana.21511

    PubMed  CAS  Google Scholar 

  52. Pellerin L, Magistretti PJ (1994) Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A 91(22):10625–10629

    PubMed  CAS  PubMed Central  Google Scholar 

  53. Brunet JF, Allaman I, Magistretti PJ, Pellerin L (2010) Glycogen metabolism as a marker of astrocyte differentiation. J Cereb Blood Flow Metab 30(1):51–55. doi:10.1038/jcbfm.2009.207

    PubMed  CAS  PubMed Central  Google Scholar 

  54. Tabernero A, Medina JM, Giaume C (2006) Glucose metabolism and proliferation in glia: role of astrocytic gap junctions. J Neurochem 99(4):1049–1061. doi:10.1111/j.1471-4159.2006.04088.x

    PubMed  CAS  Google Scholar 

  55. Li Y, Xu N, Cai L, Gao Z, Shen L, Zhang Q, Hou W, Zhong H, Wang Q, Xiong L (2013) NDRG2 is a novel p53-associated regulator of apoptosis in C6-originated astrocytes exposed to oxygen-glucose deprivation. PLoS One 8(2):e57130. doi:10.1371/journal.pone.0057130PONE-D-12-26264

    PubMed  CAS  PubMed Central  Google Scholar 

  56. Tramontina AC, Nardin P, Quincozes-Santos A, Tortorelli L, Wartchow KM, Andreazza AC, Braganhol E, de Souza DO, Goncalves CA (2012) High-glucose and S100B stimulate glutamate uptake in C6 glioma cells. Neurochem Res 37(7):1399–1408. doi:10.1007/s11064-012-0722-4

    PubMed  CAS  Google Scholar 

  57. Nardin P, Tramontina F, Leite MC, Tramontina AC, Quincozes-Santos A, de Almeida LM, Battastini AM, Gottfried C, Goncalves CA (2007) S100B content and secretion decrease in astrocytes cultured in high-glucose medium. Neurochem Int 50(5):774–782. doi:10.1016/j.neuint.2007.01.013

    PubMed  CAS  Google Scholar 

  58. Barros JS, Goncalves CA, Bairos VA (2003) Elastic fibres in the human placenta. Arch Gynecol Obstet 267(4):208–212. doi:10.1007/s00404-002-0314-7

    PubMed  Google Scholar 

  59. Benavides A, Pastor D, Santos P, Tranque P, Calvo S (2005) CHOP plays a pivotal role in the astrocyte death induced by oxygen and glucose deprivation. Glia 52(4):261–275. doi:10.1002/glia.20242

    PubMed  Google Scholar 

  60. Hertz L (2003) Astrocytic amino acid metabolism under control conditions and during oxygen and/or glucose deprivation. Neurochem Res 28(2):243–258

    PubMed  CAS  Google Scholar 

  61. Espinoza-Rojo M, Iturralde-Rodriguez KI, Chanez-Cardenas ME, Ruiz-Tachiquin ME, Aguilera P (2010) Glucose transporters regulation on ischemic brain: possible role as therapeutic target. Cent Nerv Syst Agents Med Chem 10(4):317–325. doi:10.2174/187152410793429755

    PubMed  CAS  Google Scholar 

  62. Esterbauer H, Cheeseman KH (1990) Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods Enzymol 186:407–421. doi:10.1016/0076-6879(90)86134-H

    PubMed  CAS  Google Scholar 

  63. Hu J, Castets F, Guevara JL, Van Eldik LJ (1996) S100 beta stimulates inducible nitric oxide synthase activity and mRNA levels in rat cortical astrocytes. J Biol Chem 271(5):2543–2547. doi:10.1074/jbc.271.5.2543

    PubMed  CAS  Google Scholar 

  64. Browne RW, Armstrong D (1998) Reduced glutathione and glutathione disulfide. Methods Mol Biol 108:347–352. doi:10.1385/0-89603-472-0:347

    PubMed  CAS  Google Scholar 

  65. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275

    PubMed  CAS  Google Scholar 

  66. Davis KE, Straff DJ, Weinstein EA, Bannerman PG, Correale DM, Rothstein JD, Robinson MB (1998) Multiple signaling pathways regulate cell surface expression and activity of the excitatory amino acid carrier 1 subtype of Glu transporter in C6 glioma. J Neurosci 18(7):2475–2485

    PubMed  CAS  Google Scholar 

  67. Bianchi MG, Rotoli BM, Dall'Asta V, Gazzola GC, Gatti R, Bussolati O (2006) PKC-dependent stimulation of EAAT3 glutamate transporter does not require the integrity of actin cytoskeleton. Neurochem Int 48(5):341–349. doi:10.1016/j.neuint.2005.11.013

    PubMed  CAS  Google Scholar 

  68. Krizman-Genda E, Gonzalez MI, Zelenaia O, Robinson MB (2005) Evidence that Akt mediates platelet-derived growth factor-dependent increases in activity and surface expression of the neuronal glutamate transporter, EAAC1. Neuropharmacology 49(6):872–882. doi:10.1016/j.neuropharm.2005.07.014

    PubMed  CAS  Google Scholar 

  69. Lee G, Huang Y, Washington JM, Briggs NW, Zuo Z (2005) Carbamazepine enhances the activity of glutamate transporter type 3 via phosphatidylinositol 3-kinase. Epilepsy Res 66(1–3):145–153. doi:10.1016/j.eplepsyres.2005.08.003

    PubMed  CAS  Google Scholar 

  70. Zhou H, Chen Q, Kong DL, Guo J, Wang Q, Yu SY (2011) Effect of resveratrol on gliotransmitter levels and p38 activities in cultured astrocytes. Neurochem Res 36(1):17–26. doi:10.1007/s11064-010-0254-8

    PubMed  CAS  Google Scholar 

  71. Lee E, Sidoryk-Wegrzynowicz M, Wang N, Webb A, Son DS, Lee K, Aschner M (2012) GPR30 regulates glutamate transporter GLT-1 expression in rat primary astrocytes. J Biol Chem. doi:10.1074/jbc.M112.341867

    Google Scholar 

  72. Kronfeld I, Zsukerman A, Kazimirsky G, Brodie C (1995) Staurosporine induces astrocytic phenotypes and differential expression of specific PKC isoforms in C6 glial cells. J Neurochem 65(4):1505–1514. doi:10.1046/j.1471-4159.1995.65041505.x

    PubMed  CAS  Google Scholar 

  73. Rathbone MP, Middlemiss PJ, Gysbers JW, Andrew C, Herman MA, Reed JK, Ciccarelli R, Di Iorio P, Caciagli F (1999) Trophic effects of purines in neurons and glial cells. Prog Neurobiol 59(6):663–690. doi:10.1016/S0301-0082(99)00017-9

    PubMed  CAS  Google Scholar 

  74. Connell BJ, Di Iorio P, Sayeed I, Ballerini P, Saleh MC, Giuliani P, Saleh TM, Rathbone MP, Su C, Jiang S (2013) Guanosine protects against reperfusion injury in rat brains after ischemic stroke. J Neurosci Res 91(2):262–272. doi:10.1002/jnr.23156

    PubMed  CAS  Google Scholar 

  75. Pellerin L, Bouzier-Sore AK, Aubert A, Serres S, Merle M, Costalat R, Magistretti PJ (2007) Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 55(12):1251–1262. doi:10.1002/glia.20528

    PubMed  Google Scholar 

  76. Suh SW, Bergher JP, Anderson CM, Treadway JL, Fosgerau K, Swanson RA (2007) Astrocyte glycogen sustains neuronal activity during hypoglycemia: studies with the glycogen phosphorylase inhibitor CP-316,819 ([R-R*, S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmet hyl)propyl]-1H-indole-2-carboxamide). J Pharmacol Exp Ther 321(1):45–50. doi:10.1124/jpet.106.115550

    PubMed  CAS  Google Scholar 

  77. Obara Y, Nemoto W, Kohno S, Murata T, Kaneda N, Nakahata N (2011) Basic fibroblast growth factor promotes glial cell-derived neurotrophic factor gene expression mediated by activation of ERK5 in rat C6 glioma cells. Cell Signal 23(4):666–672. doi:10.1016/j.cellsig.2010.11.020

    PubMed  CAS  Google Scholar 

  78. Swanson RA, Choi DW (1993) Glial glycogen stores affect neuronal survival during glucose deprivation in vitro. J Cereb Blood Flow Metab 13(1):162–169. doi:10.1038/jcbfm.1993.19

    PubMed  CAS  Google Scholar 

  79. Druz A, Betenbaugh M, Shiloach J (2012) Glucose depletion activates mmu-miR-466h-5p expression through oxidative stress and inhibition of histone deacetylation. Nucleic Acids Res 40(15):7291–7302. doi:10.1093/nar/gks452

    PubMed  CAS  PubMed Central  Google Scholar 

  80. Quincozes-Santos A, Andreazza AC, Goncalves CA, Gottfried C (2010) Actions of redox-active compound resveratrol under hydrogen peroxide insult in C6 astroglial cells. Toxicol In Vitro 24(3):916–920. doi:10.1016/j.tiv.2009.11.016

    PubMed  CAS  Google Scholar 

  81. Halliwell B (2001) Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging 18(9):685–716

    PubMed  CAS  Google Scholar 

  82. Halliwell B (2006) Reactive species and antioxidants. Redox biology is a fundamental theme of aerobic life. Plant Physiol 141(2):312–322. doi:10.1104/pp. 106.077073

    PubMed  CAS  PubMed Central  Google Scholar 

  83. Halliwell B (2007) Biochemistry of oxidative stress. Biochem Soc Trans 35(Pt 5):1147–1150. doi:10.1042/BST0351147

    PubMed  CAS  Google Scholar 

  84. Ciccarelli R, Di Iorio P, D'Alimonte I, Giuliani P, Florio T, Caciagli F, Middlemiss PJ, Rathbone MP (2000) Cultured astrocyte proliferation induced by extracellular guanosine involves endogenous adenosine and is raised by the co-presence of microglia. Glia 29(3):202–211. doi:10.1002/(SICI)1098-1136(20000201)29:3<202::AID-GLIA2>3.0.CO;2-C

    PubMed  CAS  Google Scholar 

  85. Di Iorio P, Ballerini P, Traversa U, Nicoletti F, D'Alimonte I, Kleywegt S, Werstiuk ES, Rathbone MP, Caciagli F, Ciccarelli R (2004) The antiapoptotic effect of guanosine is mediated by the activation of the PI 3-kinase/AKT/PKB pathway in cultured rat astrocytes. Glia 46(4):356–368. doi:10.1002/glia.20002

    PubMed  Google Scholar 

  86. Fukui M, Choi HJ, Zhu BT (2010) Mechanism for the protective effect of resveratrol against oxidative stress-induced neuronal death. Free Radic Biol Med 49(5):800–813. doi:10.1016/j.freeradbiomed.2010.06.002

    PubMed  CAS  PubMed Central  Google Scholar 

  87. Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM (2007) Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 8(10):766–775. doi:10.1038/nrn2214

    PubMed  CAS  Google Scholar 

  88. Garnier P, Ying W, Swanson RA (2003) Ischemic preconditioning by caspase cleavage of poly(ADP-ribose) polymerase-1. J Neurosci 23(22):7967–7973

    PubMed  CAS  Google Scholar 

  89. Zhang M, Ning GM, Hong DH, Yang Y, Kutor J, Zheng XX (2003) The influence of oxygen-glucose deprivation on nitric oxide and intracellular Ca(2+) in cultured hippocampal neurons. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai) 35(6):561–566

    CAS  Google Scholar 

  90. Dal-Cim T, Molz S, Egea J, Parada E, Romero A, Budni J, Martin de Saavedra MD, del Barrio L, Tasca CI, Lopez MG (2012) Guanosine protects human neuroblastoma SH-SY5Y cells against mitochondrial oxidative stress by inducing heme oxigenase-1 via PI3K/Akt/GSK-3beta pathway. Neurochem Int 61(3):397–404. doi:10.1016/j.neuint.2012.05.021

    PubMed  CAS  Google Scholar 

  91. Bau C, Middlemiss PJ, Hindley S, Jiang S, Ciccarelli R, Caciagli F, Diiorio P, Werstiuk ES, Rathbone MP (2005) Guanosine stimulates neurite outgrowth in PC12 cells via activation of heme oxygenase and cyclic GMP. Purinergic Signal 1(2):161–172. doi:10.1007/s11302-005-6214-0

    PubMed  CAS  PubMed Central  Google Scholar 

  92. Bastianetto S, Quirion R (2010) Heme oxygenase 1: another possible target to explain the neuroprotective action of resveratrol, a multifaceted nutrient-based molecule. Exp Neurol 225(2):237–239. doi:10.1016/j.expneurol.2010.06.019

    PubMed  CAS  Google Scholar 

  93. Li MH, Jang JH, Na HK, Cha YN, Surh YJ (2007) Carbon monoxide produced by heme oxygenase-1 in response to nitrosative stress induces expression of glutamate-cysteine ligase in PC12 cells via activation of phosphatidylinositol 3-kinase and Nrf2 signaling. J Biol Chem 282(39):28577–28586. doi:10.1074/jbc.M701916200

    PubMed  CAS  Google Scholar 

  94. Sakata Y, Zhuang H, Kwansa H, Koehler RC, Dore S (2010) Resveratrol protects against experimental stroke: putative neuroprotective role of heme oxygenase 1. Exp Neurol 224(1):325–329. doi:10.1016/j.expneurol.2010.03.032

    PubMed  CAS  PubMed Central  Google Scholar 

  95. Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97(6):1634–1658. doi:10.1111/j.1471-4159.2006.03907.x

    PubMed  CAS  Google Scholar 

  96. Lee M, Cho T, Jantaratnotai N, Wang YT, McGeer E, McGeer PL (2010) Depletion of GSH in glial cells induces neurotoxicity: relevance to aging and degenerative neurological diseases. FASEB J 24(7):2533–2545. doi:10.1096/fj.09-149997

    PubMed  CAS  Google Scholar 

  97. Pope SA, Milton R, Heales SJ (2008) Astrocytes protect against copper-catalysed loss of extracellular glutathione. Neurochem Res 33(7):1410–1418. doi:10.1007/s11064-008-9602-3

    PubMed  CAS  Google Scholar 

  98. Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82(1):47–95. doi:10.1152/physrev.00018.2001

    PubMed  CAS  Google Scholar 

  99. Brongholi K, Souza DG, Bainy AC, Dafre AL, Tasca CI (2006) Oxygen-glucose deprivation decreases glutathione levels and glutamate uptake in rat hippocampal slices. Brain Res 1083(1):211–218. doi:10.1016/j.brainres.2006.02.003

    PubMed  CAS  Google Scholar 

  100. Lewerenz J, Klein M, Methner A (2006) Cooperative action of glutamate transporters and cystine/glutamate antiporter system Xc- protects from oxidative glutamate toxicity. J Neurochem 98(3):916–925. doi:10.1111/j.1471-4159.2006.03921.x

    PubMed  CAS  Google Scholar 

  101. Schulz JB, Lindenau J, Seyfried J, Dichgans J (2000) Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 267(16):4904––4911

    PubMed  Google Scholar 

  102. Camacho A, Massieu L (2006) Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death. Arch Med Res 37(1):11–18. doi:10.1016/j.arcmed.2005.05.014

    PubMed  CAS  Google Scholar 

  103. Volterra A, Trotti D, Floridi S, Racagni G (1994) Reactive oxygen species inhibit high-affinity glutamate uptake: molecular mechanism and neuropathological implications. Ann N Y Acad Sci 738:153–162. doi:10.1111/j.1749-6632.1994.tb21800.x

    PubMed  CAS  Google Scholar 

  104. Volterra A, Trotti D, Tromba C, Floridi S, Racagni G (1994) Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. J Neurosci 14(5 Pt 1):2924–2932

    PubMed  CAS  Google Scholar 

  105. Escartin C, Won SJ, Malgorn C, Auregan G, Berman AE, Chen PC, Deglon N, Johnson JA, Suh SW, Swanson RA (2011) Nuclear factor erythroid 2-related factor 2 facilitates neuronal glutathione synthesis by upregulating neuronal excitatory amino acid transporter 3 expression. J Neurosci 31(20):7392–7401. doi:10.1523/JNEUROSCI.6577-10.2011

    PubMed  CAS  PubMed Central  Google Scholar 

  106. Robinson MB (2006) Acute regulation of sodium-dependent glutamate transporters: a focus on constitutive and regulated trafficking. Handb Exp Pharmacol 175:251–275

    PubMed  CAS  Google Scholar 

  107. Bettio LE, Cunha MP, Budni J, Pazini FL, Oliveira A, Colla AR, Rodrigues AL (2012) Guanosine produces an antidepressant-like effect through the modulation of NMDA receptors, nitric oxide-cGMP and PI3K/mTOR pathways. Behav Brain Res 234(2):137–148. doi:10.1016/j.bbr.2012.06.021

    PubMed  CAS  Google Scholar 

  108. Chen XQ, Lau LT, Fung YW, Yu AC (2005) Inactivation of bad by site-specific phosphorylation: the checkpoint for ischemic astrocytes to initiate or resist apoptosis. J Neurosci Res 79(6):798–808. doi:10.1002/jnr.20396

    PubMed  CAS  Google Scholar 

  109. Ciccarelli R, D'Alimonte I, Ballerini P, D'Auro M, Nargi E, Buccella S, Di Iorio P, Bruno V, Nicoletti F, Caciagli F (2007) Molecular signalling mediating the protective effect of A1 adenosine and mGlu3 metabotropic glutamate receptor activation against apoptosis by oxygen/glucose deprivation in cultured astrocytes. Mol Pharmacol 71(5):1369–1380. doi:10.1124/mol.106.031617

    PubMed  CAS  Google Scholar 

  110. Gottfried C, Tramontina F, Goncalves D, Goncalves CA, Moriguchi E, Dias RD, Wofchuk ST, Souza DO (2002) Glutamate uptake in cultured astrocytes depends on age: a study about the effect of guanosine and the sensitivity to oxidative stress induced by H(2)O(2). Mech Ageing Dev 123(10):1333–1340

    PubMed  CAS  Google Scholar 

  111. Westergaard N, Sonnewald U, Schousboe A (1995) Metabolic trafficking between neurons and astrocytes: the glutamate/glutamine cycle revisited. Dev Neurosci 17(4):203–211

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Financiadora de Estudos e Projetos (FINEP)—IBN Net (Instituto Brasileiro de Neurociências) 01.06.0842-00, Federal University of Rio Grande do Sul (UFRGS), and Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção (INCTEN/CNPq).

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  1. Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Anexo Bairro Santa Cecília, 90035 003, Porto Alegre, Rio Grande do Sul, Brazil

    André Quincozes-Santos, Larissa Daniele Bobermin, Débora Guerini de Souza, Bruna Bellaver, Carlos-Alberto Gonçalves & Diogo Onofre Souza

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  1. André Quincozes-Santos
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  2. Larissa Daniele Bobermin
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Correspondence to André Quincozes-Santos.

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Quincozes-Santos, A., Bobermin, L.D., de Souza, D.G. et al. Gliopreventive effects of guanosine against glucose deprivation in vitro. Purinergic Signalling 9, 643–654 (2013). https://doi.org/10.1007/s11302-013-9377-0

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